Relationship between sodium channel Nav1.3 expression and neuropathic pain behavior in rats

A multitude of voltage-gated sodium channel subtypes (Na(v)1) are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of action potentials. Peripheral nerve injury alters the expression of several Na(v)1 subtypes, but among these only Na(v)1.3 is up-regulated in dorsal root ganglia (DRG) neurons. The increased expression of Na(v)1.3 implicates this subtype in the development and maintenance of neuropathic pain, but its contribution to neuropathic pain behavior has not been examined. Using the spared nerve injury (SNI) model, we found that peripheral nerve lesion increased Na(v)1.3-like immunoreactivity (-LI) in DRG neurons and that mechanical allodynia was partially alleviated following oral administration of two Na(v)1 blockers, mexiletine (30 and 100 mg/kg, p.o.) and lamotrigine (30 and 100 mg/kg, p.o.). Intrathecal administration of antisense oligonucleotides (4 days) selective for Na(v)1.3 decreased Na(v)1.3 immunostaining in the DRG by 50% in the SNI model, but did not attenuate mechanical or cold allodynia. Moreover, we found that only 18% of Na(v)1.3 positive neurons also expressed activated transcription factor-3 (ATF3), a marker of injured neurons. We then selectively axotomized a cutaneous nerve (sural) and a muscle nerve (gastrocnemius) in order to identify if Na(V)1.3 up-regulation is dependent on cutaneous and/or muscle afferent activation and found that the numbers of neurons expressing Na(v)1.3 was proportional to the magnitude of the injury, but independent of the nature of innervation. These results suggest that Na(v)1.3 increases in primary sensory neurons that are not directly damaged in response to injury. Thus, although Na(v)1.3 is up-regulated in a subpopulation of DRG neurons after injury, reduction in the expression of Na(v)1.3 subtype alone is not sufficient to influence the Na(v)1-dependent behavioral hypersensitivity associated with nerve injury. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.