Cannabinoid

From Wikipedia, the free encyclopedia

A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors in cells that alter neurotransmitter release in the brain. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied effects.

Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.

Uses

Medical uses include the treatment of nausea due to chemotherapy, spasticity, and possibly neuropathic pain. Side effects, however, are common.

Cannabinoid receptors

Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB₁ and CB₂, with mounting evidence of more. The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.

Cannabinoid receptor type 1

CB₁ receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus  and the striatum. They are also found in the cerebellum and in both male and female reproductive systems. CB₁ receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.

Cannabinoid receptor type 2

CB₂ receptors are predominantly found in the immune system, or immune-derived cells with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB₂ is expressed by a subpopulation of microglia in the human cerebellum. CB₂ receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis seen in animal models.

Phytocannabinoids

Main classes of natural cannabinoids

Type	Skeleton	Cyclization
Cannabigerol-type CBG
Cannabichromene-type CBC
Cannabidiol-type CBD
Tetrahydrocannabinol- and Cannabinol-type THC, CBN
Cannabielsoin-type CBE
iso- Tetrahydrocannabinol- type iso-THC
Cannabicyclol-type CBL
Cannabicitran-type CBT

The bracts surrounding a cluster of Cannabis sativa flowers are coated with cannabinoid-laden trichomes

Cannabis-derived cannabinoids

Cannabis indica plant

The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 113 different cannabinoids have been isolated from the Cannabis plant To the right, the main classes of cannabinoids from Cannabis are shown. The best studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN).

Types

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized. The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).

• THC (tetrahydrocannabinol)
• THCA (tetrahydrocannabinolic acid)
• CBD (cannabidiol)
• CBDA (cannabidiolic acid)
• CBN (cannabinol)
• CBG (cannabigerol)
• CBC (cannabichromene)
• CBL (cannabicyclol)
• CBV (cannabivarin)
• THCV (tetrahydrocannabivarin)
• CBDV (cannabidivarin)
• CBCV (cannabichromevarin)
• CBGV (cannabigerovarin)
• CBGM (cannabigerol monomethyl ether)
• CBE (cannabielsoin)
• CBT (cannabicitran)

Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (Δ⁹-THC, THC) and delta-8-tetrahydrocannabinol (Δ⁸-THC), through intracellular CB₁ activation, induce anandamide and 2-arachidonoylglycerol synthesis produced naturally in the body and brain. These cannabinoids produce the effects associated with cannabis by binding to the CB₁ cannabinoid receptors in the brain.

Cannabidiol

Cannabidiol (CBD) is non-psychotropic. Recent evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis. Cannabidiol has little affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of cannabinoid agonists. It was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen. Cannabidiol has also been shown to act as a 5-HT_1A receptor agonist. CBD can interfere with the uptake of adenosine, which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.
CBD shares a precursor with THC and is the main cannabinoid in CBD-dominant Cannabis strains. CBD has been shown to play a role in preventing the short-term memory loss associated with THC.

There is tentative evidence that CBD had an anti-psychotic effect, but research in this area is limited.

There is now strong evidence that CBD treats chronic pain, and it is used by many in the form of a topical oil treatment. Sativex, a patented medicine from cannabis containing CBD is proving popular in pain treatments and was approved by Health Canada in June 2005 for prescription for central neuropathic pain in multiple sclerosis. 

Cannabinol

Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB₂ receptor is higher than for the CB₁ receptor.

Cannabigerol

Cannabigerol (CBG) is non-psychoactive but still contributes to the overall effects of Cannabis. CBG has been shown to promote apoptosis in cancer cells and inhibit tumor growth in mice. It acts as an α₂-adrenergic receptor agonist, 5-HT_1A receptor antagonist, and CB₁ receptor antagonist. It also binds to the CB₂ receptor.

Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV) is prevalent in certain central Asian and southern African strains of Cannabis. It is an antagonist of THC at CB₁ receptors and lessens the psychoactive effects of THC.

Cannabidivarin

Although cannabidivarin (CBDV) is usually a minor constituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral cannabis plants from the northwest Himalayas, and in hashish from Nepal.

Cannabichromene

Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC. CBC has shown antitumor effects in breast cancer xenoplants in mice. More common in tropical cannabis varieties.

Biosynthesis

Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is an analogous pathway that is based on CBGVA from divarinolic acid instead of olivetolic acid.

