Role of glutamatergic, endocannabinoid and endovaniloid systems of medial pre-frontal cortex in neurophatic pain model: Investigation of panic and chronic pain comorbidity

Abstract

The aim of our study is to investigate the neuroanatomical and pharmacological basis of chronic pain. Cortical areas, like prelimbic (PL) and infralimbic (IL) divisions of medial prefrontal cortex (MPFC), will investigate in modulation of chronic pain through possible activation of descendent pathway during the neuropathic pain induced by chronic constriction of the sciatic nerve (CCSN). The role of PL, IL and endogenous pain modulatory systems in periaqueductal gray matter, magnum raphe nucleus and locus coeruleus will evaluate after stimulation of CCSN. Immunohistochemistry will perform at 2, 7, 14 and 21 days after stimulation of CCSN to identify c-Fos protein and NMDA glutamate, endocannabinoid CB1 and TRPV1 endovaniloid receptors, analyzing the neuromolecular activity after 2, 7, 14 and 21 days of induction of CCSN. The nociceptive test that will be used is mechanical allodynia, the von Frey. After evaluate the involvement of the activation of the cortical and brainstem areas and the activation of NMDA, CB1 e TRPV1 receptors in the neuropathic pain, the pharmacological interaction between the endocannabinoid and the glutamatergic systems of PL and IL will investigate. Pretreatment doses of AM-251 (CB1 antagonist receptors) will follow by activation of glutamatergic system through of microinjection of l-glutamate (glutamatergic agonist). PL or IL-pretreatment with NMDA receptors antagonist LY23595 (NMDA antagonist receptors) will perform, followed by activation of PL or IL with endocannabinoid anandamide (endocannabinoid agonist). In the next study, capsazepine (TRPV1 antagonist) will administer in PL or IL, followed by activation of endocannabinoid system through of microinjection of anandamide in PL or IL. PL or IL-pretreatment with CB1 receptors antagonist will perform by microinjection of AM251 (CB1 receptors antagonist) followed by activation of endovaniloid system in PL or IL through microinjection of capsaicin (endovaniloid agonist) to evaluate the involvement of cortical areas in the neuropathic pain. Furthermore, the comorbidity panic and fear in rodents with neuropathy pain will investigate. The animals will subject to aggressive confrontation with constrictor snake after seven days of CCSN activation to evaluate the relation between panic/anxiety disorders and neuropathic pain.