Relationship between sodium channel Na V1.3 expression and neuropathic pain behavior in rats

Abstract

A multitude of voltage-gated sodium channel subtypes (Na V1) 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 V1subtypes, but among these only Na V1.3 is up-regulated in dorsal root ganglia (DRG) neurons. The increased expression of Na V1.3 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 V1.3-like immunoreactivity (–LI) in DRG neurons and that mechanical allodynia was partially alleviated following oral administration of two Na V1 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 V1.3 decreased Na V1.3 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 V1.3 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 V1.3 up-regulation is dependent on cutaneous and/or muscle afferent activation and found that the numbers of neurons expressing Na V1.3 was proportional to the magnitude of the injury, but independent of the nature of innervation. These results suggest that Na V1.3 increases in primary sensory neurons that are not directly damaged in response to injury. Thus, although Na V1.3 is up-regulated in a subpopulation of DRG neurons after injury, reduction in the expression of Na V1.3 subtype alone is not sufficient to influence the Na V1-dependent behavioral hypersensitivity associated with nerve injury.