Layer-specific pain relief pathways originating from primary motor cortex

The primary motor cortex (M1) is involved in the control of voluntary movements and is extensively mapped in this capacity. Although the M1 is implicated in modulation of pain, the underlying circuitry and causal underpinnings remain elusive. We unexpectedly unraveled a connection from the M1 to the nucleus accumbens reward circuitry through a M1 layer 6-mediodorsal thalamus pathway, which specifically suppresses negative emotional valence and associated coping behaviors in neuropathic pain. By contrast, layer 5 M1 neurons connect with specific cell populations in zona incerta and periaqueductal gray to suppress sensory hypersensitivity without altering pain affect. Thus, the M1 employs distinct, layer-specific pathways to attune sensory and aversive-emotional components of neuropathic pain, which can be exploited for purposes of pain relief. Description Motor cortex modulates pain perception The main function of the primary motor cortex is to initiate movements and to control voluntary motor behavior. Unexpectedly, the perception of pain also evokes motor cortical responses. However, very little is known about the neurobiological basis for this unconventional role of the motor cortex in modulating pain perception. Gan et al. investigated the neuronal pathways and mechanisms involved in the modulation of sensory and affective components of pain after selective stimulation of the mouse motor cortex. Extensive viral tracing and mouse genetics, combined with chemo- and optogenetic approaches, revealed that although activation of layer 5 neurons reversed allodynia in neuropathic mice, the specific activation of neurons in layer 6 of the primary motor cortex reduced the aversive component of pain. —PRS The circuit specificity of motor cortex neurons in suppressing sensory versus emotional-aversive dimensions of neuropathic pain is shown.