Dissecting motor cortex modulation of nociception during chronic pain

PROJECT SUMMARY (See instructions): The heavy burden of chronic pain and the opioid epidemic has prompted an urgent, worldwide search for alternative, non-addictive methods of analgesia. One promising alternative is non-invasive electrical or magnetic stimulation of the motor cortex (MC). While MC stimulation (MCS) has repeatedly been found to reduce chronic pain in human subjects and decrease nociceptive behaviors in rodent models, major questions remain about its mechanism of action and how to improve MCS efficacy. Evidence suggests that MCS antinociceptive efficacy increases when the stimulation targets the region in motor cortex that corresponds to the body part from which pain originates (somatotopically matching MCS) and that MCS analgesia requires endogenous opioid activity. Here, I propose to use a rodent model of trigeminal neuropathic pain to elucidate the underlying mechanism of MCS antinociception and to define key MCS features that pain clinicians can use to improve MCS efficacy. To characterize the MCS mechanism, I will 1) quantify the efficacy of somatotopically matched MCS (ssMCS), 2) determine what opioid receptor subtypes are required for MCS antinociception, and 3) identify how endogenous opioids modulate an opioid-sensitive MC descending circuit to the descending pain control pathways during ssMCS. To determine the efficacy of MCS between matched and off-target MCS in two different nerve constriction models, I will use classic behavioral paradigms along with cutting-edge machine learning algorithms to analyze mouse behavioral responses. I will then use complementary pharmacological and genetic mouse lines to determine how ssMCS is impacted by distinct opioid receptor types. To interrogate the combined impact of MC somatotopy and endogenous opioid signaling in MCS analgesia, I will focus on the descending projection from MC to descending pain control regions, rostral ventromedial medulla (RVM) and spinal trigeminal nucleus caudalis (SpVC). I will determine the positions of opioid receptor types and endogenous opioid peptides along this circuit and then assess the impact of ssMCS with and without opioid signaling on neural activity in MC, RVM, and SpVC using cutting-edge high-density electrophysiological techniques. Altogether, this project will determine how MCS modulates nociception through endogenous opioid signaling in somatotopically aligned circuits. The results will provide the first report of neural activity during and after ssMCS at both the target and in an MC output.