Opioid receptor

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.



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 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
kappa (κ)
OP2 (I)
κ1, κ2, κ3
mu (μ)
OP3 (I)
μ1, μ2, μ3 μ1:



  • unknown
Nociceptin receptor
  • anxiety
  • depression
  • appetite
  • development of tolerance to μ agonists

(I). Name based on order of discovery


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.


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

See also


  1. ^ Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M (December 1996). "International Union of Pharmacology. XII. Classification of opioid receptors". Pharmacol. Rev. 48 (4): 567–92. PMID 8981566. 
  2. ^ Janecka A, Fichna J, Janecki T (2004). "Opioid receptors and their ligands". Curr Top Med Chem 4 (1): 1–17. PMID 14754373. 
  3. ^ Waldhoer M, Bartlett SE, Whistler JL (2004). "Opioid receptors". Annu. Rev. Biochem. 73: 953–90. doi:10.1146/annurev.biochem.73.011303.073940. PMID 15189164. 
  4. ^ Martin WR (December 1967). "Opioid antagonists". Pharmacol. Rev. 19 (4): 463–521. PMID 4867058. http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=4867058. 
  5. ^ Ingoglia, N.A. and Dole, V.P. (1970). "Localization of d and l-methadone after intraventricular injection into rat brains.". J. Pharmacol. Exp. Ther. 175 (1): 84–87. PMID 5471456. 
  6. ^ Goldstein A, Lowney LI, Pal BK (August 1971). "Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain". Proc. Natl. Acad. Sci. U.S.A. 68 (8): 1742–7. doi:10.1073/pnas.68.8.1742. PMC 389284. PMID 5288759. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=389284. 
  7. ^ Pert CB, Snyder SH (March 1973). "Opiate receptor: demonstration in nervous tissue". Science 179 (4077): 1011–4. doi:10.1126/science.179.4077.1011. PMID 4687585. 
  8. ^ Terenius L (1973). "Stereospecific interaction between narcotic analgesics and a synaptic plasm a membrane fraction of rat cerebral cortex". Acta Pharmacol. Toxicol. (Copenh.) 32 (3): 317–20. PMID 4801733. 
  9. ^ Simon EJ, Hiller JM, Edelman I (July 1973). "Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogenate". Proc. Natl. Acad. Sci. U.S.A. 70 (7): 1947–9. doi:10.1073/pnas.70.7.1947. PMC 433639. PMID 4516196. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=433639. 
  10. ^ Caruso TP, AE Takemori, DL Larson, PS Portoghese (April 1979). "Chloroxymorphamine, an opioid receptor site-directed alkylating agent having narcotic agonist activity". Science 204 (4390): 316–8. doi:10.1126/science.86208. PMID 86208. 
  11. ^ Caruso TP, DL Larson, PS Portoghese, AE Takemori (December 1980). "Isolation of selective 3H-chlornaltrexamine-bound complexes, possible opioid receptor components in brains of mice.". Life Sciences 27 (22): 2063–9. doi:10.1016/0024-3205(80)90485-3. PMID 6259471. http://www.ncbi.nlm.nih.gov/pubmed/6259471?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2. 
  12. ^ Corbett AD, Henderson G, McKnight AT, Paterson SJ (2006). "75 years of opioid research: the exciting but vain quest for the Holy Grail". Br. J. Pharmacol. 147 Suppl 1: S153–62. doi:10.1038/sj.bjp.0706435. PMC 1760732. PMID 16402099. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1760732. 
  13. ^ a b Stein C, Schäfer M, Machelska H (2003) Attacking pain at its source: new perspectives on opioids. Nature Med;9(8):1003-1008. doi:10.1038/nm908.
  14. ^ a b Fine, Perry G.; Russell K. Portenoy (2004). "Chapter 2: The Endogenous Opioid System". A Clinical Guide to Opioid Analgesia. McGraw Hill. http://www.stoppain.org/pcd/_pdf/OpioidChapter2.pdf. 
  15. ^ Anil Aggrawal (1995-05-01). "Opium: the king of narcotics". BLTC Research. http://opioids.com/narcotic-drugs/chapter-3.html. Retrieved 2008-03-21. 
  16. ^ Lord JA, Waterfield AA, Hughes J, Kosterlitz HW. Nature. 1977; 267:495–499.
  17. ^ Lemke, Thomas L.; Williams, David H.; Foye, William O. (2002). "Opioid Analgesics; Fries, DS". Foye's principles of medicinal chemistry. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-683-30737-1. 
  18. ^ Girdlestone, D (October 2000). "Opioid receptors; Cox BM, Chavkin C, Christie MJ, Civelli O, Evans C, Hamon MD, et al.". The IUPHAR Compendium of Receptor Characterization and Classification (2nd ed.). London: IUPHAR Media. pp. 321–333. 
  19. ^ "Opioid receptors". IUPHAR Database. International Union of Pharmacology (2008-08-01).
  20. ^ Grevel J, Yu V, Sadée W (May 1985). "Characterization of a labile naloxone binding site (lambda site) in rat brain". J. Neurochem. 44 (5): 1647–56. doi:10.1111/j.1471-4159.1985.tb08808.x. PMID 2985759. 
  21. ^ Mizoguchi H, Narita M, Nagase H, Tseng LF (October 2000). "Activation of G-proteins in the mouse pons/medulla by beta-endorphin is mediated by the stimulation of mu- and putative epsilon-receptors". Life Sci. 67 (22): 2733–43. doi:10.1016/S0024-3205(00)00852-3. PMID 11105989. 
  22. ^ Wollemann M, Benyhe S (June 2004). "Non-opioid actions of opioid peptides". Life Sci. 75 (3): 257–70. doi:10.1016/j.lfs.2003.12.005. PMID 15135648. 
  23. ^ Zagon IS, Verderame MF, Allen SS, McLaughlin PJ (February 2000). "Cloning, sequencing, chromosomal location, and function of cDNAs encoding an opioid growth factor receptor (OGFr) in humans". Brain Res. 856 (1-2): 75–83. doi:10.1016/S0006-8993(99)02330-6. PMID 10677613. 
  24. ^ Zagon IS, Verderame MF, McLaughlin PJ (February 2002). "The biology of the opioid growth factor receptor (OGFr)". Brain Res. Brain Res. Rev. 38 (3): 351–76. doi:10.1016/S0165-0173(01)00160-6. PMID 11890982. 
  25. ^ Wüster M, Schulz R, Herz A (December 1979). "Specificity of opioids towards the mu-, delta- and epsilon-opiate receptors". Neurosci. Lett. 15 (2-3): 193–8. doi:10.1016/0304-3940(79)96112-3. PMID 231238. 
  26. ^ Schulz R, Wüster M, Herz A (March 1981). "Pharmacological characterization of the epsilon-opiate receptor". J. Pharmacol. Exp. Ther. 216 (3): 604–6. PMID 6259326. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6259326. 
  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. 
  28. ^ Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H (August 2004). "Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor". Bioorg. Med. Chem. 12 (15): 4133–45. doi:10.1016/j.bmc.2004.05.024. PMID 15246090. 
  29. ^ Fujii H, Nagase H (2006). "Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014". Curr. Med. Chem. 13 (10): 1109–18. doi:10.2174/092986706776360851. PMID 16719773. 
  30. ^ Contet C, Matifas A, Kieffer BL (May 2004). "No evidence for G-protein-coupled epsilon receptor in the brain of triple opioid receptor knockout mouse". Eur. J. Pharmacol. 492 (2-3): 131–6. doi:10.1016/j.ejphar.2004.03.056. PMID 15178356. 
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