Blockade of the 5‐HT₃ receptor for days causes sustained relief from mechanical allodynia following spinal cord injury

Abstract

Chronic neuropathic pain is a frequent, serious outcome of spinal cord injury (SCI) that is highly refractory to treatment. Serotonin can contribute to neuropathic pain after SCI, as suggested by our previous observation that transient blockade of the 5-HT(3) receptor by intrathecal injections of the antagonist ondansetron reduces mechanical allodynia after SCI in rats. The current study determined whether intrathecal or intravenous infusion of ondansetron for 3 or 7 days, respectively, could cause sustained blockade of mechanical allodynia at and below the level of a twelfth thoracic clip compression injury in rats. Intrathecal 3-day infusion of ondansetron (2.0 microg/hr), targeted to the cord rostral to the SCI and commencing at 28 days after SCI, decreased at-level mechanical allodynia by 40% and below-level allodynia by 60% compared with saline-treated rats (controls). This reduction was sustained throughout drug delivery and for 1 day afterward. During the next 3 days, allodynia gradually returned toward the values of saline-treated rats. An initial experiment showed that bolus intravenous injections of ondansetron (20-100 microg) at 28 days after SCI decreased both at- and below-level allodynia for 90-120 min. Intravenous 7-day infusions (20 microg/hr), commencing at 28 days after SCI, significantly decreased at-level allodynia by 48% and below-level allodynia by 51% compared with controls. This reduction of allodynia lasted throughout the infusion and for 1-3 days afterward while pain responses gradually approached those of controls. These findings suggest a potential role of 5-HT(3) receptor antagonism in the relief of neuropathic pain after SCI in humans.

Spinal Cord Transection-Induced Allodynia in Rats – Behavioral, Physiopathological and Pharmacological Characterization

“…In contrast to the capacity of i.t. injection of ondansetron to attenuate neuropathic pain caused by spinal cord compression [64], this treatment was inactive in SCT rats, probably because complete transection of the spinal cord had suppressed the bulbo-spinal connections involved in 5-HT 3 receptor-mediated effects [38].…”

Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism

“…Intrathecal ondansetron attenuated mechanical hyperalgesia and allodynia[34] and inhibited mechanical and thermal evoked responses of spinal dorsal horn neurons in this same model. Spinal administration of ondansetron was also analgesic in models of spinal cord injury, cancer-induced bone pain and osteoarthritis[35-37]. Consistent with reports of pro-nociceptive effects of peripheral 5-HT 3 receptors[38,39], inflammatory pain also appears to be mediated, in part, by spinal 5-HT 3 receptors.…”

Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats

“…Previous studies have shown that stimulation of spinal 5-HT 1A (Colpaert et al, 2004;Aira et al, 2010) and 5-HT 1B/1D (Kayser et al, 2002(Kayser et al, , 2011 receptors produces antiallodynic effects, whereas activation of spinal 5-HT 2 (Aira (Rahman et al, 2006;Chen et al, 2009;Wei et al, 2010;Marshall et al, 2012), 5-HT 4 and 5-HT 6 (Rocha-González, personal communication) and 5-HT 7 (Amaya-Castellanos et al, 2011) receptors instead elicits pronociceptive effects. Nevertheless, to the best of our knowledge, no study has investigated directly the role of spinal 5-HT 5A receptors in neuropathic pain models in rats.…”

“…Accordingly, lesions to descending serotonergic projections, by 5,7-dihydroxytryptamine or RNAi for tryptophan hydroxylase-2, reduce 5-HT tissue content and mechanical allodynia in rats with spinal nerve injury (Rahman et al, 2006;Wei et al, 2010;Leong et al, 2011). There is evidence that activation of spinal 5-HT 2 (Aira et al, 2010;Rahman et al, 2011), 5-HT 3 (Rahman et al, 2006;Chen et al, 2009;Wei et al, 2010;Marshall et al, 2012), 5-HT 4 , 5-HT 6 (Rocha-González, personal communication) and 5-HT 7 (Amaya-Castellanos et al, 2011) receptors has been associated with a descending facilitatory role of 5-HT in neuropathic pain models. In contrast, the descending inhibitory role of 5-HT in neuropathic pain models has not been systematically studied.…”