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

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.

Methylprednisolone causes minimal improvement after spinal cord injury in rats, contrasting with benefits of an anti-integrin treatment.

Spinal cord injury (SCI) leads to complex secondary events that expand and exacerbate the injury. Methylprednisolone (MP) has been considered a standard of care for acute SCI. The purpose of this study was to test the effects of MP, in severe and more moderate severe clip-compression models of SCI, on the measures of neurological function and lesion sparing that we used previously to assess a highly effective anti-inflammatory therapy, a monoclonal antibody (mAb) to the CD11d integrin.

Anti-CD11d integrin antibody treatment restores normal serotonergic projections to the dorsal, intermediate, and ventral horns of the injured spinal cord.

Spinal serotonergic pathways provide inhibitory and excitatory modulation of sensory, autonomic, and motor processing. After spinal cord injury (SCI), the acute inflammatory response is one process that damages descending pathways. Increases in serotonergic fiber density in spinal segments rostral and decreases caudal to the lesion have been observed previously and may contribute to neuropathic pain and motor dysfunction associated with SCI.

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.

Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function.

The early inflammatory response to spinal cord injury (SCI) causes significant secondary damage. Strategies that nonselectively suppress inflammation have not improved outcomes after SCI, perhaps because inflammation has both adverse and beneficial effects after SCI. We have shown that the selective, time-limited action of a monoclonal antibody (mAb) to the CD11d subunit of the CD11d/CD18 integrin, delivered intravenously during the first 48 hr after SCI in rats, markedly decreases the infiltration of neutrophils and delays the entry of hematogenous monocyte-macrophages into the injured cord.

Chronic pain after clip-compression injury of the rat spinal cord.

Chronic tactile allodynia and hyperalgesia are frequent complications of spinal cord injury (SCI) with poorly understood mechanisms. Possible causes are plastic changes in the central arbors of nociceptive and nonnociceptive primary sensory neurons and changes in descending modulatory serotonergic pathways. A clinically relevant clip-compression model of SCI in the rat was used to investigate putative mechanisms of chronic pain.