Role of endocannabinoid, glutamatergic and endovanilloid systems of medial prefrontal cortex in neuropathic pain model and investigation of neurological disorders and chronic pain comorbidity

• Grant number: 13/12916-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: June 01, 2014
• End date: May 31, 2019
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Renato Leonardo de Freitas
• Grantee: Renato Leonardo de Freitas
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Norberto Cysne Coimbra ; Sérgio Henrique Ferreira
• Associated research grant(s): 14/11869-0 - Multi-use equipment approved in grant 2013/12916-0: deep brain stimulation (DBS) (Thomas mini matrix system - Thomas recording GmbH® - Winchester Strasse - Giessen - Germany), AP.EMU
• Associated scholarship(s): 17/07209-3 - Effect of infralimbic cortex neural stimulation and the psychopharmacological interaction among glutamatergic and endocannabinoid systems in the chronic neuropathic pain modulation in rats, BP.IC; 17/07211-8 - Effect of chronic treatment with fluoxetine or cannabidiol on the comorbidity between neuropathic pain and depression in rats: investigation of cannabidiol psychopharmacological mechanisms, BP.IC; 14/26228-0 - Psychopharmacological investigation on comorbidity influence between chronic neuropathic pain and depression, BP.IC; 14/16720-5 - Neuromolecular and psychopharmacological investigation on the endovanilloid system and TRPV1 channels of medial prefrontal cortex in mediating chronic neuropathic pain, BP.IC; 14/07902-2 - Role of endocannabinoid, glutamatergic and endovanilloid systems of medial prefrontal cortex in neuropathic pain model and investigation of neurological disorders and chronic pain comorbidity, BP.JP

Abstract

The aim of our study is to investigate the medial prefrontal cortex (MPFC), 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 MPFC and endogenous pain modulatory systems like periaqueductal gray matter (PAG), magnum raphe nucleus (MRN) and locus coeruleus (LC) will evaluate after stimulation of CCSN. Immunohistochemistry will perform at 7, 14, 21 and 28 days after stimulation of CCSN to identify c-Fos protein and NMDA glutamate, endocannabinoid CB1 and TRPV1 receptors, analyzing the neuromolecular activity. In addition, 28 days after the CCSN, the MPFC, PAG, MRN and LC will be separate and Western Blotting will perform to evaluate if chronic pain increases the expression of NMDA, CB1 and TRPV1 receptors. Furthermore, to verify the possible increase of amount of protein to these receptors is also accompanied by increase of mRNA in MPFC, SCP, NMR and LC will be used the technique of real-time polymerase chain reaction (RT-PCR). The next step will be the neurostimulation of MPFC through of technique of deep brain stimulation (DBS) evaluating its effect on the neuropathic pain, and also record the activity of neuronal nuclei of endogenous pain inhibitory system. The nociceptive test will be used is mechanical allodynia, the von Frey at 7, 14, 21 and 28 days after stimulation of CCSN. After evaluate the involvement of the activation of the cortical and the activation of NMDA, CB1 e TRPV1 receptors in the NP, the pharmacological interaction between the endocannabinoid and the glutamatergic and endocannabinoid and endovaniloid systems of MPFC will investigate. Furthermore, the comorbidity depression, anxiety and panic in rodents with chronic pain will investigate. The neurophysiological (neurostimulation by DBS) and neuropharmacological procedures (pharmacological interactions) will be also investigate. The animals will subject to experimental model of depression and anxiety/panic 21 days after the CCSN to evaluate the relation between depression or anxiety/panic disorders and neuropathic pain in Wistar rat. (AU)

Scientific publications

(17)

(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)

MEDEIROS, PRISCILA; DE FREITAS, RENATO LEONARDO; BOCCELLA, SERENA; IANNOTTA, MONICA; BELARDO, CARMELA; MAZZITELLI, MARIACRISTINA; ROMANO, ROSARIA; DE GREGORIO, DANILO; COIMBRA, NORBERTO CYSNE; PALAZZO, ENZA; et al. Characterization of the sensory, affective, cognitive, biochemical, and neuronal alterations in a modified chronic constriction injury model of neuropathic pain in mice. Journal of Neuroscience Research, AUG 2019. (14/11869-0, 13/12916-0)

MEDEIROS, PRISCILA; OLIVEIRA-SILVA, MARIANA; NEGRINI-FERRARI, SYLMARA ESTHER; MEDEIROS, ANA CAROLINA; ELIAS-FILHO, DAOUD HIBRAIM; COIMBRA, NORBERTO CYSNE; DE FREITAS, RENATO LEONARDO. CB1-cannabinoid-, TRPV1-vanilloid- and NMDA-glutamatergic-receptor-signalling systems interact in the prelimbic cerebral cortex to control neuropathic pain symptoms. Brain Research Bulletin, v. 165, p. 118-128, DEC 2020. (17/13560-5, 09/17258-5, 12/25167-2, 14/11869-0, 14/07902-2, 13/12916-0)

