Beginning of pregnancy controversy

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https://en.wikipedia.org/wiki/Beginning_of_pregnancy_controversy

 

The viewpoint that pregnancy, or at least morally significant human life, begins at the exact moment that sperm and egg interact is highly controversial, although it is commonly held by groups such as the Roman Catholic Church and many traditionally religious individuals, and other alternate viewpoints are put forth.

Controversy over the beginning of pregnancy occurs in different contexts, particularly as it is discussed within the debate of abortion in the United States. Because an abortion is defined as ending an established pregnancy, rather than as destroying a fertilized egg, depending on when pregnancy is considered to begin, some methods of birth control as well as some methods of infertility treatment might be classified as causing abortions.

The controversy is not primarily a scientific issue, since knowledge of human reproduction and development has become very refined; the linguistic questions remain debated for other reasons. The issue poses larger social, legal, medical, religious, philosophical, and political ramifications because some people, such as Concerned Women for America, equate the beginning of a pregnancy with the beginning of an individual human being's life. Many of these arguments are related to the anti-abortion movement. In this way of thinking, if the pregnancy has not yet begun, then stopping the process is not abortion and therefore can contain none of the moral issues associated with abortion, but if it is a pregnancy, then stopping it is a morally significant act.

A major complication is that ideological and religious concepts such as "ensoulment" (whether or not a human being is said to have gone from mere matter to having a spiritual entity inside) and "personhood" (whether or not a human being is said to be a distinct individual with innate human rights versus otherwise) exist outside of scientific analysis, and thus many individuals have argued that the beginning of pregnancy cannot be determined strictly through physical evidence alone. No experiment exists (or can exist) to measure the spirituality of an object or living thing in the same way that height, temperature, weight, etc. can be studied.

Generally speaking, some ideological and religious commentaries have argued that pregnancy should be stated as beginning at the first, exact moment of conception in which a human sperm makes full contact with an egg cell. In contrast, other commentaries have argued that the duration of pregnancy begins at some other point, such as when the fertilization process ends (when a new, independent cell genetically distinct from the prior egg and sperm exists) or when implantation occurs (when the new set of cells lodges itself against the uterine wall, allowing it to grow rapidly). The ambiguity's implications mean that, despite the scientific community being able to describe the physical processes in detail, the decision about what should be called "abortion" and what should be called "contraception" or pregnancy prevention are not agreed upon.

Definitions of pregnancy beginning

Traditionally, doctors have measured pregnancy from a number of convenient points, including the day of last menstruation, ovulation, fertilization, implantation and chemical detection. This has led to some confusion about the precise length of human pregnancy, as each measuring point yields a different figure.

Comparison of dating systems for a typical pregnancy

Event	Gestational age (from the start of the last menstrual period)	Fertilization age	Implantation age
Menstrual period begins	Day 1 of pregnancy	Not pregnant	Not pregnant
Has sex and ovulates	2 weeks pregnant	Not pregnant	Not pregnant
Fertilization; cleavage stage begins	Day 15	Day 1	Not pregnant
Implantation of blastocyst begins	Day 20	Day 6	Day 0
Implantation finished	Day 26	Day 12	Day 6 (or Day 0)
Embryo stage begins; first missed period	4 weeks	Day 15	Day 9
Primitive heart function can be detected	5 weeks, 5 days	Day 26	Day 20
Fetal stage begins	10 weeks, 1 day	8 weeks, 1 day	7 weeks, 2 days
First trimester ends	13 weeks	11 weeks	10 weeks
Second trimester ends	26 weeks	24 weeks	23 weeks
Childbirth	39–40 weeks	37–38 weeks	36–37 weeks

At its 2004 Annual Meeting, The American Medical Association passed a resolution in favor of making "Plan B" emergency contraception available over-the-counter, and one of the claims in the resolution was that hormonal contraception that may affect implantation "cannot terminate an established pregnancy." Similarly, the British Medical Association has defined an "established pregnancy" as beginning at implantation. The legal definition in the United Kingdom is not clear.

Other definitions exist. The American Heritage Stedman's Medical Dictionary defines "pregnancy" as "from conception until birth." Definitions like this may add to a lay person's confusion, as "conception" in a scientific context may be defined as fertilization, in a medical context can mean either fertilization or implantation but in lay terms may mean both.

Whether conception refers to fertilization or implantation would seemingly even impact "established pregnancies" such as an ectopic pregnancy. If conception is defined as at implantation, ectopic pregnancies could not be called pregnancies. However, some medical professionals who oppose birth control, such as Walter Larimore of the Focus on the Family group, have argued that the medical definition of conception should include fertilization.

Finally, the standard historical method of counting the duration of pregnancy begins from the last menstruation and this remains common with doctors, hospitals, and medical companies. This system is convenient because it is easy to determine when the last menstrual period was, while both fertilization and implantation occur out of sight. An interesting consequence is that the dating of pregnancy measured this way begins two weeks before ovulation.

Although many anti-abortion advocates have argued that both pregnancy and status of a separate human life beginning happen at fertilization, several examples also exist of people within those movements taking alternate views. For example, doctor and social activist Bernard Nathanson wrote in his 1979 work Aborting America that a confirmed moment of implantation should be considered the point at which a distinct human being exists. He specifically stated (note that 'alpha' is his shorthand for an organized group of cells), "Biochemically, this is when alpha announces its presence as part of the human community by means of its hormonal messages, which we now have the technology to receive... know[ing] biochemically that it is an independent organism distinct from the mother."

Legal implications

In August 2008, the U.S. Department of Health and Human Services proposed a regulation to protect certain actions of health workers: refusal to provide patient services that the health workers believe to be abortifacient. The ban on discrimination against these employees would apply to all organizations that receive grant money from HHS. A draft version leaked in July proposed that the U.S. federal government define abortion as including "termination of [human] life... before... implantation." The official proposal dropped the definition of abortion, instead leaving it to the objecting individual to define abortion for him- or herself. Groups on both sides of the controversy believe the ban is intended to allow health workers to refuse to dispense IUDs and hormonal contraceptives, including emergency contraception. It has drawn widespread criticism from major medical and health groups.

History

In the past, pregnancy has been defined in terms of conception. For example, Webster's Dictionary defined "pregnant" (or "pregnancy") as "having conceived" (or "the state of a female who has conceived"), in its 1828 and 1913 editions. However, in the absence of an accurate understanding of human development, early notions about the timing and process of conception were often vague.

Both the 1828 and 1913 editions of Webster's Dictionary said that to "conceive" meant "to receive into the womb and ... begin the formation of the embryo." However most references say that it was only in 1875 that Oskar Hertwig discovered that fertilization includes the penetration of a spermatozoon into an ovum. Thus, the term "conception" was in use long before the details of fertilization were discovered. By 1966, a more precise meaning of the word "conception" could be found in common-use dictionaries: the formation of a viable zygote.

In 1959, Dr. Bent Boving suggested that the word "conception" should be associated with the process of implantation instead of fertilization. Some thought was given to possible societal consequences, as evidenced by Boving's statement that "the social advantage of being considered to prevent conception rather than to destroy an established pregnancy could depend on something so simple as a prudent habit of speech." In 1965, the American College of Obstetricians and Gynecologists (ACOG) adopted Boving's definition: "conception is the implantation of a fertilized ovum."

The 1965 ACOG definition was imprecise because, by the time it implants, the embryo is called a blastocyst, so it was clarified in 1972 to "Conception is the implantation of the blastocyst." Some dictionaries continue to use the definition of conception as the formation of a viable zygote.

Birth control – mechanism of action

See also: Combined oral contraceptive pill § Mechanism of action

Birth control methods usually prevent fertilization. This cannot be seen as abortifacient because, by any of the above definitions, pregnancy has not started. However, some methods might have a secondary effect of preventing implantation, thus allowing the pre-embryo to die. Those who define pregnancy from fertilization subsequently may conclude that the agents should be considered abortifacients.

Speculation about post-fertilization mechanisms is widespread, even appearing on patient information inserts for hormonal contraception, but there is no clinical support. One small study, using fourteen women, might be considered as providing evidence of such an effect for IUDs and a study of the combined oral contraceptive pill has been proposed.

Possibly affected methods

• Hormonal contraception, including emergency contraception, are known to be effective at preventing ovulation. Some scientists believe hormonal methods may have a secondary effect of interfering with implantation of embryos.
• Intrauterine devices (IUDs) have been proven to have strong spermicidal and ovicidal effects; the current medical consensus is that this is the only way in which they work. Still, a few physicians have suggested they may have a secondary effect of interfering with the development of pre-implanted embryos; this secondary effect is considered more plausible when the IUD is used as emergency contraception.
• The lactational amenorrhea method works primarily by preventing ovulation, but is also known to cause luteal phase defect (LPD). LPD is believed to interfere with the implantation of embryos.
• Natural Family Planning (NFP) methods are intended to prevent fertilization through avoiding intercourse during fertile periods. Luc Bovens argues that, under an assumption that the age of gametes has an effect on embryo viability, errors in NFP method result in the occurrence of lower-viability embryos. This is intended to be an ethical thought experiment; Bovens states that his assumption "is not backed up by empirical evidence, but does have a certain plausibility." His argument is controversial. The age of gametes at the time of fertilization has been shown to have no effect on miscarriage rates in most cases, but is a significant risk factor where there is history of miscarriage. Age of gametes at the time of fertilization has been shown to have no effect on low birth weight or preterm delivery.

Viability and established pregnancy

A related issue that comes up in this debate is how often fertilization leads to an established, viable pregnancy. Research in in-vitro fertilization patients suggests that fertilized embryos fail to implant some 30% to 70% of the time, although it is unknown whether this rate corresponds to inherently low human implantation rates (in natural conception) or to an altered physiological state. Of those that do implant, about 25% suffer early pregnancy loss by the sixth week LMP (after the woman's Last Menstrual Period), and an additional 7% miscarry or are stillborn. As a result, even without the use of birth control, between 50% and 70% of zygotes never result in established pregnancies, much less birth.

Ethics of preventing implantation

The intention of a woman to prevent pregnancy is an important factor in whether or not the act of contraception is seen as abortive by some anti-abortion groups. Hormonal contraceptives have a possible effect of preventing implantation of a blastocyst, as discussed previously. Use of these drugs with the intention of preventing pregnancy is seen by some anti-abortion groups as immoral. This is because of the possibility of causing the end of a new human life.

However, hormonal contraception can also be used as a treatment for various medical conditions. When implantation prevention is unintentionally caused as a side effect of medical treatment, such anti-abortion groups do not consider the practice to be immoral, citing the bioethical principle of double effect. Likewise, when a hormonal contraceptive is used with the intention of preventing fertilisation, the intended reduction in implantation failures, miscarriages and deaths from childbearing may outweigh the possibility that the method might cause some implantation failures.

A related application of the principle of double effect is breastfeeding. Breastfeeding greatly suppresses ovulation, but eventually an ovum is released. Luteal phase defect, caused by breastfeeding, makes the uterine lining hostile to implantation and as such may prevent implantation after fertilization. Some pro-choice groups have expressed concern that the movement to recognize hormonal contraceptives as abortifacient will also cause breastfeeding to be considered an abortion method.

Detectable pregnancy

A protein called early pregnancy factor (EPF) is detectable in a woman's blood within 48 hours of ovulation if fertilization has occurred. However, testing for EPF is time-consuming and expensive; most early pregnancy tests detect human chorionic gonadotropin (hCG), a hormone that is not secreted until after implantation. Defining pregnancy as beginning at implantation thus makes pregnancy a condition that can be easily tested.

Philosophical issues

The distinction in ethical value between existing persons and potential future persons has been questioned. Subsequently, it has been argued that contraception and even the decision not to procreate at all could be regarded as immoral on a similar basis as abortion. In this sense, beginning of pregnancy may not necessarily be equated with where it is ethically right or wrong to assist or intervene. In a consequentialistic point of view, an assisting or intervening action may be regarded as basically equivalent whether it is performed before, during or after the creation of a human being, because the result would basically be the same, that is, the existence or non-existence of that human being.

Beginning of human personhood

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Beginning_of_human_personhood 

Human embryo at 8-cell stage

The beginning of human personhood is the moment when a human is first recognized as a person. There are differences of opinion as to the precise time when human personhood begins and the nature of that status. The issue arises in a number of fields including science, religion, philosophy, and law, and is most acute in debates relating to abortion, stem cell research, reproductive rights, and fetal rights.

Traditionally, the concept of personhood has entailed the concept of soul, a metaphysical concept referring to a non-corporeal or extra-corporeal dimension of human being. In modernity, the concepts of subjectivity and intersubjectivity, personhood, mind, and self have come to encompass a number of aspects of human being previously considered to be characteristics of the soul. With regard to the beginning of human personhood, one historical question has been when the soul enters the body. In modern terms, the question could be put instead at what point the developing individual develops personhood or selfhood.

Related issues attached to the question of the beginning of human personhood include both the legal status, bodily integrity, and subjectivity of mothers, as well as the philosophical concept of "natality", i.e. "the distinctively human capacity to initiate a new beginning", which a new human life embodies.

Biological markers

Fertilization

Fertilization is the fusing of the gametes, that is a sperm cell and an ovum (egg cell), to form a zygote. At this point, the zygote is genetically distinct from either of its parents.

Fertilization was not understood in ancient times. Hippocrates believed that the embryo was the product of male semen and a female factor. But Aristotle held that only male semen gave rise to an embryo, while the female only provided a place for the embryo to develop, (a concept he acquired from the preformationist Pythagoras). In 1651 William Harvey refuted Aristotle's idea that menstrual blood could be involved in the formation of a fetus, asserting that eggs from the female were somehow caused to become a fetus as a result of sexual intercourse. Sperm cells were discovered in 1677 by Antonie van Leeuwenhoek, who believed that Aristotle had been proven correct. Some observers believed they could see an entirely pre-formed little human body in the head of a sperm. The human ova was first observed in 1827 by Karl Ernst von Baer. Only in 1876 did Oscar Hertwig prove that fertilization is due to fusion of an egg and sperm cell.

Fertilization is a process lasting around 24 hours, after which more than a third of zygotes are lost in the first few days. Many fail to implant into the uterine wall, sloughing off with the endometrial lining during menstruation. Of those which implant, around 50% are miscarried, usually without the woman knowing anything has happened. A zygote that is not lost will sometimes split into two zygotes. Separately, two individually fertilized zygotes will sometimes fuse into one zygote.

A single-cell embryonic human zygote can be described as a "whole living human being" in contrast to sperm or egg cells, which are also human life but are only parts of other human beings and are not genetically unique. Even then, the twinning process occurring after fertilization "weakens the possibility of seeing individuality as something irreversibly resolved" after fertilization.

Some members of the medical community accept fertilization as the point at which life begins. Dr. Bradley M. Patten from the University of Michigan wrote in Human Embryology that the union of the sperm and the ovum "initiates the life of a new individual" beginning "a new individual life history." In the standard college text book Psychology and Life, Dr. Floyd L. Ruch wrote "At the time of conception, two living germ cells—the sperm from the father and the egg, or ovum, from the mother—unite to produce a new individual." Dr. Herbert Ratner wrote that "It is now of unquestionable certainty that a human being comes into existence precisely at the moment when the sperm combines with the egg." This certain knowledge, Ratner says, comes from the study of genetics. At fertilization, all of the genetic characteristics, such as the color of the eyes, "are laid down determinatively." James C. G. Conniff noted the prevalence of the above views in a study published by The New York Times Magazine in which he wrote, "At that moment conception takes place and, scientists generally agree, a new life begins—silent, secret, unknown."

The view that life begins at fertilization reached acceptance from mainstream sources at one point. In 1967, New York City school officials launched a large sex education program. The fifth grade textbook stated "Human life begins when the sperm cells of the father and the egg cells of the mother unite. This union is referred to as fertilization. For fertilization to take place and a baby to begin growing, the sperm cell must come in direct contact with the egg cell." Similarly, a textbook used in Evanston, Illinois stated: "Life begins when a sperm cell and an ovum (egg cell) unite."

Implantation

In his book Aborting America, Bernard Nathanson argued that implantation should be considered the point at which life begins.

Biochemically, this is when alpha announces its presence as part of the human community by means of its hormonal messages, which we now have the technology to receive. We also know biochemically that it is an independent organism distinct from the mother. [Note: in writing the book, "alpha" was Nathanson's term for any human before birth.]

In their book, When Does Human Life Begin?, John L. Merritt, MD and his son J. Lawrence Meritt II, MD, present the idea that if "the breath of life" (Genesis 2:7) is oxygen, then a blastocyst starts taking in the breath of life from the mother's blood the moment it successfully implants in her womb, which is about a week after fertilization. If the end-point to human life is the moment the body stops using oxygen, then it may follow that the corresponding starting-point is the moment the body starts using oxygen.

Segmentation

Non-conjoined monozygotic twins form up to day 14 of embryonic development, but when twinning occurs after 14 days, the twins will likely be conjoined. Some argue that an early embryo cannot be a person because "If every person is an individual, one cannot be divided from oneself."

However, Fr. Norman Ford stated that "the evidence would seem to indicate not that there is no individual at conception, but that there is at least one and possibly more." He went on to support the idea that, similar to processes found in other species, one twin could be the parent of the other asexually. Theodore Hall agreed with the plausibility of this explanation saying, "We wonder if the biological process in twinning isn't simply another example of how nature reproduces from other individuals without destroying that person's or persons' individuality."

Brain function (brain birth)

In the years since the designation of brain death as a new criterion for death, attention has been directed towards the central role of the nervous system in a number of areas of ethical decision-making. The notion that there exists a neurological end-point to human life has led to efforts at defining a corresponding neurological starting-point. This latter quest has led to the concept of brain birth (or brain life), signifying the converse of brain death. The quest for a neurological marker of the beginning of human personhood owes its impetus to the perceived symmetry between processes at the beginning and end of life, thus if brain function is a criterion used to determine the medical death of a person, it should also be the criterion for its beginning.

Just as there are two types of brain death - whole brain death (which refers to the irreversible cessation of function of both the brain stem and higher parts of the brain) and higher brain death (destruction of the cerebral hemispheres alone, with possible retention of brain stem function), there are two types of brain birth (based on their reversal) - brain stem birth at the first appearance of brain waves in lower brain (brain stem) at 6–8 weeks of gestation, and higher brain birth, at the first appearance of brain waves in higher brain (cerebral cortex) at 22–24 weeks of gestation.

Fetal viability

"Until the fetus is viable, any rights granted to it may come at the expense of the pregnant woman, simply because the fetus cannot survive except within the woman's body. Upon viability, the pregnancy can be terminated, as by a c-section or induced labor, with the fetus surviving to become a newborn infant. Several groups believe that abortion before viability is acceptable, but is unacceptable after" is the perspective of Planned Parenthood, a major abortion provider. In some countries, early abortions are legal in all circumstances, but late-term abortions are limited to circumstances where there is a clear medical need. While there is no sharp limit of development, gestational age, or weight at which a human fetus automatically becomes viable, a 2013 study found that "While only a small proportion of births occur before 24 completed weeks of gestation (about 1 per 1000), survival is rare and most of them are either fetal deaths or live births followed by a neonatal death."

Birth

Others believe that as long as the fetus is still inside the body of the woman (whether it is viable or not), it does not have any rights of its own. In Jewish law, life begins at first breath.

Other markers

There are also other ideas of when personhood is achieved:

• at ensoulment, or quickening
• at "formation" – an early concept of bodily development (see Preformationism).
• at the emergence of consciousness
• at the emergence of rationality (see Kant)

Human personhood may also be seen as a work-in-progress, with the beginning being a continuum rather than a strict point in time.

Individuation

Philosophers such as Aquinas use the concept of individuation. In regard to the abortion debate, they argue that abortion is not permissible from the point at which individual human identity is realised. Anthony Kenny argues that this can be derived from everyday beliefs and language and one can legitimately say "if my mother had an abortion six months into her pregnancy, she would have killed me" then one can reasonably infer that at six months the "me" in question would have been an existing person with a valid claim to life. Since division of the zygote into twins through the process of monozygotic twinning can occur until the fourteenth day of pregnancy, Kenny argues that individual identity is obtained at this point and thus abortion is not permissible after two weeks.

Quickening

Quickening is the moment that the pregnant woman starts to feel the fetus' movement in the uterus. The word quick originally meant alive, and quicken means to grant life. Historically some early abortion laws were based around this standard.

Although not commonly in use today, the quickening standard for personhood was historically used in England, as well as other places that based their legal systems off of the English legal system, like the U.S. states of Connecticut and New York.

Adulthood

Historically, children weren't always seen as people. Infanticide in many historical cultures was commonly practised. Even as recently as the mid 19th century, the law in the US was ambiguous as to whether children under 18 were persons.

Philosophical and religious perspectives

Answers to the question of when human life begins and when personhood begins have varied among social contexts, and have changed with shifts in ethical and religious beliefs, sometimes as a result of advances in scientific knowledge; in general they have developed in parallel with attitudes to abortion and to the use of infanticide as a means of reproductive control.

Since the zygote is genetically identical to the embryo, the fully formed fetus, and the baby, questioning the beginning of personhood could lead to an instance of the Sorites paradox, also known as the paradox of the heap.

Neil Postman has written that in pre-modern societies, the lives of children were not regarded as unique or valuable in the same way they are in modern societies, in part as a result of high infant mortality. However, when childhood began to develop its own distinctive features (including graded schools to teach reading, children's stories, games, etc.) this view changed. According to Postman, "the custom of celebrating a child's birthday did not exist in America throughout most of the eighteenth century, and, in fact, the precise marking of a child's age in any way is a relatively recent cultural habit, no more than two hundred years old."

Ancient writers held diverse views on the subject of the beginning of personhood, understood as the soul's entry or development in the human body. In Panpsychism in the West, David Skrbina noted the various kinds of soul envisioned by the early Greeks.

Generally, the question of the ensoulment of the fetus revolved around the question of when the rational soul entered the body, whether it was an integral part of the bodily form and substance, or whether it was pre-existent and subject to reincarnation or pre-existence.

Aristotle developed a theory of progressive ensoulment. In On the Generation of Animals, he declared that the soul develops first a vegetative soul, then animal, and finally human, adding that abortions were permissible early in pregnancy, before certain biological processes began. He believed that the female substance was passive, the male active, and that it required time for the male substance to "animate" the whole.

Hippocrates and the Pythagoreans stated that fertilization marked the beginning of a human life, and that the human soul was created at the time of fertilization.

According to Hinduism Today, Vedic literature states that the soul enters the body at conception.

Concepts of pre-existence are found in various forms in Platonism, Judaism, and Islam.

The Jewish Talmud holds that all life is precious but that a fetus is not a person, in the sense of termination of pregnancy being considered murder. If a woman's life is endangered by a pregnancy, an abortion is permitted. However, if the "greater part" of the fetus has emerged from the womb, then its life may not be taken even to save the woman's, "because you cannot choose between one human life and another".

Some medieval Christian theologians held that ensoulment occurs when an infant takes its first breath of air. They cite, among other passages, Genesis 2:7, which reads: "And the Lord God formed man of the dust of the ground, and breathed into his nostrils the breath of life; and man became a living soul."

The Early Church held various views on the subject, primarily either the ensoulment at conception or delayed hominization. Tertullian held a view, traducianism, which was later condemned as heresy. This view held that the soul was derived from the parents and generated in parallel with the generation of the physical body. This viewpoint was deemed unsatisfactory by St. Augustine, as it did not account for original sin. Basing himself on the Septuagint version of Exodus 21:22, he affirmed the Aristotelian view of delayed hominization.

St. Thomas Aquinas and St. Augustine of Hippo held the view that fetuses were "animated" (using Aristotle's term for ensoulment) near the 40th day after conception. However, both held that abortion was always gravely wrong, because it involves the medical termination of a human PID (person-in-development).

In general, the soul was viewed as some kind of animating principle; and the human variety was referred to as the "rational soul".

Some, but not all, followers of Jainism have promoted the idea that sperm cells contain life or jivas and thus harming them goes against the principle of non-violence (ahimsa). Celibacy or abstinence from sex (bramacharya) can be practiced as a way to avoid releasing sperm, but is unrelated to the broader practice of celibacy in Jainism.

Catholic philosopher Peter Kreeft goes so far as to say "This is widely accepted still today and has been verified by the scientific community".

That a human individual's existence begins at fertilization is the accepted position of the Roman Catholic Church, whose Pontifical Academy for Life declared: "The moment that marks the beginning of the existence of a new 'human being' is constituted by the penetration of sperm into the oocyte. Fertilization promotes a series of linked events and transforms the egg cell into a 'zygote'." The Congregation for the Doctrine of the Faith also has stated and reaffirmed: "From the time that the ovum is fertilized, a new life is begun which is neither that of the father nor of the mother; it is rather the life of a new human being with his own growth." Eastern Orthodox churches and most of the more conservative Protestant denominations also teach this view of life.

Ethical perspectives

The distinction in ethical value between existing persons and potential future persons has been questioned. Subsequently, it has been argued that contraception and even the decision not to procreate at all could be regarded as immoral on a similar basis as abortion. Subsequently, any marker of the beginning of human personhood doesn't necessarily mark where it is ethically right or wrong to assist or intervene. In a consequentialistic point of view, an assisting or intervening action may be regarded as basically equivalent whether it is performed before, during or after the creation of a human being, because the end result would basically be the same, that is, the existence or non-existence of that human being. In a view holding value in bringing potential persons into existence, it has been argued to be justified to perform abortion of an unintended pregnancy in favor for conceiving a new child later in better conditions.

Personhood in law

Ecclesiastical courts

Following the decline of the Western Roman Empire and the adoption of Christianity as the Roman state religion, ecclesiastical courts held wide jurisdiction throughout Europe. According to Donald DeMarco, PhD, the Church treated the killing of an unformed or "unanimated" fetus as a matter of "anticipated homicide", with a corresponding lesser penance required. In the Catechism of the Catholic Church, the following statement regarding the beginning of human life and personhood is provided: "Human life must be respected and protected absolutely from the moment of conception. From the first moment of his existence, a human being must be recognized as having the rights of a person - among which is the inviolable right of every innocent being to life."

Common law

Although abortion in the United Kingdom was traditionally dealt with in the ecclesiastical courts, English common law addressed the issue from 1115 on, beginning with first mention in Leges Henrici Primi. In this treatise, abortion, even of a "formed" fetus, was a "quasi-homicide", carrying a penalty of 10 years' penance. This was a much lesser penalty than would accrue to full homicide. With the exception of Bracton, later writers insisted that killing a fetus was "great misprision, and no murder", as formulated by Sir Edward Coke in his Institutes of the Lawes of England. Coke noted that the murder victim must have been "a reasonable creature in rerum natura", in accordance with the standards of murder in English law. This formulation was repeated by Sir William Blackstone in England and in Bouvier's Law Dictionary in the United States.

The reasonableness of the creature is of some considerable weight in the legal conception of personhood. Children are not considered full persons under the law until they reach the age of majority.

Nonetheless, children have been treated as persons with respect to bodily offences, beginning with Offences against the Person Act 1828, although this protection did not prevent children from being sold by their parents, as in the Eliza Armstrong case, long after the slave trade had been abolished in England.

In addition, "a child en ventre sa mere" (in utero) was regarded by common law as "in being," or "as born" when ensuring that wills and trusts do not run afoul of the rule against perpetuities; nine (or sometimes ten) months of gestation were allotted for this purpose.

Legal perspectives

Ireland

Main articles: Eighth Amendment of the Constitution of Ireland and Abortion in the Republic of Ireland

The 1983 Eighth Amendment granted the full right to life, and personhood, to any "unborn". As such, abortion was banned in nearly all cases, except to save the life of the mother. This was repealed on 25 May 2018 by a 66% voting margin, with abortion becoming legal on 1 January 2019.

United States

In its 1885 decision McArthur v. Scott, the US Supreme Court affirmed the common law principle that a child in its mother's womb can be regarded as "in being" for the purpose of resolving a dispute about wills and trusts.

In 1973, Harry Blackmun wrote the court opinion for Roe v. Wade, saying "We need not resolve the difficult question of when life begins. When those trained in the respective disciplines of medicine, philosophy, and theology are unable to arrive at any consensus, the judiciary, at this point in the development of man's knowledge, is not in a position to speculate."

In 2002, the Born-Alive Infants Protection Act was enacted, which ensures that the legal concepts of person, baby, infant, and child include those which have been born alive in the course of a miscarriage or abortion, regardless of development, gestational age, or whether the placenta and umbilical cord are still attached. This law makes no comment on personhood in utero but ensures that no person after birth is characterized as not a person.

In 2003, the Partial-Birth Abortion Ban Act was enacted, which prohibits an abortion if "either the entire baby's head is outside the body of the mother, or any part of the baby's trunk past the navel is outside the body of the mother."

In 2004, President George W. Bush signed the Unborn Victims of Violence Act into law. The law effectively extends personhood status to a "child in utero at any stage of development, who is carried in the womb" if they are targeted, injured or killed during the commission of any of over 60 listed violent crimes. The law also prohibits the prosecutions of "any person for conduct relating" to a legally consented to abortion.

Today, 38 U.S. States legally recognize a human fetus or "unborn child" as a crime victim, at least for the purpose of homicide or feticide laws. According to progressive media watchdog Media Matters for America, "Further, a prenatal personhood measure might subject a woman who suffers a pregnancy-related complication or a miscarriage to criminal investigations and possibly jail time for homicide, manslaughter or reckless endangerment. And because so many laws use the terms "persons" or "people," a prenatal personhood measure could affect large numbers of a state's laws, changing the application of thousands of laws and resulting in unforeseeable, unintended, and absurd consequences."

In the United States, the 1992 United States Supreme Court case of Planned Parenthood v. Casey held that a law cannot place legal restrictions imposing an undue burden for "the purpose or effect of placing a substantial obstacle in the path of a woman seeking an abortion of a nonviable fetus." This standard was also upheld in the Supreme Court case of Whole Woman's Health v. Hellerstedt (2016) in which several Texas restrictions were struck down, but was overturned in 2022 by Dobbs v. Jackson Women's Health Organization holding that there was no constitutional right to an abortion.

Theories of general anaesthetic action

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https://en.wikipedia.org/wiki/Theories_of_general_anaesthetic_action 

 

Structures of general anaesthetics widely used in medicine. 1 - ethanol, 2 - chloroform, 3 - diethyl ether, 4 - fluroxene, 5 - halothane, 6 - methoxyflurane, 7 - enflurane, 8 - isoflurane, 9 - desflurane, 10 - sevoflurane

A general anaesthetic (or anesthetic) is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist in order to induce or maintain general anaesthesia to facilitate surgery.

General anaesthetics have been widely used in surgery since 1842 when Crawford Long for the first time administered diethyl ether to a patient and performed a painless operation. It has long been believed that general anaesthetics exert their effects (analgesia, unconsciousness, immobility) through a membrane mediated mechanism or by directly modulating the activity of membrane proteins in the neuronal membrane. In general, different anaesthetics exhibit different mechanisms of action such that there are numerous molecular targets at all levels of integration within the central nervous system. However, for certain intravenous anaesthetics, such as propofol and etomidate, the main molecular target has been identified to be GABA_A receptor, with particular β subunits playing a crucial role.

The concept of specific interactions between receptors and drugs first introduced by Paul Ehrlich in 1897 states that drugs act only when they are bound to their targets (receptors). The identification of concrete molecular targets for general anaesthetics, however, was made possible only with the modern development of molecular biology techniques for single amino acid mutations in proteins of genetically engineered mice.

Lipid solubility-anaesthetic potency correlation (the Meyer-Overton correlation)

The Meyer-Overton correlation for anaesthetics

A nonspecific mechanism of general anaesthetic action was first proposed by Emil Harless and Ernst von Bibra in 1847. They suggested that general anaesthetics may act by dissolving in the fatty fraction of brain cells and removing fatty constituents from them, thus changing activity of brain cells and inducing anaesthesia. In 1899 Hans Horst Meyer published the first experimental evidence of the fact that anaesthetic potency is related to lipid solubility. Two years later a similar theory was published independently by Charles Ernest Overton.

Meyer compared the potency of many agents, defined as the reciprocal of the molar concentration required to induce anaesthesia in tadpoles, with their olive oil/water partition coefficient. He found a nearly linear relationship between potency and the partition coefficient for many types of anaesthetic molecules such as alcohols, aldehydes, ketones, ethers, and esters. The anaesthetic concentration required to induce anaesthesia in 50% of a population of animals (the EC₅₀) was independent of the means by which the anaesthetic was delivered, i.e., the gas or aqueous phase.

Meyer and Overton had discovered the striking correlation between the physical properties of general anaesthetic molecules and their potency: the greater the lipid solubility of a compound in olive oil, the greater its anaesthetic potency. This correlation is true for a wide range of anaesthetics with lipid solubilities ranging over 4-5 orders of magnitude if olive oil is used as the oil phase. However, this correlation can be improved considerably in terms of both the quality of the correlation and the increased range of anaesthetics if bulk octanol or a fully hydrated fluid lipid bilayer is used as the "oil" phase. It was also noted that volatile anaesthetics are additive in their effects (a mixture of a half dose of two different volatile anaesthetics gave the same anaesthetic effect as a full dose of either drug alone).

Early lipid hypotheses of general anaesthetic action

As bulky and hydrophobic anaesthetic molecules accumulate inside the neuronal cell membrane, this causes membrane distortion and expansion (thickening) due to volume displacement. Membrane thickening reversibly alters function of membrane ion channels thus providing anaesthetic effect. The actual chemical structure of the anaesthetic agent per se was not important, but its molecular volume plays the major role: the more space within membrane is occupied by anaesthetic - the greater is the anaesthetic effect.

From the correlation between lipid solubility and anaesthetic potency, both Meyer and Overton had surmised a unitary mechanism of general anaesthesia. They assumed that solubilization of lipophilic general anaesthetic in lipid bilayer of the neuron causes its malfunction and anaesthetic effect when critical concentration of anaesthetic is reached. Later in 1973 Miller and Smith suggested the critical volume hypothesis also called lipid bilayer expansion hypothesis. They assumed that bulky and hydrophobic anaesthetic molecules accumulate inside the hydrophobic (or lipophilic) regions of neuronal lipid membrane causing its distortion and expansion (thickening) due to volume displacement. Accumulation of critical amounts of anaesthetic causes membrane thickening sufficient to reversibly alter function of membrane ion channels thus providing anaesthetic effect. Actual chemical structure of the anaesthetic agent per se is not important, but its molecular volume plays the major role: the more space within membrane is occupied by anaesthetic - the greater is the anaesthetic effect. Based on this theory, in 1954 Mullins suggested that the Meyer-Overton correlation with potency can be improved if molecular volumes of anaesthetic molecules are taken into account. This theory existed for over 60 years and was supported by experimental fact that increases in atmospheric pressure reverse anaesthetic effect (pressure reversal effect).

Then other, physicochemical theories of anaesthetic action emerged that took into account the diverse chemical nature of general anaesthetics and suggested that anaesthetic effect is exerted through some perturbation of the lipid bilayer. Several types of bilayer perturbations were proposed to cause anaesthetic effect, including (1) changes in phase separation, (2) changes in bilayer thickness, (3) changes in order parameters, or (4) changes in curvature elasticity.

According to the lateral phase separation theory anaesthetics exert their action by fluidizing nerve membranes to a point when phase separations in the critical lipid regions disappear. This anaesthetic-induced fluidization makes membranes less able to facilitate the conformational changes in proteins that may be the basis for such membrane events as ion gating, synaptic transmitter release, and transmitter binding to receptors. More recent techniques with super resolution imaging show that the anesthetics do not overcome phase separation—the phase separation persists. Rather saturated lipids within the phase separation can undergo a transitions from ordered to disordered which is dramatically affected by anesthetics. Nonetheless the concept of proteins moving between phase separated lipids in response to anesthetic has now been shown to be correct.

All these early lipid theories were generally thought to suffer from four weaknesses (full description with rebuttals see in sections below):

• Stereoisomers of an anaesthetic drug have very different anaesthetic potency whereas their oil/gas partition coefficients are similar
• Certain drugs that are highly soluble in lipids, and therefore expected to act as anaesthetics, exert convulsive effect instead (and therefore were called nonimmobilizers).
• A small increase in body temperature affects membrane density and fluidity as much as general anaesthetics, yet it does not cause anaesthesia.
• Increasing the chain length in a homologous series of straight-chain alcohols or alkanes increases their lipid solubility, but their anaesthetic potency stops increasing beyond a certain cutoff length.

Therefore, the correlation between lipid solubility and potency of general anaesthetics was thought to be a necessary but insufficient condition for inferring a lipid target site. General anaesthetics could equally well be binding to hydrophobic target sites on proteins in the brain, but given the chemical diversity of anesthetics this would likely need to include more than one site and those sites would not inherently preclude a site in the membrane. For protein's, one reason that more polar general anaesthetics could be less potent is that they have to cross the blood–brain barrier to exert their effect on neurons in the brain.

Objections to the early lipid hypotheses

1. Stereoisomers of an anaesthetic drug

Stereoisomers that represent mirror images of each other are termed enantiomers or optical isomers (for example, the isomers of R-(+)- and S-(−)-etomidate). Physicochemical effects of enantiomers are always identical in an achiral environment (for example in the lipid bilayer). However, in vivo enantiomers of many general anaesthetics (e.g. isoflurane, thiopental, etomidate) can differ greatly in their anaesthetic potency despite the similar oil/gas partition coefficients. For example, the R-(+) isomer of etomidate is 10 times more potent anaesthetic than its S-(-) isomer. This means that optical isomers partition identically into lipid, but have differential effects on ion channels and synaptic transmission. This objection provides a compelling evidence that the primary target for anaesthetics is not the achiral lipid bilayer itself but rather stereoselective binding sites on membrane proteins that provide a chiral environment for specific anaesthetic-protein docking interactions.

Rebuttal to the objection: 1) Stereo selective transport of the anesthetic was never considered. Anesthetics are hydrophobic and transported bound to proteins in the blood. Any stereo selective binding to the transport protein would change the concentration at the site of action. Furthermore a protein sink in the membrane could bind one of the isomers slightly better and reduce the effective concentration the membrane experiences. All stereo isomers are effective anesthetics, they only shifted the sensitivity, suggesting selective transport and selective protein sinks need to be considered. 2) Lipids are chiral, the same as proteins. And like proteins, lipids have ordered and disordered regions. The field failed to investigate the chirality of ordered lipids due to a lack of knowledge of their existence.

2. Nonimmobilizers

All general anaesthetics induce immobilization (absence of movement in response to noxious stimuli) through depression of spinal cord functions, whereas their amnesic actions are exerted within the brain. According to the Meyer-Overton correlation the anaesthetic potency of the drug is directly proportional to its lipid solubility, however, there are many compounds that do not satisfy this rule. These drugs are strikingly similar to potent general anaesthetics and are predicted to be potent anaesthetics based on their lipid solubility, but they exert only one constituent of the anaesthetic action (amnesia) and do not suppress movement (i.e. do not depress spinal cord functions) as all anaesthetics do. These drugs are referred to as nonimmobilizers. The existence of nonimmobilizers suggests that anaesthetics induce different components of anaesthetic effect (amnesia and immobility) by affecting different molecular targets and not just the one target (neuronal bilayer) as it was believed earlier. Good example of non-immobilizers are halogenated alkanes that are very hydrophobic, but fail to suppress movement in response to noxious stimulation at appropriate concentrations. See also: flurothyl.

Rebuttal to the objection: This is a logical fallacy. The hypothesis does not require that every molecule ever tested obeys the hypothesis for the hypothesis to be true. The existence of less than 10-20 related compounds that are known to disobey the Meyer-Overton hypothesis in no way negates the hundreds if not thousands of chemically diverse compounds that do obey the Meyer-Overton hypothesis. Exceptions can exists for reasons unrelated to the mechanism underlying the Meyer-Overton hypothesis.

3. Temperature increases do not have anaesthetic effect

Experimental studies have shown that general anaesthetics including ethanol are potent fluidizers of natural and artificial membranes. However, changes in membrane density and fluidity in the presence of clinical concentrations of general anaesthetics are so small that relatively small increases in temperature (~1 °C) can mimic them without causing anaesthesia. The change in body temperature of approximately 1 °C is within the physiological range and clearly it is not sufficient to induce loss of consciousness per se. Thus membranes are fluidized only by large quantities of anaesthetics, but there are no changes in membrane fluidity when concentrations of anaesthetics are small and restricted to pharmacologically relevant.

Rebuttal to the objection: Early studies only considered the fluidity of the bulk lipid membrane. Recent work has shown that small temperature changes can cause large changes in fluidity in ordered nanoscopic lipid domains in both animals and cells.

4. Effect vanishes beyond a certain chain length

According to the Meyer-Overton correlation, in a homologous series of any general anaesthetic (e.g. n-alcohols, or alkanes), increasing the chain length increases the lipid solubility, and thereby should produce a corresponding increase in anaesthetic potency. However, beyond a certain chain length the anaesthetic effect disappears. For the n-alcohols, this cutoff occurs at a carbon chain length of about 13 and for the n-alkanes at a chain length of between 6 and 10, depending on the species.

The Meyer-Overton rule predicts the constant increase of anaesthetic potency of n-alkanols with increasing chain length. However, above certain length the potency vanishes.

If general anaesthetics disrupt ion channels by partitioning into and perturbing the lipid bilayer, then one would expect that their solubility in lipid bilayers would also display the cutoff effect. However, partitioning of alcohols into lipid bilayers does not display a cutoff for long-chain alcohols from n-decanol to n-pentadecanol. A plot of chain length vs. the logarithm of the lipid bilayer/buffer partition coefficient K is linear, with the addition of each methylene group causing a change in the Gibbs free energy of -3.63 kJ/mol.

The cutoff effect was first interpreted as evidence that anaesthetics exert their effect not by acting globally on membrane lipids but rather by binding directly to hydrophobic pockets of well-defined volumes in proteins. As the alkyl chain grows, the anaesthetic fills more of the hydrophobic pocket and binds with greater affinity. When the molecule is too large to be entirely accommodated by the hydrophobic pocket, the binding affinity no longer increases with increasing chain length. Thus the volume of the n-alkanol chain at the cutoff length provides an estimate of the binding site volume. This objection provided the basis for protein hypothesis of anaesthetic effect (see below).

A) Short hydrocarbon chains are relatively rigid in terms of conformational enthropy and are close to alkanol hydroxyl group ("buoy") tethered to the interface. This makes short chain alkanols efficient mediators that redistribute lateral stress from membrane interior to its interface. B) This ability decreases in the row of n-alkanols since longer chains are more flexible and are not so tightly tethered to the hydroxyl group. C) Polyhydroxyalkanes 1,6,11,16-hexadecanetetraol and 2,7,12,17-octadecanetetraol exhibit significant anaesthetic potency as was predicted by cutoff effect because the length of the hydrocarbon chain between hydroxyl groups is smaller than the cutoff.

However, cutoff effect can still be explained in the frame of lipid hypothesis. In short-chain alkanols (A) segments of the chain are rather rigid (in terms of conformational enthropy) and very close to hydroxyl group tethered to aqueous interfacial region ("buoy"). Consequently, these segments efficiently redistribute lateral stresses from the bilayer interior toward the interface. In long-chain alkanols (B) hydrocarbon chain segments are located further from hydroxyl group and are more flexible than in short-chain alkanols. Efficiency of pressure redistribution decreases as the length of hydrocarbon chain increases until anaesthetic potency is lost at some point. It was proposed that polyalkanols (C) will have anaesthetic effect similar to short-chain 1-alkanols if the chain length between two neighbouring hydroxyl groups is smaller than the cutoff. This idea was supported by the experimental evidence because polyhydroxyalkanes 1,6,11,16-hexadecanetetraol and 2,7,12,17-octadecanetetraol exhibited significant anaesthetic potency as was originally proposed.

Rebuttal to the objection: The argument assumes that all classes of anaesthetics must work the same on the membrane. It is quite possible that one or two classes of molecules could work through a non-membrane mediated mechanism. For example, the alcohols were shown to incorporate into the lipid membrane via an enzymatic transphosphatidylation reaction. The ethanol metabolite bound to and inhibited an anesthetic channel. And while this mechanism may contradict a single unitary mechanism of anaesthesia, it does not preclude a membrane mediated one.

Modern lipid hypothesis

General anaesthetic changes membrane lateral pressure profile which determines conformation of membrane ion channel (green lock)

There are two modern lipid hypothesis. The most recent hypothesis postulates that ordered lipids in the plasma membrane contain a structured binding site for the lipid palmitate. It is a lipid binding site within a lipid structure, not a protein structure. Proteins that contain a covalently attached palmitate (palmitoylation) are targeted to the ordered lipids through the lipid-lipid interaction. The binding of palmitate to the lipid domain is cholesterol dependent and the cell regulates the protein by nanoscopic localization. The anesthetics work by inserting into the membrane between the cholesterol and the palmitate, which disrupts the ability of the cholesterol to bind to and sequester the protein into an inactive state. This membrane mediated mechanism was demonstrated experimentally by Pavel and colleagues in 2020. They showed the enzyme phospholipase D2 (PLD2) is anesthetic sensitive and activates the potassium channel TREK-1 through a membrane mediated mechanism. The anesthetics displaced PLD2 from ordered lipid domains allowing the enzyme to be activated by substrate presentation and activate the channel.

The second lipid hypothesis states that anaesthetic effect happens if solubilization of general anaesthetic in the bilayer causes a redistribution of membrane lateral pressures.

Each bilayer membrane has a distinct profile of how lateral pressures are distributed within it. Most membrane proteins (especially ion channels) are sensitive to changes in this lateral pressure distribution profile. These lateral stresses are rather large and vary with depth within the membrane. According to the modern lipid hypothesis a change in the membrane lateral pressure profile shifts the conformational equilibrium of certain membrane proteins known to be affected by clinical concentrations of anaesthetics such as ligand-gated ion channels. This mechanism is also nonspecific because the potency of the anaesthetic is determined not by its actual chemical structure, but by the positional and orientational distribution of its segments and bonds within the bilayer.