Double bond position

In addition, each of the compounds above may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ⁹-THC, while the minor form is called Δ⁸-THC. Under the alternate terpene numbering system, these same compounds are called Δ¹-THC and Δ⁶-THC, respectively.

Length

Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side chain are named using the suffix varin, and are designated, for example, THCV, CBDV, or CBNV.

Cannabinoids in other plants

Phytocannabinoids are known to occur in several plant species besides cannabis. These include Echinacea purpurea, Echinacea angustifolia, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata. The best-known cannabinoids that are not derived from Cannabis are the lipophilic alkamides (alkylamides) from Echinacea species, most notably the cis/trans isomers dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide. At least 25 different alkylamides have been identified, and some of them have shown affinities to the CB₂-receptor. In some Echinacea species, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and flowers. Yangonin found in the Kava plant has significant affinity to the CB1 receptor. Tea (Camellia sinensis) catechins have an affinity for human cannabinoid receptors. A widespread dietary terpene, beta-caryophyllene, a component from the essential oil of cannabis and other medicinal plants, has also been identified as a selective agonist of peripheral CB₂-receptors, in vivo. Black truffles contain anandamide.

Most of the phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents.

Cannabis plant profile

Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly called hemp) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content or for a specific chemical balance.

Quantitative analysis of a plant's cannabinoid profile is often determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.

Pharmacology

Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication.

Some is also stored in fat in addition to being metabolized in the liver. Δ⁹-THC is metabolized to 11-hydroxy-Δ⁹-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody-based "drug tests"; in the case of THC or others, these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous blood alcohol levels), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble, lipophilic molecules that accumulate in fatty tissues.

Separation

Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other distillation techniques. Also, techniques such as SPE or SPME are found useful in the extraction of this compounds.

History

Cannabinoids were first discovered in the 1940s when CBD and CBN were identified. The structure of THC was first determined in 1964.

Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant from the precursor CBG.

Endocannabinoids

Anandamide, an endogenous ligand of CB₁ and CB₂

Endocannabinoids are substances produced from within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the receptor.

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)

Anandamide was the first such compound identified as arachidonoyl ethanolamine. The name is derived from the Sanskrit word for bliss and -amide. It has a pharmacology similar to THC, although its structure is quite different. Anandamide binds to the central (CB₁) and, to a lesser extent, peripheral (CB₂) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB₁ receptor. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate.

Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamine, have similar pharmacology. All of these compounds are members of a family of signalling lipids called N-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and orexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds and in molluscs.

2-Arachidonoylglycerol (2-AG)

Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB₁ and CB₂ receptors with similar affinity, acting as a full agonist at both. 2-AG is present at significantly higher concentrations in the brain than anandamide, and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo. In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.

2-Arachidonyl glyceryl ether (noladin ether)

In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain. Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species. It binds to the CB₁ cannabinoid receptor (K_i = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB₁ receptor, and only weakly to the CB₂ receptor.

N-Arachidonoyl dopamine (NADA)

Discovered in 2000, NADA preferentially binds to the CB₁ receptor. Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.

Virodhamine (OAE)

A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB₂ and a partial agonist at CB₁, it behaves as a CB₁ antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.

Lysophosphatidylinositol (LPI)

Recent evidence has highlighted lysophosphatidylinositol as the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.

Function

Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters such as dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.

The endocannabinoid 2-AG has been found in bovine and human maternal milk.

A review by Matties et al (1994) summed up the phenomenon of gustatory enchancement by certain cannabinoids. Recently, a paper by Yoshida et al showed a selective stimulation of sweet receptor (Tlc1) by indirectly increasing its expression and suppressing the activity of leptin, the Tlc1 antagonist. It is proposed that the competition of leptin and cannabinoids for Tlc1 is implicated in energy homeostasis.

Retrograde signal

Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid-mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

Range

Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.

Synthetic cannabinoids

Historically, laboratory synthesis of cannabinoids was often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.

When synthetic cannabinoids are used recreationally, they present significant health dangers to users. In the period of 2012 through 2014, over 10,000 contacts to poison control centers in the United States were related to use of synthetic cannabinoids.

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

• Dronabinol (Marinol), is Δ⁹-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
• Nabilone (Cesamet, Canemes), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III
• Rimonabant (SR141716), a selective cannabinoid (CB₁) receptor inverse agonist once used as an anti-obesity drug under the proprietary name Acomplia. It was also used for smoking cessation

Other notable synthetic cannabinoids include:

• JWH-018, a potent synthetic cannabinoid agonist discovered by John W. Huffman at Clemson University. It is being increasingly sold in legal smoke blends collectively known as "spice". Several countries and states have moved to ban it legally.
• JWH-073
• CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC.
• Dimethylheptylpyran
• HU-210, about 100 times as potent as THC
• HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
• SR144528, a CB₂ receptor antagonist
• WIN 55,212-2, a potent cannabinoid receptor agonist
• JWH-133, a potent selective CB₂ receptor agonist
• Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine
• AM-2201, a potent cannabinoid receptor agonist

Peripheral neuropathy

From Wikipedia, the free encyclopedia

Peripheral neuropathy
Micrograph showing a vasculitic peripheral neuropathy; plastic embedded; Toluidine blue stain
Specialty	Neurology

Peripheral neuropathy (PN) is damage to or disease affecting nerves, which may impair sensation, movement, gland or organ function, or other aspects of health, depending on the type of nerve affected. Common causes include systemic diseases (such as diabetes or leprosy), hyperglycemia-induced glycation, vitamin deficiency, medication (e.g., chemotherapy, or commonly prescribed antibiotics including metronidazole and the fluoroquinolone class of antibiotics (Ciprofloxacin, Levaquin, Avelox etc.)), traumatic injury, including ischemia, radiation therapy, excessive alcohol consumption, immune system disease, coeliac disease, or viral infection. It can also be genetic (present from birth) or idiopathic (no known cause). In conventional medical usage, the word neuropathy (neuro-, "nervous system" and -pathy, "disease of") without modifier usually means peripheral neuropathy.

Neuropathy affecting just one nerve is called "mononeuropathy" and neuropathy involving nerves in roughly the same areas on both sides of the body is called "symmetrical polyneuropathy" or simply "polyneuropathy". When two or more (typically just a few, but sometimes many) separate nerves in disparate areas of the body are affected it is called "mononeuritis multiplex", "multifocal mononeuropathy", or "multiple mononeuropathy".

Peripheral neuropathy may be chronic (a long-term condition where symptoms begin subtly and progress slowly) or acute (sudden onset, rapid progress, and slow resolution). Acute neuropathies demand urgent diagnosis. Motor nerves (that control muscles), sensory nerves, or autonomic nerves (that control automatic functions such as heart rate, body temperature, and breathing) may be affected. More than one type of nerve may be affected at the same time. Peripheral neuropathies may be classified according to the type of nerve predominantly involved, or by the underlying cause.
Neuropathy may cause painful cramps, fasciculations (fine muscle twitching), muscle loss, bone degeneration, and changes in the skin, hair, and nails. Additionally, motor neuropathy may cause impaired balance and coordination or, most commonly, muscle weakness; sensory neuropathy may cause numbness to touch and vibration, reduced position sense causing poorer coordination and balance, reduced sensitivity to temperature change and pain, spontaneous tingling or burning pain, or skin allodynia (severe pain from normally nonpainful stimuli, such as light touch); and autonomic neuropathy may produce diverse symptoms, depending on the affected glands and organs, but common symptoms are poor bladder control, abnormal blood pressure or heart rate, and reduced ability to sweat normally.

Classification

Peripheral neuropathy may be classified according to the number and distribution of nerves affected (mononeuropathy, mononeuritis multiplex, or polyneuropathy), the type of nerve fiber predominantly affected (motor, sensory, autonomic), or the process affecting the nerves; e.g., inflammation (neuritis), compression (compression neuropathy), chemotherapy (chemotherapy-induced peripheral neuropathy).

Mononeuropathy

Mononeuropathy is a type of neuropathy that only affects a single nerve. Diagnostically, it is important to distinguish it from polyneuropathy because when a single nerve is affected, it is more likely to be due to localized trauma or infection.

The most common cause of mononeuropathy is physical compression of the nerve, known as compression neuropathy. Carpal tunnel syndrome and axillary nerve palsy are examples. Direct injury to a nerve, interruption of its blood supply resulting in (ischemia), or inflammation also may cause mononeuropathy.

