# Modulation of the prefrontal cortical network in neuropathic pain > **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $572,867 ## Abstract Summary The neurobiological basis of chronic pain is poorly understood and no scientifically validated therapies exist for such condition. Yet, chronic pain has an enormous socio-economic price, estimated to reach US$ 635 billion annually in healthcare costs and lost productivity. To make things worse, the majority of opioid abusers begin their addiction with prescription medications for chronic pain. Consequently, the search for new, non-opioid, pharmacological treatments for chronic pain constitutes one of the most urgent unmet medical needs. Beside its sensory symptoms, chronic pain is characterized by impairment of cognitive tasks such as attention and working memory, which depend on cholinergic modulation of medial prefrontal cortex (mPFC). Accordingly, mPFC deactivation was found to have a causal role for the neuropathic pain phenotype, and our preliminary data show that excitatory cholinergic modulation is severely impaired in mPFC pyramidal neurons of male rats. Yet, the precise mechanisms mediating the mPFC deactivation, how this deactivation influences pain perception and cognitive performance, and whether it similarly impacts males and females remain largely unknown. Our preliminary data show that a current mediated by the M1 receptor is critical for mPFC pyramidal cell excitability and is strongly reduced in neuropathic pain; our overarching hypothesis is that impaired cholinergic modulation of the mPFC represents a major mechanism of mPFC deactivation in neuropathic pain and mediates several of the sensory, cognitive and emotional symptoms. In particular, we hypothesize that in neuropathic pain: (1) cholinergic modulation of mPFC activity is disrupted and this critically contributes to the global mPFC deactivation in both sexes; (2) blockade of M1-mediated mPFC excitation is sufficient to mimic, at least in part, the neuropathic pain phenotype; (3) pharmacological manipulations that counterbalance the cholinergic disruption and restore mPFC output ameliorate cognitive and sensory symptoms of neuropathic pain. To test these hypotheses we will take advantage of the Spared-Nerve-Injury (SNI) model of neuropathic pain to pursue two specific aims. In Aim 1 we will combine optogenetic activation of individual cholinergic inputs, patch clamp recordings in acute slices and PCR analysis, to test the hypothesis that impaired cholinergic modulation contributes to the global mPFC deactivation, to determine the identity of the receptors involved, and to dissect the relative impact of cholinergic inputs from local interneurons and from the basal forebrain on mPFC activity in both females and males. In Aim 2 we will test the behavioral effects of impaired mPFC cholinergic modulation. We will use in-vivo chemogenetic and pharmacological modulation of the mPFC to reverse the SNI phenotype. We obtained preliminary data showing that enhancing mPFC excitability through pharmacological antagonism of the 5HT1a receptor has potent analgesic effects. Conver... ## Key facts - **NIH application ID:** 10126068 - **Project number:** 5R01NS112292-02 - **Recipient organization:** NORTHWESTERN UNIVERSITY - **Principal Investigator:** MARCO MARTINA - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $572,867 - **Award type:** 5 - **Project period:** 2020-04-01 → 2025-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10126068 ## Citation > US National Institutes of Health, RePORTER application 10126068, Modulation of the prefrontal cortical network in neuropathic pain (5R01NS112292-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126068. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*