The Study Of Astrocytes Participation In The Treatment Of Ketamine On Neuropathic Pain

Background: Neuropathic pain is an intractable clinical problem. Intrathecal ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to be useful for treating neuropathic pain in clinic by inhibiting the activity of spinal neurons. Although ketamine is widely used as an analgesic agent and has an anti-allodynic effect on neuropathic pain, the underlying analgesic mechanisms are not fully explained by the modern"neuronal-based"theories. As emerging studies have focused on the critical role of spinal astrocytes in the pathological pain states, we have hypothesized that there exist some"astrocytes-related"mechanisms in the analgesic function of ketamine. Moreover, c-Jun N-terminal kinase (JNK), a member of mitogen-activated protein kinase (MAPK) family members, was reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine could decrease lipopolysaccharide (LPS)-induced phosphorylated JNK (pJNK) expression and exert anti-inflammatory effect. We thus hypothesized that inhibiting astrocytic JNK activation might be involved in the suppression effect of ketamine on SNL-induced spinal astrocytic activation. Therefore, in the present study, using the spinal nerve ligation (SNL) pain model, we investigated the anti-nociceptive effects of intraperitoneal or intrathecal ketamine on SNL-induced neuropathic pain response, meanwhile, we investigated the astrocytic activation after ketamine administration on SNL rats. Furthermore, the underlying mechanisms were disclosed.Material and methods: Behavioral tests were conducted to confirm the effects of ketamine on mechanical allodynia. Immunofluorescence was applied for detecting the expression of astrocytic specific marker glial fibrillary acidic protein (GFAP) and the expression and localization of SNL-induced spinal pJNK in the spinal dorsal horn. Western blot was used for quantifying the variations of GFAP and pJNK expression after different treatment.Results: 1 Behavioral data showed that either intraperitoneal or intrathecal ketamine inhibited SNL-induced allodynia, however, immunohistochemistry showed that SNL induced astrocytic activation was suppressed by intrathecal but not intraperitoneal ketamine. Using quantitative Western blot analysis, our report showed that intrathecal ketamine down-regulated GFAP expression, suggesting inhibition of SNL-induced astrocytic activation, which wasn't influenced by intraperitoneal administration. 2 The results showed that SNL-induced pJNK up-regulation in the ipsilateral spinal dorsal horn, which was specifically localized in spinal astrocytes but not in microglia or neurons. Intrathecal ketamine attenuated SNL-induced mechanical allodynia and spinal astrocytic JNK activation in a dose-dependent manner.Conclusions: we conclude from results that intraperitoneal ketamine could alleviate SNL-induced neuropathic pain via the classical"neuronal-based"mechanisms, but in addition,"astrocytes-related"mechanisms were also important underlying the anti-allodynic effect of intrathecal ketamine. Inhibiting JNK activation could be involved in the suppression effect of ketamine on SNL-induced spinal astrocytes activation, which is also important underlying the anti-allodynic effect of intrathecal ketamine.