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.