Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat.
We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states.
Asante
Curtis O
CO
Department of Neuroscience Physiology and Pharmacology, University College London, Gower Street, London WC1E6BT, UK. curtisasante@googlemail.com
Dickenson
Anthony H
AH
D000200:Action Potentials / Q000187:drug effects; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002351:Carrageenan / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D017294:Ondansetron / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D012702:Serotonin Antagonists / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology*; D013696:Temperature
D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D012702:Serotonin Antagonists; D017294:Ondansetron; C401859:temsirolimus; D002351:Carrageenan; D020123:Sirolimus