Opioid receptor

Opioid receptors are a group of G protein-coupled receptors with opioids as ligands.^[1][2][3] The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opiate receptors are distributed widely in the brain, and are found in the spinal cord and digestive tract.

Discovery

By the mid-1960s, it had become apparent from pharmacologic studies that opiate drugs were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites.^[4] Early studies had indicated that opiates appeared to accumulate in the brain.^[5] The receptors were first identified as specific molecules through the use of binding studies, in which opiates that had been labeled with radioisotopes were found to bind to brain membrane homogenates. The first such study was published in 1971, using ³H-levorphanol.^[6] In 1973, Candace Pert and Solomon H. Snyder published the first detailed binding study of what would turn out to be the μ opioid receptor, using ³H-naloxone.^[7] That study has been widely credited as the first definitive finding of an opioid receptor, although two other studies followed shortly after.^[8][9]

Purification

Purification of the receptor further verified its existence. The first attempt to purify the receptor involved the use of a novel opioid receptor antagonist called chlornaltrexamine that was demonstrated to bind to the opioid receptor ^[10] Caruso et al., 1980 ^[11] purified the detergent-extracted component of rat brain membrane that eluted with the specifically bound ³H-chlornaltrexamine.

Major subtypes

There are four major subtypes of opioid receptors:^[12]

Receptor	Subtypes	Location [13][14]	Function [13][14]
delta (δ) OP1 (I)	δ1, δ2	brain pontine nuclei amygdala olfactory bulbs deep cortex peripheral sensory neurons	analgesia antidepressant effects physical dependence
kappa (κ) OP2 (I)	κ1, κ2, κ3	brain hypothalamus periaqueductal gray claustrum spinal cord substantia gelatinosa peripheral sensory neurons	analgesia sedation miosis inhibition of ADH release dysphoria
mu (μ) OP3 (I)	μ1, μ2, μ3	brain cortex (laminae III and IV) thalamus striosomes periaqueductal gray rostral ventromedial medulla spinal cord substantia gelatinosa peripheral sensory neurons intestinal tract	μ1: analgesia physical dependence μ2: respiratory depression miosis euphoria reduced GI motility physical dependence μ3: unknown
Nociceptin receptor OP4	ORL1	brain cortex amygdala hippocampus septal nuclei habenula hypothalamus spinal cord	anxiety depression appetite development of tolerance to μ agonists

(I). Name based on order of discovery

Naming

The receptors were named using the first letter of the first ligand that was found to bind to them. Morphine was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is m, but in biochemistry there is a tendency to use Greek letters, thus turning the m to μ. In similar manner, a drug known as ketocyclazocine was first shown to attach itself to κ receptors,^[15] while the δ receptor was named after the mouse vas deferens tissue in which the receptor was first characterised.^[16] An additional opioid receptor was later identified and cloned based on homology with the cDNA. This receptor is known as the nociceptin receptor or ORL 1 receptor.

The opioid receptor types are ~70% identical with differences located at N and C termini. The μ receptor is perhaps the most important. It is thought that the G protein binds to the third intracellular loop of the opioid receptors. Both in mice and humans, the genes for the various receptor subtypes are located on different chromosomes.

Separate subtypes have been identified in human tissue. Research has so far failed to identify the genetic evidence of the subtypes, and it is thought that they arise from post-translational modification of cloned receptor types.^[17]

An IUPHAR subcommittee^[18][19] has recommended that appropriate terminology for the 3 classical (μ, δ, κ) receptors, and the non-classical (nociceptin) receptor, should be MOP, DOP, KOP and NOP respectively.

Additional receptors

σ receptors were once considered to be opioid receptors due to the antitussive actions of many opioid drugs' being mediated via σ receptors, and the first selective σ agonists being derivatives of opioid drugs (e.g., allylnormetazocine). However, σ receptors were found to not be activated by endogenous opioid peptides, and are quite different from the other opioid receptors in both function and gene sequence, so they are now not usually classified with the opioid receptors.

The existence of further opioid receptors has also been suggested, due to pharmacological evidence of actions produced by endogenous opioid peptides but shown not to be mediated through any of the four known opioid receptor subtypes.^[20][21][22] The only one of these additional receptors to have been definitively identified is the zeta (ζ) opioid receptor, which has been shown to be a cellular growth factor modulator with met-enkephalin being the endogenous ligand. This receptor is now most commonly referred to as the opioid growth factor receptor (OGFr).^[23][24]

Another postulated opioid receptor is the ε opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide beta-endorphin was shown to produce additional actions that did not seem to be mediated through any of the known opioid receptors.^[25][26] Activation of this receptor produces strong analgesia and release of met-enkephalin, and a number of widely used opioid agonists such as the μ agonist etorphine and the κ agonist bremazocine have been shown to act as agonists for this effect (even in the presence of antagonists to their more well known targets),^[27] while buprenorphine has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor,^[28][29] however efforts to locate a gene for this receptor have been unsuccessful, and epsilon-mediated effects were absent in μ/δ/κ "triple knockout" mice,^[30] suggesting the epsilon receptor is likely to be either a splice variant derived from alternate post-translational modification, or a heteromer derived from hybridization of two or more of the known opioid receptors.

Pathology

Some forms of mutations in δ-opioid receptors have resulted in constant receptor activation.^[31]

See also

• List of opioids
• Opioid antagonist

References

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27. ^ Narita M, Tseng LF (March 1998). "Evidence for the existence of the beta-endorphin-sensitive "epsilon-opioid receptor" in the brain: the mechanisms of epsilon-mediated antinociception" (^{[dead link]} – ^{Scholar search}). Jpn. J. Pharmacol. 76 (3): 233–53. doi:10.1254/jjp.76.233. PMID 9593217. 
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External links

• MeSH Opioid+Receptors
• "Opioid Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1295. 
• Corbett A, McKnight S, Henderson G. "Opioid Receptors". BLTC Research. http://opioids.com/receptors/index.html. Retrieved 2008-03-21. 
• Lomize A, Lomize M, Pogozheva I. "Orientations of Proteins in Membranes (OPM) database". University of Michigan. http://opm.phar.umich.edu/. Retrieved 2008-03-21. 
  • "Mu-opioid receptor model (inactive state) with antagonist". http://opm.phar.umich.edu/protein.php?pdbid=2iql. Retrieved 2008-03-21. 
  • "Mu-opioid receptor model in active state with agonist". http://opm.phar.umich.edu/protein.php?pdbid=2iqo. Retrieved 2008-03-21.