In 1997, Cantor suggested a detailed mechanism of general anesthesia based on lattice statistical thermodynamics. It was proposed that incorporation of amphiphilic and other interfacially active solutes (e.g. general anaesthetics) into the bilayer increases the lateral pressure selectively near the aqueous interfaces, which is compensated by a decrease in lateral pressure toward the centre of the bilayer. Calculations showed that general anaesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein by the following mechanism:

• A channel tries to open in response to a nerve impulse thus increasing the cross-sectional area of the protein more near the aqueous interface than in the middle of the bilayer;
• Then the anaesthetic-induced increase in lateral pressure near the interface shifts the protein conformational equilibrium back to the closed state, since channel opening will require greater work against the higher pressure at interface. This is the first hypothesis that provided not just correlations of potency with structural or thermodynamic properties, but a detailed mechanistic and thermodynamic understanding of anaesthesia.

Thus, according to the modern lipid hypothesis anaesthetics do not act directly on their membrane protein targets, but rather perturb specialized lipid matrices at the protein-lipid interface, which act as mediators. This is a new kind of transduction mechanism, different from the usual key-lock interaction of ligand and receptor, where the anaesthetic (ligand) affects the function of membrane proteins by binding to the specific site on the protein. Thus, some membrane proteins are proposed to be sensitive to their lipid environment. A slightly different detailed molecular mechanism of how bilayer perturbation can influence the ion-channel was proposed in the same year. Oleamide (fatty acid amide of oleic acid) is an endogenous anaesthetic found in vivo (in the cat's brain) and it is known to potentiate sleep and lower the temperature of the body by closing the gap junction channel connexion. The detailed mechanism is shown on the picture: the well-ordered lipid(green)/cholesterol(yellow) ring that exists around connexon (magenta) becomes disordered on treatment with anaesthetic (red triangles), promoting a closure of connexon ion channel. This decreases brain activity and induces lethargy and anaesthetic effect. Recently super resolution imaging showed direct experimental evidence that volatile anesthetic disrupt the ordered lipid domains as predicted. In the same study, a related mechanism emerged where the anesthetics released the enzyme phospholipase D (PLD) from lipid domains and the enzyme bound to and activated TREK-1 channel by the production of phosphatidic acid. These results showed experimentally that the membrane is a physiologically relevant target of general anesthetics.

Membrane protein hypothesis of general anaesthetic action

Inhaled general anaesthetics frequently do not change structure of their target protein (of Cys-loop receptor here) but change its dynamics especially dynamics in the flexible loops that connect α-helices in a bundle thus disrupting modes of motion essential for the protein function.

In the early 1980s, Nicholas P. Franks and William R. Lieb demonstrated that the Meyer-Overton correlation can be reproduced using a soluble protein. They found that two classes of proteins are inactivated by clinical doses of anaesthetic in the total absence of lipids. These are luciferases, which are used by bioluminescent animals and bacteria to produce light, and cytochrome P450, which is a group of heme proteins that hydroxylate a diverse group of compounds, including fatty acids, steroids, and xenobiotics such as phenobarbital. Remarkably, inhibition of these proteins by general anaesthetics was directly correlated with their anaesthetic potencies. Luciferase inhibition also exhibits a long-chain alcohol cutoff, which is related to the size of the anaesthetic-binding pocket.

These observations were important because they demonstrated that general anaesthetics may also interact with hydrophobic protein sites of certain proteins, rather than affect membrane proteins indirectly through nonspecific interactions with lipid bilayer as mediator. The sites are enzymatic surfaces that non specifically block the binding of the enzymes substrate. Whether anesthetics bind in a lock and key mechanism capable of initiating the large scale conformational changes that open ion channels and transporters has not yet been definitely demonstrated.

It was shown that anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C, however, the proteins considered the most likely molecular targets of anaesthetics are ion channels. According to this theory general anaesthetics are much more selective than in the frame of lipid hypothesis and they bind directly only to small number of targets in the central nervous system mostly ligand-gated ion channels in synapses and G-protein coupled receptors altering their ion flux. Particularly Cys-loop receptors are plausible targets for general anaesthetics that bind at the interface between the subunits. The Cys-loop receptor superfamily includes inhibitory receptors (GABA_A receptors, GABA_C receptors, glycine receptors) and excitatory receptors (nicotinic acetylcholine receptor and 5-HT3 serotonin receptor). General anaesthetics can inhibit the channel functions of excitatory receptors or potentiate functions of inhibitory receptors, respectively.

A number of experimental and computational studies have shown that general anaesthetics could alter the dynamics in the flexible loops that connect α-helices in a bundle and are exposed to the membrane-water interface of Cys-loop receptors. The main binding pockets of general anaesthetics, however, are located within transmembrane four-α-helix bundles of Cys-loop receptors.

GABA_A receptor is a major target of general anesthetics

GABA_A receptor and where various ligands bind.

The GABA_A receptor (GABA_AR) is an ionotropic receptor activated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Activation of the GABA_A receptor leads to influx of chloride ions, which causes hyperpolarization of the neuronal membranes. The GABA_A receptor has been identified as the main target of intravenous anesthetics such as propofol and etomidate. The binding site of propofol on mammalian GABA_A receptors has been identified by photolabeling using a diazirine derivative. Strong activation of tonic GABA_A receptor conductance by clinical concentrations of propofol has been confirmed with electrophysiological recordings from hippocampal CA1 neurons in adult rat brain slices. GABA_A receptors that contain β3-subunits are the main molecular targets for the anesthetic actions of etomidate, whereas the β2-containing GABA_A receptors are involved in the sedation elicited by this drug. Electrophysiological experiments with amnestic concentrations of etomidate have also shown enhancement of tonic GABA_A conductance of CA1 pyramidal neurons in hippocampal slices. Potent activation of GABA_A receptor-mediated inhibition with resulting strong depression of firing rates of neocortical neurons has been also demonstrated for clinical concentrations of volatile anesthetics such as isoflurane, enflurane and halothane.

Other molecular targets

The enhancement of GABA_A receptor activity is unlikely to be the only mechanism to account for the wide range of behavioural effects of general anaesthetics. Accumulating experimental data suggests that modulation of two-pore domain potassium channels, or voltage-gated sodium channels may also account for some of the actions of volatile anaesthetic agents. Alternatively, inhibition of glutamate-gated N-methyl-D-aspartate receptors by ketamine, xenon, and nitrous oxide provides a mechanism of action in keeping with a predominant analgesic profile.