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Investigation of chronic neuropathic pain and post-traumatic stress disorder comorbidity: role of glutamatergic, cannabinoid and vanilloid systems involving the prelimbic cortex and the periaqueductal grey

Grant number: 13/13398-2
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2014
Effective date (End): January 31, 2017
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Norberto Cysne Coimbra
Grantee:Joyce Mendes Gomes Tessari
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Investigation of Chronic Pain and Post-Traumatic Stress Disorder Comorbidity: Involvement of Glutamatergic, Endocannabinoid and Endovanilloid Pathways that link the Medial Pre-Frontal Cortex to the Ventrolateral Periaqueductal GreyAnxiety is highly comorbid with chronic pain, as a result, some researchers postulate that chronic neuropathic pain (NP) can be an expression of post-traumatic stress disease (PTSD). Accordingly, it has been demonstrated that there are functional and metabolic similarities between NP and PTSD and that, the medial pre-frontal cortex (MPFC) can participate in the integration of these two conditions. In addition many studies have demonstrated that the periaqueductal grey is involved in mediating defensive responses as well as the bidirectional control of pain. For example, lesions in the ventrolateral periaqueductal grey (vlPAG) caused impairment of defensive immobility and inhibited conditioned antinociceptive processes. The aim of the present study is to investigate, in male hamsters, the role of the MPFC in the modulation of chronic pain in situations of conditioned fear, via the recruitment of glutamatergic, endocannabinoid and endovanilloid neurons situated into the vlPAG. To analyse the connections between the MPFC and the vlPAG, the anterograde neurotracer biotinylated dextran amine will be iontophoretically injected into the MPFC. In addition, NMDA, CB1 and TRPV receptor expression in the target vlPAG neurons will be examined with immunohistochemical techniques. Since the second objective of this study is to investigate the role of these brain structures in the modulation of chronic pain and post-traumatic stress disorder comorbidity, another group of hamsters will be submitted to the following experiment. First, they will receive sustained constriction of the ischiatic nerve (CCIN), a model of chronic neuropathic pain (NP). After 21 days, the rodents will be exposed to a model of post-traumatic stress based on the confrontation between prey (golden hamsters: Mesocricetus auratus) and venomous snakes (Bothrops alternatus) in order to induce conditioned fear. 24 hours later the involvement of the endocanabinoid, endovanilloid, and glutamatergic systems will be studied in this model by pre-treatment of the vlPAG with CB1 antagonist/inverse agonist AM-251, the NMDA-receptor selective antagonist LY235959 or the TRPV1 receptor antagonist capsazepine, and the MPFC will be activated with an injection of L-glutamic acid. Following this, the animals will be re-exposed to the context (without the predator) and subsequently the nociceptive responses will be evaluated using Von Frey's mechanical allodynia test. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ULLAH, FARHAD; DOS ANJOS-GARCIA, TAYLLON; MENDES-GOMES, JOYCE; HIBRAHIM ELIAS-FILHO, DAOUD; FALCONI-SOBRINHO, LUIZ LUCIANO; DE FREITAS, RENATO LEONARDO; KHAN, ASMAT ULLAH; DE OLIVEIRA, RICARDO; COIMBRA, NORBERTO CYSNE. Connexions between the dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal grey matter are critical in the elaboration of hypothalamically mediated panic-like behaviour. Behavioural Brain Research, v. 319, p. 135-147, . (14/11869-0, 07/01174-1, 11/09850-1, 12/03798-0, 13/13398-2, 09/17258-5, 13/12916-0, 13/10984-8)
MENDES-GOMES, JOYCE; MOTTA, SIMONE CRISTINA; BINDI, RICARDO PASSONI; DE OLIVEIRA, AMANDA RIBEIRO; ULLAH, FARHAD; BALDO, MARCUS VINICIUS C.; COIMBRA, NORBERTO CYSNE; CANTERAS, NEWTON SABINO; BLANCHARD, D. CAROLINE. Defensive behaviors and brain regional activation changes in rats confronting a snake. Behavioural Brain Research, v. 381, . (17/11855-8, 14/05432-9, 13/13398-2, 18/00576-3)

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