Potentiation of morphine-induced mechanical antinociception by σ1 receptor inhibition: Role of peripheral σ1 receptors

Abstract We studied the modulation of morphine-induced mechanical antinociception and side effects by σ 1 receptor inhibition. Both wild-type (WT) and σ 1 receptor knockout (σ 1 -KO) mice showed similar responses to paw pressure (100–600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ 1 antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, σ 1 -KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1–16 mg/kg). Similarly, systemic treatment of WT mice with σ 1 antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective σ 1 agonist PRE-084. Although the local administration of morphine (50–200 μg) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in σ 1 -KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with σ 1 antagonists and the opioid. None of the σ 1 antagonists tested enhanced morphine-antinociception in σ 1 -KO mice, confirming a σ 1 -mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in σ 1 -KO mice. These results cannot be explained by a direct interaction of σ 1 ligands with μ-opioid receptors or adaptive changes of μ-receptors in σ 1 -KO mice, given that [ 3 H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the σ 1 drugs tested bound to μ-opioid receptors. These results show that σ 1 receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level.