Opioids and their receptors: Are we there yet?

Abstract

Opioids have an important place in pharmacology. While their clinical use as analgesics is fundamental in medicine, their use is constrained by their side-effects and abuse potential. Pharmacologists have sought analgesics lacking side-effects and the abuse liability of the current agents. The identification of the opioid receptors in 1973 marked the beginning of our understanding of the molecular mechanisms of these agents. The isolation of the opioid peptides quickly followed, along with the classification of three families of opioid receptors. Clinicians have long been aware of subtle differences among the mu opioids that were not easily reconciled with a single receptor and selective antagonists implied two subdivisions of mu receptors. However, the cloning of the mu opioid receptor MOR-1 has led to the realization of the extensive complexity of the mu opioid receptor gene and its vast array of splice variants. Many of these splice variants are truncated and do not conform to the structure of traditional G-protein coupled receptors. Yet, evidence now shows that they are quite important and may prove valuable targets in the development of potent analgesics lacking the undesirable properties of current opioids. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: G-protein coupled receptor; MOR-1; Morphine; Mu receptor; Opioid receptor; Splice variant; Truncated.

Figure 1. Schematic of the mouse Oprm1 gene and the MOR-1 splice variants

Figure 2. ¹²⁵I-BNtxA binding in knockout mice

Mice with the indicated exon disruption were tested for ¹²⁵I-BNtxA binding. Wildtype and mice with disruptions of exons containing within MOR-1 were assayed in the presence of blockers to eliminate binding to the traditional opioid receptors (mu: CTAP 1 µM; delta: DPDPE 1 µM; kappa₁: U50,488H 1 µM). Blockers were not used in the triple knockout mice since they had no traditional opioid binding due to the knockouts. From the literature (Majumdar et al., 2011).

Figure 3. Pharmacological characterization of IBNtxA actions in vivo

a) IBNtxA analgesia was assessed in wildtype mice and triple knockout mice at the indicated dose. The ED₅₀ values for the two groups were not significantly different. b) IBNtxA (0.5 mg/kg, s.c.) was given and analgesia assessed using the radiant heat tailflick assay in wildtype and exon 11 knockout mice. No observable analgesia could be detected in the knockout animals. c) Respiratory rate was determined in groups of mice given saline or high equianalgesic doses of morphine (20 mg/kg, s.c.)or IBNtxA (2.5 mg/kg, s.c.). d) Conditioned place preference was carried out and the activity of morphine (10 mg/kg, s.c.) and IBNtxA (1 mg/kg, s.c.) compared to saline. Results are from the literature (Majumdar et al., 2011).