Molecular insights into mu opioid pharmacology: From the clinic to the bench

Abstract

Most of the opioids used in clinical practice exert their effects through mu opioid receptors. Yet, subtle but important pharmacological differences have been observed among the mu opioids. Their potency, effectiveness, and adverse effects can vary unpredictably among patients. These clinical differences among the mu opioids strongly argue against a single receptor mediating their actions. The cloning of the mu opioid receptor has greatly enhanced our understanding of the complexity of this system and has provided possible mechanisms to explain these observations. A single mu opioid receptor gene has been identified, but we now know that it generates a multitude of different mu opioid receptor subtypes through a mechanism commonly used to enhance protein diversity, alternative splicing. Early studies identified a number of splice variants involving the tip of the C-terminus. This region of the receptor is far away from the binding pocket, explaining why these variants still exhibit the same selectivity for mu opioids. However, the differences in structure at the C-terminus influence the activation patterns of the mu opioids. In addition, a second series of variants has been isolated that involves alternative splicing at the N-terminus. Together, these sets of mu opioid receptor splice variants may help explain the clinical variability of the mu drugs among patients and provide insights into why it is so important to individualize therapy for every patient in pain.

Figure 1

Structures of Common μOpioids.

Figure 2

Alternative mRNA Splicing.

Figure 3. Alternative mRNA Splicing of MOR-1 Leads to a Combinatorial Diversity of μ Opioid Receptor Proteins

MOR-1 receptor splice variants are depicted.

Figure 4

Domains of the MOR-1 Protein and Alternative Splice Variants of the C-Terminus.

Figure 5. Opioid Analgesia in a MOR-1 Exon-1 Knockout Mouse

Analgesic action of opioids in wild-type, heterozygous or homozygous mice. (a) Groups of mice (n = 8) received subcutaneous injections of 13 mg/kg morphine, 2 mg/kg methadone, 5 mg/kg of the κ₁ drug U50,488H, or 60 mg/kg of the κ₃ drug NalBzoH (naloxone benzoylhydrazone), and were tested for analgesia 30 minutes later. (b) Groups of mice (n = 9) received intracerebroventricular injections of 0.7 μg morphine, 6 ng of the μ peptide DAMGO (([D-Ala2,MePhe4,Gly(ol)5]-enkephalin), 12.5 ng M6G (morphine-6β-glucuronide) or 1.2 μg 6-acetylmorphine, and were tested for analgesia 15 minutes later. (c) Groups of mice (n = 8) received intrathecal injections of 0.8 μg morphine, 12.5 ng M6G or 500 ng of the δ peptide DPDPE ([D-Pen2,D-Pen5]enkephalin) and were tested for analgesia 15 minutes later. Analgesia is expressed as the percentage of mice responding.[Permission needed.]