期刊
NEUROPHARMACOLOGY
卷 70, 期 -, 页码 348-358出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2013.03.002
关键词
Sigma-1 (sigma(1)) receptors; Morphine; Pain; Peripheral antinociception; Hyperlocomotion; Gastrointestinal transit
资金
- Spanish Ministerio de Educacion y Ciencia (MEC)
- University of Granada
- Spanish Ministry of Education and Science (MEC) [SAF2006-06122]
- Junta de Andalucia [CTS 109]
- Laboratorios Esteve
- Centre for Industrial Technological Development (Spanish Government) [Genius Pharma project]
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 Si RA) 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 mu g) 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 [H-3]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. (C) 2013 Elsevier Ltd. All rights reserved.
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