Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation

Background: Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. Methods: Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L-6 transverse process; (2) ligated (Group L), which underwent left L-5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L-5 SNL and was pretreated with intrathecal 2% lidocaine (50 mu l). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav(1.3) and Nav(1.8)) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). Results: Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav(1.3) and down-regulation of Nav(1.8), and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p < 0.01) and thermal hyperalgesia (p < 0.001), attenuated Nav(1.3) up-regulation (p = 0.003), and mitigated spinal microglial activation (p = 0.026) by inhibiting phosphorylation (activation) of p38 MAP kinase (p = 0.034). p38 activation was also suppressed on POD7 (p = 0.002). Conclusions: Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav(1.3) up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain.