Opioid- and NMDA-receptor-dependent neural plasticity mediates long-term analgesia from motor cortical stimulation

Exogenous opioids that activate mu-opioid receptors (MORs) in nociceptive circuits mediate transient pain relief lasting minutes to hours but have more limited utility for treating chronic pain. By comparison, electrical or magnetic stimulation of the motor cortex can induce pain relief lasting weeks, for which the underlying mechanisms have remained unclear. Here we report an unconventional role for endogenous opioidergic signaling in the rapid induction of long-lasting analgesia from motor cortical stimulation, which triggers opioid-peptide-dependent neural plasticity in the rostral ventromedial medulla (RVM), a key node in the brain's descending pain control pathways. To dissect the circuit and cellular bases for these effects, we created a miniaturized, millimeter-sized device allowing focal, non-invasive transcranial magnetic stimulation (TMS) of the mouse motor cortex. In mice with chronic neuropathic pain, reflexive and affective pain behaviors diminished for 1-2 weeks after one session of TMS treatment. Chemogenetic and optogenetic manipulations showed that motor cortical layer 5 pyramidal neurons with axonal projections to the RVM mediated TMS-induced pain relief. High-density electrophysiological recordings revealed that TMS treatment shifted the balance of RVM activity between pain-ON and pain-OFF neurons to a state promoting greater suppression of pain. Genetic and neuropharmacological manipulations revealed that NMDA-receptor-dependent signaling and MOR activation by endogenous opioid peptides in the RVM jointly mediate the long-lasting analgesia induced by a transient bout of TMS. Strikingly, enkephalinase inhibition in the RVM during TMS treatment enhanced the amplitude and duration of analgesia, showing that transiently boosting endogenous opioidergic signaling during TMS increases analgesia-conferring plasticity. In accord, re-analyses of data from human subjects with chronic pain support the idea that opioid administration amplifies analgesia from motor cortical TMS. Overall, our results showcase miniaturized TMS devices as versatile tools for basic and translational neuroscience and detail a hybrid, long-range neural network and NMDA- and opioid-receptor-dependent plasticity mechanism for durable pain relief. These findings point the way to mechanistically grounded, synergistic neurostimulation and drug therapies for brain diseases and disorders that jointly target neural circuit and molecular signaling pathways.