Opioid Receptors

Opioid receptors are distributed widely in brain and found in spinal cord and peripheral sensory and autonomic nerves. There are three well-characterized members of the opioid receptor family, designated by the Greek symbols δ, k and μ. The ORL₁ receptor is placed with this family due to its high degree of structural homology. These receptors were renamed OP₁, OP_2, OP₃ and OP₄, respectively, by an International Union of Pharmacology (IUPHAR) nomenclature committee in 1996 but this nomenclature proved unpopular. The nomenclature (X-Opioid Peptide receptor) was proposed giving μ, mu or MOP; δ, delta or DOP; k, kappa or KOP and ORL₁ or NOP receptors. To keep matters straightforward the original nomenclature is used in the following discussion.

Opioid receptors are activated physiologically by the products of endogenous opioid peptide genes; proenkephalin (giving methionine- and leucine-enkephalin; Met-enk; Leu-enk, respectively), prodynorphin (dynorphins A and B and α-neo-endorphin) pro-opiomelanocortin (β-endorphin) and pronociceptin (nociceptin, also known as Orphanin FQ). Met-enk and Leu-enk have highest affinity for δ receptors, less affinity for μ, and very low affinity for k receptors; the dynorphins have preferential affinity for k receptors, but bind to the μ and δ types with high affinity; β-endorphin binds with high affinity to μ and δ receptors, but has little affinity for k receptors. All the peptides are full agonists at their cognate receptors. Endomorphin-1 and -2, derived from an unknown precursor, are endogenous peptides with high selectivity for μ receptors. These peptides are unusual in that they are partial agonists. None of the proenkephalin, prodynorphin or pro-opiomelanocortin peptide products or the endomorphins displays affinity for the ORL₁ receptor. Similarly, the ORL₁ receptor agonist nociceptin has no appreciable affinity for μ, δ or k receptors.

The four receptor types have been cloned and shown to be 7-transmembrane receptors activating G proteins of the pertussis-toxin insensitive Gα_i/o family, but including Gαz.  Evidence for subtypes of μ, δ and k opioid receptors exists, but the molecular basis for the observed functional and pharmacological differences is unclear. Putative δ₁ and δ₂ receptors are differentiated by several agonist and antagonist ligands. However, there is only one δ receptor gene, the protein product of which has properties of the putative δ₂ receptor. The distinction between the proposed μ₁ and μ₂ receptors is based largely on the apparent preferential blockade of the μ₁ type by the antagonist, naloxonazine. There is only one cloned μ receptor gene, corresponding to the putative μ₁ receptor, but several forms of the μ-receptor mRNA arising from alternative splicing have been reported. The receptors these encode differ at the end of the C-terminal tail and show subtle differences in the binding profile of opioid ligands; a role for the variants is not known. The cloned k receptor, with high affinity for U69593 is the k₁ subtype. The proposed k₂ and k₃ subtypes are poorly defined in both molecular and pharmacological terms. An explanation for subtypes has evolved with the identification of opioid receptor heterodimers or hetero-oligomers that appear to have properties different from the monomeric receptors. An interesting addition to ligands that bind to the k₁ receptor is the hallucinogen salvinorin-A. This is a highly efficacious and potent k agonist, but is most unusual in that it has no nitrogen atom.

Endogenous opioid systems have a functional role in modulating pain perception; opioid agonists are therefore potent analgesics. Opioid receptors are also present in hypothalamus, where they influence temperature regulation and control of hormonal secretion. In the forebrain, endogenous opioids are involved in behavioral reinforcement and appear to play a role in anxiety and in the expression of emotions. Opioids influence gastrointestinal and autonomic nervous system function.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Materials" section below.

Footnotes

a) Putative δ1 ligands.

b) Putative δ2 ligands.

c) Not selective but used to define “non-κ1” sites.

d) These ligands bind irreversibly or pseudoirreversibly.

e) Inverse agonist.

f) Has agonist properties in some systems.

Abbreviations

nor-BNI: nor-Binaltorphimine
BNTX: (E)-7-Benzylidenenaltrexone
BW373U86: (±)-(1[S*]2α,5β)-4-([2,5-Dimethyl-4-(2-propenyl)-1-piperazinyl][3-hydroxyphenyl]methyl)-N,N-diethylbenzamide
β-CNA: β-Chlornaltrexamine
CTAP: D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂
CTOP: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH₂
DALCE: [D-Ala²,Leu⁵,Cys⁶]-Enkephalin
DAMGO: [D-Ala²,N-Me-Phe⁴,Gly-ol⁵]-Enkephalin
DPDPE: [D-Pen^2,5]-Enkephalin
DSLET: [D-Ser²,Leu⁵,Thr⁶]-Enkephalin
β-FNA: β-Funaltrexamine
GNTI: 5’-Guanidinylnaltrindole
ICI 174864: N.N-diallyl-Tyr-Aib-Aib-Phe-Leu
J-113397: 1-[(3R,4R)-1-cycloocylomethyl-3-hydroxymethyl-4-piperdinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
MCAM: Methocinnomox
5’-NTII: Naltrindole 5'-isothiocyanate
Ro 64-6198: (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4 one.
SNC80: (+)-4-[(αR)-α-((2S5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide
(–)-TAN-67: (–)-2-Methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino[2,3,3-q]isoquinoline
TIPP(ψ): H-Tyr-Ticψ-[CH2NH]Phe-Phe-OH.
U-69593: (+)-(5α,7α,8β)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl)benzeneacetamide
U-50488: 3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide