A sensory-motor-sensory circuit underlies antinociception ignited by primary motor cortex in mice.

Sensory-motor integration is crucial in the processing of chronic pain. The primary motor cortex (M1) is emerging as a promising target for chronic pain treatment. However, it remains elusive how nociceptive sensory inputs influence M1 activity and how rectifying M1 defects, in turn, regulates pain processing at cellular and network levels. We show that injury/inflammation leads to hypoactivity of M1Glu pyramidal neurons by excitation-inhibition imbalance between the primary somatosensory cortex (S1) and the M1. The impaired M1 output further weakens inputs to excitatory parvalbumin neurons of the lateral hypothalamus (LHPV) and impairs the descending inhibitory system, hence exacerbating spinal nociceptive sensitivity. When rectifying M1 defects with repetitive transcranial magnetic stimulation (rTMS), the imbalance of the S1-M1 microcircuitry can be effectively reversed, which aids in restoring the ability of the M1 to trigger the descending inhibitory system, thereby alleviating nociceptive hypersensitivity. Thus, a sensory-motor-sensory loop is identified for pain-related interactions between the sensory and motor systems and can be potentially exploited for treating chronic pain.