The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury.
Spinal cord injury (SCI) results in the development of mechanical allodynia immediately rostral to the lesion site, within the dermatome border of normal sensation and sensory loss (at-level mechanical allodynia). We propose that an observed threefold increase in serotonergic fibre immunoreactivity within spinal segments corresponding to these allodynic dermatomes facilitates the maintenance of chronic neuropathic pain via activation of the 5-HT(3) receptor (5-HT(3)-R). Serotonin (5-HT), the non-selective 5-HT(1)/5-HT(2) receptor antagonist, methysergide, the 5-HT(3)-R agonist, m-chlorophenylbiguanide (m-CPBG) or the 5-HT(3)-R antagonist, ondansetron were intrathecally administered five weeks following SCI in rats. Ondansetron produced a robust, long-term reduction of at-level mechanical allodynia, while m-CPBG exacerbated allodynia. Exogenous 5-HT transiently reduced at-level mechanical allodynia. This effect was opposed by methysergide, which enhanced mechanical allodynia. Co-administration of 5-HT and ondansetron produced a short-lasting partial summation of effects, further decreasing mechanical allodynia while co-administration of methysergide attenuated the anti-allodynic effect of ondansetron. Depletion of spinal 5-HT via 5,7-dihydroxytryptamine (5,7-DHT) resulted in decreased at-level mechanical allodynia. The reduction of allodynia by ondansetron was lost following 5,7-DHT administration, suggesting that reduced allodynia following intrathecal ondansetron is via blockade of 5-HT-induced excitation of the 5-HT(3)-R. These results suggest that increased 5-HT fibre density immediately rostral to the SCI lesion site could have transient effects to reduce mechanical allodynia via actions at 5-HT(1) and/or 5-HT(2) receptors. However, the more long-lasting effects of this enhanced serotonergic input may facilitate chronic, at-level allodynia via the 5-HT(3)-R.
The Spinal Cord Injury Team, Biotherapeutics Research Group, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ont., Canada N6A 5K8.
Mark A
MA
Oatway
Yuhua
Y
Chen
Lynne C
LC
Weaver
D015115:5,6-Dihydroxytryptamine / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal; D001645:Biguanides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004924:Escape Reaction / Q000187:drug effects; D006941:Hyperesthesia; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D017294:Ondansetron / Q000494:pharmacology; D010146:Pain / Q000209:etiology* / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D013997:Time Factors
D001645:Biguanides; D009498:Neurotoxins; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D017294:Ondansetron; C065734:1-(3-chlorophenyl)biguanide; D015115:5,6-Dihydroxytryptamine; D008784:Methysergide