DE FREITAS, RENATO LEONARDO; MEDEIROS, PRISCILA; KHAN, ASMAT ULLAH; COIMBRA, NORBERTO CYSNE. mu(1)-Opioid receptors in the dorsomedial and ventrolateral columns of the periaqueductal grey matter are critical for the enhancement of post-ictal antinociception. Synapse, v. 70, n. 12, p. 519-530, DEC 2016. (14/11869-0, 12/25167-2, 13/12916-0, 09/00668-6, 09/17258-5)

MEDEIROS, P.; DE FREITAS, R. L.; SILVA, M. O.; COIMBRA, N. C.; MELO-THOMAS, L.. CB1 CANNABINOID RECEPTOR-MEDIATED ANANDAMIDE SIGNALING MECHANISMS OF THE INFERIOR COLLICULUS MODULATE THE HALOPERIDOL-INDUCED CATALEPSY. Neuroscience, v. 337, p. 17-26, NOV 19 2016. (14/11869-0, 11/01409-4, 12/25167-2, 13/12916-0)

DE FREITAS, RENATO LEONARDO; MEDEIROS, PRISCILA; DA SILVA, JULIANA ALMEIDA; DE OLIVEIRA, RITHIELE CRISTINA; DE OLIVEIRA, RICARDO; ULLAH, FARHAD; KHAN, ASMAT ULLAH; COIMBRA, NORBERTO CYSNE. THE mu(1)-OPIOID RECEPTOR AND 5-HT2A- AND 5HT(2C)-SEROTONERGIC RECEPTORS OF THE LOCUS COERULEUS ARE CRITICAL IN ELABORATING HYPOALGESIA INDUCED BY TONIC AND TONIC-CLONIC SEIZURES. Neuroscience, v. 336, p. 133-145, NOV 12 2016. (14/11869-0, 09/02458-9, 11/09850-1, 12/25167-2, 13/12916-0, 09/00668-6, 09/17258-5, 15/10313-1)

CALVO, FABRICIO; LOBAO-SOARES, BRUNO; DE FREITAS, RENATO LEONARDO; PASCHOALIN-MAURIN, TATIANA; DOS ANJOS-GARCIA, TAYLLON; MEDEIROS, PRISCILA; DA SILVA, JULIANA ALMEIDA; LOVICK, THELMA ANDERSON; COIMBRA, NORBERTO CYSNE. The endogenous opioid system modulates defensive behavior evoked by Crotalus durissus terrificus: Panicolytic-like effect of intracollicular non-selective opioid receptors blockade. JOURNAL OF PSYCHOPHARMACOLOGY, v. 33, n. 1, p. 51-61, JAN 2019. (14/11869-0, 07/01174-1, 15/10313-1, 17/11855-8, 09/02458-9, 12/03798-0, 13/12916-0, 12/25167-2)

DA SILVA, JULIANA ALMEIDA; BIAGIONI, AUDREY FRANCESCHI; ALMADA, RAFAEL CARVALHO; DE FREITAS, RENATO LEONARDO; COIMBRA, NORBERTO CYSNE. Panicolytic-like effects caused by substantia nigra pars reticulata pretreatment with low doses of endomorphin-1 and high doses of CTOP or the NOP receptors antagonist JTC-801 in male Rattus norvegicus. Psychopharmacology, v. 234, n. 20, p. 3009-3025, OCT 2017. (14/11869-0, 09/02458-9, 14/10742-7, 17/11855-8, 12/03798-0, 09/54014-7, 10/15140-4, 13/12916-0, 09/17258-5, 07/01174-1, 15/10313-1, 12/22681-7)

MEDEIROS, PRISCILA; NEGRINI-FERRARI, SYLMARA ESTHER; PALAZZO, ENZA; MAIONE, SABATINO; FERREIRA, SERGIO HENRIQUE; DE FREITAS, RENATO LEONARDO; COIMBRA, NORBERTO CYSNE. N-methyl-d-aspartate Receptors in the Prelimbic Cortex are Critical for the Maintenance of Neuropathic Pain. Neurochemical Research, v. 44, n. 9, p. 2068-2080, SEP 2019. (14/11869-0, 12/25167-2, 13/08216-2, 13/12916-0, 11/19670-0, 17/13560-5, 09/17258-5, 14/07902-2)

MATIAS JUNIOR, IVAIR; MEDEIROS, PRISCILA; DE FREITA, RENATO LEONARDO; VICENTE-CESAR, HILTON; FERREIRA JUNIOR, JOSE RANIERY; MACHADO, HELIO RUBENS; MENEZES-REIS, RAFAEL. Effective Parameters for Gait Analysis in Experimental Models for Evaluating Peripheral Nerve Injuries in Rats. NEUROSPINE, v. 16, n. 2, p. 305-316, JUN 2019. (14/11869-0, 12/25167-2, 13/12916-0, 13/10543-1, 09/17258-5, 14/07902-2)

