A new study in mice, carried out by researchers at Heidelberg University Medical Faculty Heidelberg, has helped illuminate how the brain’s primary motor cortex (a region known as M1) helps to suppress dimensions of neuropathic pain.

M1 is a brain region most commonly associated with the control of motor function, but the newly reported results suggest a direct link between this brain region and pain control. The researchers suggested that their findings could inform new neurostimulation therapies for chronic pain management. Reporting on their study in Science Layer-specific pain relief pathways originating from primary motor cortex”, first author Zheng Gan, PhD, corresponding author Rohini Kuner, PhD, and colleagues concluded, “These results uncover a notable functional dichotomy of circuit connectivity of layer 5 and layer 6 pyramidal neurons of the hindlimb M1 in regulating two distinct components of pain.”

Area M1 has been extensively studied with respect to neuronal circuitry that initiates bodily movements. Unexpectedly, this brain region is known to undergo neural change when humans perceive pain; the interactions between pain and motor functions have been used in exercise therapies for pain management. “TheM1 undergoes plasticity in chronic pain and interactions between pain and motor functions are exploited in exercise therapies,” the team noted. Despite this, not much is understood about the neurobiological basis for the role of M1 in modulating pain perception. “… very little is known about the neurobiological basis for this putative, unconventional role for the M1 in modulating pain perception,” they continued.

To better understand this link, Gan and colleagues used a suite of approaches, including viral mapping, in vivo imaging, electrophysiology, and layer- and cell type-specific optogenetic and chemogenetic manipulations to investigate the neuronal circuits and mechanisms involved in the modulation of sensory and emotional components of neuropathic pain in mice.

The researchers found that distinct layer-specific neuronal circuits in M1 alter both the sensory functions and emotional states associated with chronic pain. According to the findings, activation of a pathway connecting layer 5 M1 neurons to specific populations of cells in the brain’s zona incerta and periaqueductal grey suppressed sensory hypersensitivity to pain in the mice.

In addition, activation of another circuit, this one connecting layer 6 M1 neurons to the nucleus accumbens, reduced the negative emotional and behavioral components of neuropathic pain. “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,” the scientists stated. The combined findings, they suggested, will help provide insights for developing and improving neurostimulation therapies. “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 … These insights, coupled with our observation that chronically established neuropathic pain can be reversed by activation of layer 5/layer 6-dependent pathways, will help provide insights for developing and improving neurostimulation therapies for optimal pain control.”


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