Involvement of Gi/o proteins and GIRK channels in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice.
The analgesic efficacy of opiates can be enhanced in inflammatory states due to peripheral and spinal alterations. We describe here that the analgesic effect induced by intrathecal (i.t.) morphine assessed by measuring thermal withdrawal latencies is enhanced in carrageenan-inflamed mice. The spinal micro-opioid receptor (MOR) population is not up-regulated as demonstrated by Western blot assays. In contrast, behavioural experiments show the involvement of changes in transduction mechanisms activated by spinal opioid receptors. The i.t. administration of the nitric oxide (NO) synthase inhibitor L-NMMA (3-30 microg) antagonised with a similar potency and efficacy morphine-induced analgesia in inflamed and non-inflamed mice, discarding that an increase in NO release could be responsible of the enhancement of morphine-induced analgesia. The analgesic effects evoked by the i.t. administration of the direct G(i/o) protein activator mastoparan (0.03-10 microg), but not those induced by the N-type calcium channel blocker omega-conotoxin GVIA (3-30 ng), were potentiated in inflamed mice, suggesting that postsynaptic and not presynaptic mechanisms could be involved. Furthermore, the inhibitory effects on morphine-induced analgesia produced by the G(i/o) protein inhibitor pertussis toxin (0.1-17 ng) or the G-coupled inwardly rectifying potassium (GIRK) channels inhibitor tertiapin-Q (0.75-750 ng) were greatly enhanced in inflamed mice. These results suggest that differences in the transduction mechanism activated by MOR at postsynaptic level, probably related with GIRK channels activity, could participate in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice.
González-Rodríguez
Sara
S
Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, C/ Julián Clavería 6, 33006, Oviedo, Asturias, Spain.
Hidalgo
Agustín
A
Baamonde
Ana
A
Menéndez
Luis
L
D000208:Acute Disease; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology; D004357:Drug Synergism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007278:Injections, Spinal; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010455:Peptides / Q000008:administration & dosage; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology; D014862:Wasp Venoms / Q000008:administration & dosage
D000701:Analgesics, Opioid; D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D017450:Receptors, Opioid, mu; D014862:Wasp Venoms; C029738:tertiapin; C037500:mastoparan; D009020:Morphine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go