P. MEDEIROS; I.R. DOS SANTOS; A.C. MEDEIROS; J.A. DA SILVA; S.H. FERREIRA; R.L. DE FREITAS; N.C. COIMBRA. Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury. Brazilian Journal of Medical and Biological Research, v. 53, n. 5, 2020-04-27. (09/17258-5, 13/12916-0, 14/11869-0, 17/13560-5, 13/08216-2, 12/25167-2, 14/07902-2, 11/19670-0)

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, FEB 15 2017. (14/11869-0, 07/01174-1, 11/09850-1, 12/03798-0, 13/13398-2, 09/17258-5, 13/12916-0, 13/10984-8)

MEDEIROS, PRISCILA; DOS SANTOS, IEDA REGINA; MATIAS JUNIOR, IVAIR; PALAZZO, ENZA; DA SILVA, JOSE APARECIDO; MACHADO, HELIO RUBENS; FERREIRA, SERGIO HENRIQUE; MAIONE, SABATINO; COIMBRA, NORBERTO CYSNE; DE FREITAS, RENATO LEONARDO. An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats. PAIN MEDICINE, v. 22, n. 2, p. 338-351, FEB 2021. (11/19670-0, 13/08216-2, 13/12916-0, 17/13560-5, 14/11869-0, 12/25167-2, 14/07902-2, 09/17258-5)

FERREIRA, LAIS LEITE; GENEROSO, LAURA PEREIRA; MEDEIROS, ANA CAROLINA; DE MEDEIROS, PRISCILA; DE FREITAS, RENATO LEONARDO; DA SILVA, MARCELO LOURENCO; TORRES DA SILVA, JOSIE RESENDE. Infralimbic medial prefrontal cortex alters electroacupuncture effect in animals with neuropathic chronic pain. Behavioural Brain Research, v. 424, p. 11-pg., 2022-04-29. (13/12916-0)

MEDEIROS, PRISCILA; DE FREITAS, RENATO LEONARDO; BOCCELLA, SERENA; IANNOTTA, MONICA; BELARDO, CARMELA; MAZZITELLI, MARIACRISTINA; ROMANO, ROSARIA; DE GREGORIO, DANILO; COIMBRA, NORBERTO CYSNE; PALAZZO, ENZA; et al. Characterization of the sensory, affective, cognitive, biochemical, and neuronal alterations in a modified chronic constriction injury model of neuropathic pain in mice. Journal of Neuroscience Research, v. 98, n. 2, p. 15-pg., 2019-08-08. (14/11869-0, 13/12916-0)

MEDEIROS, ANA C.; MEDEIROS, PRISCILA; FREITAS, RENATO L.; SILVA JUNIOR, PEDRO ISMAEL; COIMBRA, NORBERTO C.; DOS SANTOS, WAGNER F.. Acanthoscurria gomesiana spider-derived synthetic mygalin in the dorsal raphe nucleus modulates acute and chronic pain. JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, v. 35, n. 10, AUG 2021. (09/54014-7, 17/13560-5, 13/12916-0, 12/25167-2, 09/17258-5, 14/11869-0)

NEGRINI-FERRARI, SYLMARA ESTHER; MEDEIROS, PRISCILA; MALVESTIO, RAFAEL BRAGHETTO; SILVA, MARIANA DE OLIVEIRA; MEDEIROS, ANA CAROLINA; COIMBRA, NORBERTO CYSNE; MACHADO, HELIO RUBENS; DE FREITAS, RENATO LEONARDO. The primary motor cortex electrical and chemical stimulation attenuates the chronic neuropathic pain by activation of the periaqueductal grey matter: The role of NMDA receptors. Behavioural Brain Research, v. 415, OCT 11 2021. (14/07902-2, 13/12916-0, 14/11869-0, 12/25167-2, 17/13560-5, 09/17258-5)

MEDEIROS, ANA CAROLINA; MEDEIROS, PRISCILA; RUGGIERO, RAFAEL NAIME; DE GREGORIO, DANILO; GOBBI, GABRIELLA; SILVA JR, PEDRO ISMAEL; DOS SANTOS, WAGNER FERREIRA; COIMBRA, NORBERTO CYSNE; DE FREITAS, RENATO LEONARDO. Acanthoscurria gomesiana spider-derived Mygalin in the prelimbic prefrontal cortex modulates neuropathic pain and depression comorbid. JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, v. 37, n. 7, p. 14-pg., 2023-04-17. (14/11869-0, 13/12916-0)