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. Conversely, we will also investigate whether blockade of M1-mediated mPFC excitation in naive animals is sufficient to mimic the SNI phenotype. Our work will thus identify new potential targets for non-opioid neuropathic pain treatment.

Public Health Relevance

Chronic pain has estimated costs in the US of $635 billion annually , yet no scientifically validated therapy exists for such condition; as a consequence many patients receive long-term treatments with prescription opioids and risk becoming addicted. Recent data show that functional deactivation of the medial prefrontal cortex represents a critical step causing the pain phenotype, but the underlying cellular mechanisms remain largely unclear. We will take advantage of electrophysiological, chemo- and opto-genetic, behavioral, and molecular techniques to test the overarching hypothesis that impaired cholinergic modulation of the prefrontal cortex causes several emotional, cognitive and sensory symptoms of neuropathic pain and that pharmacological normalization of the cholinergic signaling importantly ameliorates the neuropathic pain phenotype.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS112292-01A1
Application #
9980663
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Mohapatra, Durga Prasanna
Project Start
2020-04-01
Project End
2025-03-30
Budget Start
2020-04-01
Budget End
2021-03-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611