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Depletion of endogenous spinal 5-HT attenuates the behavioural hypersensitivity to mechanical and cooling stimuli induced by spinal nerve ligation

Rahman, Wahidaa,*; Suzuki, Riea; Webber, Markb; Hunt, Stephen P.b; Dickenson, Anthony H.a

doi: 10.1016/j.pain.2006.02.033

There is compelling evidence for a strong facilitatory drive modulating spinal nociceptive transmission. This is in part via serotonergic pathways and originates from the rostroventral medulla. We previously demonstrated that neuropathic pain is associated with an enhanced descending facilitatory drive onto the mechanical evoked responses of dorsal horn neurones, mediated by 5-HT acting at spinal 5-HT3 receptors. Furthermore, depletion of spinal 5-HT has been shown to reduce the at-level mechanical allodynia that follows spinal cord injury. To further clarify the role and direction of effect of endogenous 5-HT, we investigated the effects of depleting spinal 5-HT, via intrathecal injection of 5,7di-hydroxytryptamine (5,7DHT), on pain behaviours after spinal nerve ligation (SNL). Depletion of spinal 5-HT in normal animals leads to reductions in mechanical and thermal evoked responses of deep dorsal horn neurones implying that spinal 5-HT has a predominant facilitatory function. After nerve injury, the frequency of paw withdrawals to low intensity mechanical and cooling stimulation of the ipsilateral hindpaw in the SNL-5,7DHT group was significantly attenuated when compared with the SNL-saline group from day seven post-nerve injury. Sham-5,7DHT and sham-saline animals showed very little response sensitivity on either hindpaw. This 5-HT-mediated difference in behaviour was independent of both the up-regulation of the NK1 receptor and spinal microglial activation produced by nerve injury. These data suggest that supraspinal serotonergic influences under these conditions are facilitatory and are implicated in the maintenance of spinal cord neuronal events leading to the behavioural hypersensitivity manifested after peripheral nerve damage.

aDepartment of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK

bDepartment of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK

*Corresponding author. Tel.: +44 207 679 3737; fax: +44 207 679 0181.


Received October 14, 2005; received in revised form February 15, 2006; accepted February 27, 2006.

© 2006 Lippincott Williams & Wilkins, Inc.
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