N-methyl-d-aspartate Receptors in the Prelimbic Cortex are Critical for the Maintenance of Neuropathic Pain

Author(s)

Medeiros, Priscila ^{[1, 2, 3]} ; Negrini-Ferrari, Sylmara Esther ^{[1, 2, 3]} ; Palazzo, Enza ^[4] ; Maione, Sabatino ^{[4, 1, 2]} ; Ferreira, Sergio Henrique ^{[1, 2, 3, 5]} ; de Freitas, Renato Leonardo ^{[6, 1, 2, 3, 5, 7, 8]} ; Coimbra, Norberto Cysne ^{[6, 1, 2, 3, 5]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Neurosci Lab, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Pain & Emot & Multiuser Ctr Neuroelectrophysiol, Dept Surg & Anat, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo FMRP USP, Ribeirao Preto Med Sch, Dept Pharmacol, Lab Neuroanat & Neuropsychobiol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] Univ Campania Luigi Vanvitelli, Dept Expt Med, Div Pharmacol, Naples - Italy

^[5] Univ Sao Paulo FMRP USP, Ribeirao Preto Med Sch, Dept Pharmacol, Lab Pain & Inflammat, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[6] Behav Neurosci Inst INeC, Av Cafe 2450, BR-14050220 Ribeirao Preto, SP - Brazil

^[7] Univ Sao Paulo, Ribeirao Preto Sch Philosophy Sci & Literature, Dept Psychol, BR-14040901 Ribeirao Preto, SP - Brazil

^[8] Univ Fed Alfenas, UNIFAL MG, Biomed Sci Inst, Str Gabriel Monteiro Silva 700, BR-37130000 Alfenas, MG - Brazil

• Document type: Journal article
• Source: Neurochemical Research; v. 44, n. 9, p. 2068-2080, SEP 2019.
• Web of Science Citations: 2

Abstract

The mechanisms underlying chronic and neuropathic pain pathology involve peripheral and central sensitisation. The medial prefrontal cortex (mPFC) seems to participate in pain chronification, and glutamatergic neurotransmission may be involved in this process. Thus, the aim of the present work was to investigate the participation of the prelimbic (PrL) area of the mPFC in neuropathic pain as well as the role of N-methyl d-aspartate (NMDA) glutamate receptors in neuropathic pain induced by a modified sciatic nerve chronic constriction injury (CCI) protocol in Wistar rats. Neural inputs to the PrL cortex were inactivated by intracortical treatment with the synapse blocker cobalt chloride (CoCl2, 1.0 mM/200 nL) 7, 14, 21, or 28 days after the CCI or sham procedure. The glutamatergic agonist NMDA (0.25, 1 or 4 nmol) or the selective NMDA receptor antagonist LY235959 (2, 4 or 8 nmol) was microinjected into the PrL cortex 21 days after surgery. CoCl2 administration in the PrL cortex decreased allodynia 21 and 28 days after CCI. NMDA at 1 and 4 nmol increased allodynia, whereas LY235959 decreased mechanical allodynia at the highest dose (8 nmol) microinjected into the PrL cortex. These findings suggest that NMDA receptors in the PrL cortex participate in enhancing the late phase of mechanical allodynia after NMDA-induced increases and LY235959-induced decreases in allodynia 21 days after CCI. The glutamatergic system potentiates chronic neuropathic pain by NMDA receptor activation in the PrL cortex. {[}GRAPHICS] Mechanism of neuropathic pain. The infusion of CoCl2, a synapse activity blocker, into the prelimbic (PrL) division of the medial prefrontal cortex (mPFC) decreased the severity of mechanical allodynia, showing the late participation of the limbic cortex. The glutamatergic system potentiates chronic neuropathic pain via NMDA receptor activation in the PrL cortex. (AU)

• FAPESP's process: 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
• Grantee: Renato Leonardo de Freitas
• Support type: Scholarships in Brazil - Young Researchers
• FAPESP's process: 13/12916-0 - Role of endocannabinoid, glutamatergic and endovanilloid systems of medial prefrontal cortex in neuropathic pain model and investigation of neurological disorders and chronic pain comorbidity
• Grantee: Renato Leonardo de Freitas
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 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)
• Grantee: Renato Leonardo de Freitas
• Support type: Multi-user Equipment Program
• FAPESP's process: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis
• Grantee: Fernando de Queiroz Cunha
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 09/17258-5 - Study of the involvement of nitrergic system and of glutamatergic and cannabinoid-mediated neurotransmission from the medial prefrontal cortex in the analgesia induced by elaborated escape reactions evoked by GABAergic blockade in the medial hypothalamus
• Grantee: Renato Leonardo de Freitas
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/25167-2 - Role of glutamatergic, endocannabinoid and endovaniloid systems of medial pre-frontal cortex in neurophatic pain model: Investigation of panic and chronic pain comorbidity
• Grantee: Priscila de Medeiros
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/13560-5 - Effect of deep brain stimulation and cannabidiol treatment in the subthalamic nucleus on the motors and non-Motors symptoms in the experimental model of Parkinson Disease
• Grantee: Priscila de Medeiros
• Support type: Scholarships in Brazil - Post-Doctorate