A tropomyosine receptor kinase inhibitor blocks spinal neuroplasticity essential for the anti-hypersensitivity effects of gabapentin and clonidine in rats with peripheral nerve injury

Ken-ichiro Hayashida, James C Eisenach
Journal of Pain 2011, 12 (1): 94-100

UNLABELLED: Spinally released brain-derived nerve growth factor (BDNF) after nerve injury is essential to anatomic and functional changes in spinal noradrenergic and cholinergic systems, which are engaged or targeted by commonly used treatments for neuropathic pain. Since BDNF signals via tropomyosine receptor kinases (trks), we tested whether trk blockade by repeated spinal injection of the trk inhibitor K252a would reduce anatomical (spinal noradrenergic and cholinergic fiber density), functional (α2-adrenoceptor-mediated direct stimulation of spinal cholinergic terminals), and behavioral (anti-hypersensitivity from systemic gabapentin and spinal clonidine) plasticity, which depends on BDNF. Spinal K252a treatment did not alter hypersensitivity from spinal nerve ligation (SNL), but blocked the SNL-associated increase in dopamine-β-hydroxylase (DβH) fiber density in the spinal cord dorsal horn while reducing spinal choline acetyltransferase (ChAT)-immunoreactivity. K252a treatment also abolished the facilitatory effect of dexmedetomidine on KCl-evoked acetylcholine release in spinal cord synaptosomes and reduced the anti-hypersensitivity effects of oral gabapentin and spinal clonidine. These results suggest that spinal trk signaling is essential for the anatomic and functional plasticity in noradrenergic and cholinergic systems after nerve injury and consequently for the analgesia from drugs that rely on these systems.

PERSPECTIVE: Many drugs approved for neuropathic pain engage spinal noradrenergic and cholinergic systems for analgesia. This study demonstrates that spinal trk signaling after nerve injury is important to neuroplasticity of these systems, which is critical for the analgesic action of common treatments for neuropathic pain.

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