کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5814794 | 1556643 | 2013 | 11 صفحه PDF | دانلود رایگان |

- Ï1 inhibition does not affect mechanical nociception (in the absence of morphine).
- Ï1 receptor inhibition potentiates morphine-induced mechanical antinociception.
- Peripheral Ï1 receptors tonically limit peripheral morphine antinociception.
- Acute morphine-induced side effects are unaltered in Ï1 knockout mice.
We studied the modulation of morphine-induced mechanical antinociception and side effects by Ï1 receptor inhibition. Both wild-type (WT) and Ï1 receptor knockout (Ï1-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of Ï1 antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, Ï1-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1-16 mg/kg). Similarly, systemic treatment of WT mice with Ï1 antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective Ï1 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 Ï1-KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with Ï1 antagonists and the opioid. None of the Ï1 antagonists tested enhanced morphine-antinociception in Ï1-KO mice, confirming a Ï1-mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in Ï1-KO mice. These results cannot be explained by a direct interaction of Ï1 ligands with μ-opioid receptors or adaptive changes of μ-receptors in Ï1-KO mice, given that [3H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the Ï1 drugs tested bound to μ-opioid receptors. These results show that Ï1 receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level.
Journal: Neuropharmacology - Volume 70, July 2013, Pages 348-358