Opioid Receptors

In 1973, three independent teams of investigators described the presence of opioid binding sites in the nervous system from radioligand binding assays. Based on pharmacological experiments, three types of opioid receptors were postulated. They were named μ for morphine type, κ for the ketocyclazocine type, and σ for the SKF10047 (N-allylnormetazocine) type. In addition, a high-affinity receptor for enkephalins was found in the mouse vas deferens, and named as a δ-receptor. Furthermore, an epsilon-receptor was proposed as the binding

TABLE 11-1 -- Classification of opioid compounds

Naturally occurring

Morphine

Codeine

Papaverine

Thebaine

Semisynthetic

Heroin

Dihydromorphone/morphinone

Thebaine derivatives (e.g., etorphine, buprenorphine)

Synthetic

Morphinan series (e.g., levorphanol, butorphanol)

Diphenylpropylamine series (e.g., methadone)

Benzomorphan series (e.g., pentazocine)

Phenylapiperidine series (e.g., meperidine, fentanyl, sufentanil, alfentanil, remifentanil)

From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 276.

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Figure 11-1 Chemical structures of piperidine and phenylpiperidine analgesics. (From Gutstein HB, Akil H: Opioid analgesics. In Hardman JG, Limbird LE [eds]: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 569–619.)

Biochemical studies attempted to purify the opioid receptor protein but have not been successful. Since the early 1990s, molecular biological studies have elucidated the molecular structures and signal transduction mechanisms of the opioid receptors. Four different types of cDNA have been isolated as the members of the opioid receptor family.^[2] It was demonstrated that three of them correspond to the pharmacologically defined μ-, δ, and κ-opioid receptors. The fourth receptor did not bind with opioid ligands with high affinities. Later, a novel peptide called nociceptin, or orphanin FQ (see later), was identified as an endogenous agonist of the fourth member of the opioid receptor family.^{[3] [4]} The characteristics of three opioid receptors and the nociceptin/orphanin FQ receptor are listed in Table 11-4 .

The μ-receptors are located in both the brain and the spinal cord^[5] and are thought to mediate a variety of pharmacologic effects of opioids. Further pharmacologic classification of the μ-receptor as μ₁ , μ₂ , and μ₃ has been proposed. It may be possible that posttranslational modification of the μ-receptor is the molecular basis of μ-receptor subtypes. However, the molecular identity of these receptors remains to be clarified.

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Hydropathy analysis of the primary structures of the opioid receptors indicates that opioid receptors possess seven transmembrane domains ( Fig. 11-2 ). This is a characteristic structural feature of the G protein-coupled receptor. The μ-, δ-, and κ-opioid receptors and the nociceptin receptor share ∼50% amino acid sequence homology with each other.