Polyneuropathy

"Polyneuropathy" is a pattern of nerve damage that is quite different from mononeuropathy, often more serious and affecting more areas of the body. The term "peripheral neuropathy" sometimes is used loosely to refer to polyneuropathy. In cases of polyneuropathy, many nerve cells in various parts of the body are affected, without regard to the nerve through which they pass; not all nerve cells are affected in any particular case. In distal axonopathy, one common pattern is that the cell bodies of neurons remain intact, but the axons are affected in proportion to their length; the longest axons are the most affected. Diabetic neuropathy is the most common cause of this pattern. In demyelinating polyneuropathies, the myelin sheath around axons is damaged, which affects the ability of the axons to conduct electrical impulses. The third and least common pattern affects the cell bodies of neurons directly. This usually picks out either the motor neurons (known as motor neuron disease) or the sensory neurons (known as sensory neuronopathy or dorsal root ganglionopathy).

The effect of this is to cause symptoms in more than one part of the body, often symmetrically on left and right sides. As for any neuropathy, the chief symptoms include motor symptoms such as weakness or clumsiness of movement; and sensory symptoms such as unusual or unpleasant sensations such as tingling or burning; reduced ability to feel sensations such as texture or temperature, and impaired balance when standing or walking. In many polyneuropathies, these symptoms occur first and most severely in the feet. Autonomic symptoms also may occur, such as dizziness on standing up, erectile dysfunction, and difficulty controlling urination.

Polyneuropathies usually are caused by processes that affect the body as a whole. Diabetes and impaired glucose tolerance are the most common causes. Hyperglycemia-induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy.^[9] Other causes relate to the particular type of polyneuropathy, and there are many different causes of each type, including inflammatory diseases such as Lyme disease, vitamin deficiencies, blood disorders, and toxins (including alcohol and certain prescribed drugs).

Most types of polyneuropathy progress fairly slowly, over months or years, but rapidly progressive polyneuropathy also occurs. It is important to recognize that at one time it was thought that many of the cases of small fiber peripheral neuropathy with typical symptoms of tingling, pain, and loss of sensation in the feet and hands were due to glucose intolerance before a diagnosis of diabetes or pre-diabetes. However, in August 2015, the Mayo Clinic published a scientific study in the Journal of the Neurological Sciences showing "no significant increase in...symptoms...in the prediabetes group", and stated that "A search for alternate neuropathy causes is needed in patients with prediabetes."

The treatment of polyneuropathies is aimed firstly at eliminating or controlling the cause, secondly at maintaining muscle strength and physical function, and thirdly at controlling symptoms such as neuropathic pain.

Mononeuritis multiplex

Mononeuritis multiplex, occasionally termed polyneuritis multiplex, is simultaneous or sequential involvement of individual noncontiguous nerve trunks, either partially or completely, evolving over days to years and typically presenting with acute or subacute loss of sensory and motor function of individual nerves. The pattern of involvement is asymmetric, however, as the disease progresses, deficit(s) becomes more confluent and symmetrical, making it difficult to differentiate from polyneuropathy. Therefore, attention to the pattern of early symptoms is important.

Mononeuritis multiplex also may cause pain, which is characterized as deep, aching pain that is worse at night and frequently in the lower back, hip, or leg. In people with diabetes mellitus, mononeuritis multiplex typically is encountered as acute, unilateral, and severe thigh pain followed by anterior muscle weakness and loss of knee reflex.

Electrodiagnostic medicine studies will show multifocal sensory motor axonal neuropathy.
It is caused by, or associated with, several medical conditions:

• diabetes mellitus
• vasculitides: polyarteritis nodosa, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis
• immune-mediated diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE)
• infections: leprosy, lyme disease, Parvovirus B19, HIV
• sarcoidosis
• cryoglobulinemia
• reactions to exposure to chemical agents, including trichloroethylene and dapsone
• rarely, following the sting of certain jellyfish, such as the sea nettle

Autonomic neuropathy

Autonomic neuropathy is a form of polyneuropathy that affects the non-voluntary, non-sensory nervous system (i.e., the autonomic nervous system), affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Autonomic nerve fibers form large collections in the thorax, abdomen, and pelvis outside the spinal cord. They have connections with the spinal cord and ultimately the brain, however. Most commonly autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and 2. In most—but not all—cases, autonomic neuropathy occurs alongside other forms of neuropathy, such as sensory neuropathy.
Autonomic neuropathy is one cause of malfunction of the autonomic nervous system, but not the only one; some conditions affecting the brain or spinal cord also may cause autonomic dysfunction, such as multiple system atrophy, and therefore, may cause similar symptoms to autonomic neuropathy.
The signs and symptoms of autonomic neuropathy include the following:

• Urinary bladder conditions: bladder incontinence or urine retention
• Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, malabsorption, fecal incontinence, gastroparesis, diarrhoea, constipation
• Cardiovascular system: disturbances of heart rate (tachycardia, bradycardia), orthostatic hypotension, inadequate increase of heart rate on exertion
• Respiratory system: impairments in the signals associated with regulation of breathing and gas exchange (central sleep apnea, hypopnea, bradypnea).
• Other areas: hypoglycemia unawareness, genital impotence, sweat disturbances

Neuritis

Neuritis is a general term for inflammation of a nerve or the general inflammation of the peripheral nervous system. Symptoms depend on the nerves involved, but may include pain, paresthesia (pins-and-needles), paresis (weakness), hypoesthesia (numbness), anesthesia, paralysis, wasting, and disappearance of the reflexes.
Causes of neuritis include:

• Physical injury
• Infection
  • Diphtheria
  • Herpes zoster (shingles)
  • Leprosy
  • Lyme disease
• Chemical injury such as chemotherapy
• Radiation therapy

Types of neuritis include:

• Brachial neuritis
• Cranial neuritis such as Bell's palsy
• Optic neuritis
• Vestibular neuritis
• Wartenberg's migratory sensory neuropathy
• Underlying conditions including: :
  • Alcoholism
  • Autoimmune disease, especially multiple sclerosis and Guillain–Barré syndrome
  • Beriberi (vitamin B1 deficiency)
  • Cancer
  • Celiac disease
  • Diabetes mellitus (Diabetic neuropathy)
  • Hypothyroidism
  • Porphyria
  • Vitamin B12 deficiency
  • Vitamin B6 excess

Signs and symptoms

Those with diseases or dysfunctions of their nerves may present with problems in any of the normal nerve functions. Symptoms vary depending on the types of nerve fiber involved.^{[citation needed]} In terms of sensory function, symptoms commonly include loss of function ("negative") symptoms, including numbness, tremor, impairment of balance, and gait abnormality. Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins-and-needles. Motor symptoms include loss of function ("negative") symptoms of weakness, tiredness, muscle atrophy, and gait abnormalities; and gain of function ("positive") symptoms of cramps, and muscle twitch (fasciculations).

In the most common form, length-dependent peripheral neuropathy, pain and parasthesia appears symmetrically and generally at the terminals of the longest nerves, which are in the lower legs and feet. Sensory symptoms generally develop before motor symptoms such as weakness. Length-dependent peripheral neuropathy symptoms make a slow ascent of leg, while symptoms may never appear in the upper limbs; if they do, it will be around the time that leg symptoms reach the knee. When the nerves of the autonomic nervous system are affected, symptoms may include constipation, dry mouth, difficulty urinating, and dizziness when standing.

Causes

The causes are grouped broadly as follows:

• Genetic diseases: Friedreich's ataxia, Fabry disease, Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsy
• hyperglycemia-induced formation of advanced glycation end products (AGEs)
• Metabolic and endocrine diseases: diabetes mellitus, chronic kidney failure, porphyria, amyloidosis, liver failure, hypothyroidism
• Toxic causes: drugs (vincristine, metronidazole, phenytoin, nitrofurantoin, isoniazid, ethyl alcohol, statins), organic herbicides TCDD dioxin, organic metals, heavy metals, excess intake of vitamin B₆ (pyridoxine). Peripheral neuropathies also may result from long term (more than 21 days) treatment with Linezolid (Zyvox).
• Adverse effects of fluoroquinolones: irreversible neuropathy is a serious adverse reaction of fluoroquinolone drugs
• Inflammatory diseases: Guillain–Barré syndrome, systemic lupus erythematosus, leprosy, multiple sclerosis, Sjögren's syndrome, Babesiosis, Lyme disease, vasculitis, sarcoidosis,
• Vitamin deficiency states: Vitamin B₁₂ (Methylcobalamin), vitamin A, vitamin E, vitamin B₁ (thiamin)
• Physical trauma: compression, pinching, cutting, projectile injuries (for example, gunshot wound), strokes including prolonged occlusion of blood flow, electric discharge, including lightning strikes
• Effect of chemotherapy – see Chemotherapy-induced peripheral neuropathy
• Exposure to Agent Orange
• Others: electric shock, HIV, malignant disease, radiation, shingles, MGUS (Monoclonal gammopathy of undetermined significance).

Diagnosis

Peripheral neuropathy may first be considered when an individual reports symptoms of numbness, tingling, and pain in feet. After ruling out a lesion in the central nervous system as a cause, diagnosis may be made on the basis of symptoms, laboratory and additional testing, clinical history, and a detailed examination.

During physical examination, specifically a neurological examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, although those with a pathology (problem) of the nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies, such as Guillain–Barré syndrome; or may show focal sensory disturbance or weakness, such as in mononeuropathies. Classically, ankle jerk reflex is absent in peripheral neuropathy.

A physical examination will involve testing the deep ankle reflex as well as examining the feet for any ulceration. For large fiber neuropathy, an exam will usually show an abnormally decreased sensation to vibration, which is tested with a 128-Hz tuning fork, and decreased sensation of light touch when touched by a nylon monofilament.

Diagnostic tests include electromyography (EMG) and nerve conduction studies (NCSs), which assess large myelinated nerve fibers. Testing for small-fiber peripheral neuropathies often relates to the autonomic nervous system function of small thinly- and unmyelinated fibers. These tests include a sweat test and a tilt table test. Diagnosis of small fiber involvement in peripheral neuropathy may also involve a skin biopsy in which a 3 mm-thick section of skin is removed from the calf by a punch biopsy, and is used to measure the skin intraepidermal nerve fiber density (IENFD), the density of nerves in the outer layer of the skin. Reduced density of the small nerves in the epidermis supports a diagnosis of small-fiber peripheral neuropathy.

Laboratory tests include blood tests for vitamin B-12 levels, a complete blood count, measurement of thyroid stimulating hormone levels, a comprehensive metabolic panel screening for diabetes and pre-diabetes, and a serum immunofixation test, which tests for antibodies in the blood.

Treatment

The treatment of peripheral neuropathy varies based on the cause of the condition, and treating the underlying condition can aid in the management of neuropathy. When peripheral neuropathy results from diabetes mellitus or prediabetes, blood sugar management is key to treatment. In prediabetes in particular, strict blood sugar control can significantly alter the course of neuropathy. In peripheral neuropathy that stems from immune-mediated diseases, the underlying condition is treated with intravenous immunoglobulin or steroids. When peripheral neuropathy results from vitamin deficiencies or other disorders, those are treated as well.

Medications

A range of medications that act on the central nervous system has been found to be useful in managing neuropathic pain. Commonly used treatments include tricyclic antidepressants (such as nortriptyline or amitriptyline), the serotonin-norepinephrine reuptake inhibitor (SNRI) medication duloxetine, and antiepileptic therapies such as gabapentin, pregabalin, or sodium valproate. Few studies have examined whether nonsteroidal anti-inflammatory drugs are effective in treating peripheral neuropathy.

Symptomatic relief for the pain of peripheral neuropathy may be obtained by application of topical capsaicin. Capsaicin is the factor that causes heat in chili peppers. The evidence suggesting that capsaicin applied to the skin reduces pain for peripheral neuropathy is of moderate to low quality and should be interpreted carefully before using this treatment option. Local anesthesia often is used to counteract the initial discomfort of the capsaicin. Some current research in animal models has shown that depleting neurotrophin-3 may oppose the demyelination present in some peripheral neuropathies by increasing myelin formation.

Evidence supports the use of cannabinoids for some forms of neuropathic pain.

Medical devices

Transcutaneous electrical nerve stimulation therapy may be effective and safe in the treatment of diabetic peripheral neuropathy. A recent review of three trials involving 78 patients found some improvement in pain scores after 4 and 6, but not 12 weeks of treatment and an overall improvement in neuropathic symptoms at 12 weeks. Another review of four trials found significant improvement in pain and overall symptoms, with 38% of patients in one trial becoming asymptomatic. The treatment remains effective even after prolonged use, but symptoms return to baseline within a month of cessation of treatment.

Research

A 2008 literature review concluded that, "based on principles of evidence-based medicine and evaluations of methodology, there is only a 'possible' association [of celiac disease and peripheral neuropathy], due to lower levels of evidence and conflicting evidence. There is not yet convincing evidence of causality."