| First Author | Sánchez-Fernández C | Year | 2013 |
| Journal | Neuropharmacology | Volume | 70 |
| Pages | 348-58 | PubMed ID | 23524304 |
| Mgi Jnum | J:214202 | Mgi Id | MGI:5588554 |
| Doi | 10.1016/j.neuropharm.2013.03.002 | Citation | Sanchez-Fernandez C, et al. (2013) Potentiation of morphine-induced mechanical antinociception by sigma(1) receptor inhibition: role of peripheral sigma(1) receptors. Neuropharmacology 70:348-58 |
| abstractText | We studied the modulation of morphine-induced mechanical antinociception and side effects by sigma(1) receptor inhibition. Both wild-type (WT) and sigma(1) receptor knockout (sigma(1)-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of sigma(1) antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, sigma(1)-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1-16 mg/kg). Similarly, systemic treatment of WT mice with sigma(1) antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective sigma(1) agonist PRE-084. Although the local administration of morphine (50-200 mug) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in sigma(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 sigma(1) antagonists and the opioid. None of the sigma(1) antagonists tested enhanced morphine-antinociception in sigma(1)-KO mice, confirming a sigma(1)-mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in sigma(1)-KO mice. These results cannot be explained by a direct interaction of sigma(1) ligands with mu-opioid receptors or adaptive changes of mu-receptors in sigma(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 sigma(1) drugs tested bound to mu-opioid receptors. These results show that sigma(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. |
