Pharmacological restoration of anti-nociceptive functions in the prefrontal cortex relieves chronic pain. (June 2021)

• Record Type: Journal Article
• Authors: Talay, Robert S.; Liu, Yaling; Michael, Matthew; Li, Anna; Friesner, Isabel D.; Zeng, Fei; Sun, Guanghao; Chen, Zhe Sage; Zhang, Qiaosheng; Wang, Jing
• Is Part Of: Progress in neurobiology. Volume 201(2021)
• Publication Date: 2021-06
• Subjects: PFC prefrontal cortex -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- PL-PFC prelimbic region of the prefrontal cortex -- SNI spared nerve injury -- CNS central nervous system -- NAc nucleus accumbens -- PAG periaqueductal gray -- NYUSOM New York University School of Medicine -- IACUC Institutional Animal Care and Use Committee -- AAV adeno-associated virus -- DMSO dimethyl sulfoxide -- AP anteroposterior -- ML mediolateral -- DV dorsoventral -- PP pin prick -- vF von Frey -- SVM support vector machine -- PFA paraformaldehyde -- PSTH peri-stimulation time histogram -- NpHR halorhodopsin -- ACC anterior cingulate cortex -- NBQX 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2, 3-dione; Neuropathic pain -- PFC -- Prelimbic -- Prefrontal cortex -- AMPAkine -- CX546; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2021.102001
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Chronic neuropathic pain suppresses the endogenous anti-nociceptive response of neurons in the PL-PFC. AMPAkines can recover normal nociceptive response in PFC neurons. Direct administration of CX546 into the PL-PFC inhibits chronic neuropathic pain. Optogenetic and pharmacological inhibition of AMPA receptors in the PL-PFC abolishes the analgesic effects of AMPAkines. Abstract: Chronic pain affects one in four adults, and effective non-sedating and non-addictive treatments are urgently needed. Chronic pain causes maladaptive changes in the cerebral cortex, which can lead to impaired endogenous nociceptive processing. However, it is not yet clear if drugs that restore endogenous cortical regulation could provide an effective therapeutic strategy for chronic pain. Here, we studied the nociceptive response of neurons in the prelimbic region of the prefrontal cortex (PL-PFC) in freely behaving rats using a spared nerve injury (SNI) model of chronic pain, and the impact of AMPAkines, a class of drugs that increase central glutamate signaling, on such response. We found that neurons in the PL-PFC increase their firing rates in response to noxious stimulations; chronic neuropathic pain, however, suppressed this important cortical pain response. Meanwhile, CX546, a well-known AMPAkine, restored the anti-nociceptive response of PL-PFC neurons in the chronic pain condition. In addition, both systemic administration and direct delivery of CX546 into the PL-PFC inhibited symptoms of chronic pain, whereas optogenetic inactivation of the PFC neurons or administration of AMPA receptor antagonists in the PL-PFC blocked the anti-nociceptive effects of CX546. These results indicate that restoration of the endogenous anti-nociceptive functions in the PL-PFC by pharmacological agents such as AMPAkines constitutes a successful strategy to treat chronic neuropathic pain.