Motor Cortex-Periaqueductal Gray-Spinal Cord Neuronal Circuitry May Involve in Modulation of Nociception: A Virally Mediated Transsynaptic Tracing Study in Spinally Transected Transgenic Mouse Model

Abstract

Several studies have shown that motor cortex stimulation provided pain relief by motor cortex plasticity and activating descending inhibitory pain control systems. Recent evidence indicated that the melanocortin-4 receptor (MC4R) in the periaqueductal gray played an important role in neuropathic pain. This study was designed to assess whether MC4R signaling existed in motor cortex- periaqueductal gray- spinal cord neuronal circuitry modulated the activity of sympathetic pathway by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV)-614 was injected into the left gastrocnemius muscle in adult male MC4R-green fluorescent protein (GFP) transgenic mice (n = 15). After a survival time of 4–6 days, the mice (n = 5) were randomly assigned to humanely sacrifice, and spinal cords and brains were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the left gastrocnemius muscle were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML, periaqueductal gray and motor cortex. Our findings support the hypothesis that MC4R signaling in motor cortex-periaqueductal gray-spinal cord neural pathway may participate in the modulation of the melanocortin-sympathetic signaling and contribute to the descending modulation of nociceptive transmission, suggesting that MC4R signaling in motor cortex- periaqueductal gray-spinal cord neural pathway may modulate the activity of sympathetic outflow sensitive to nociceptive signals.

Hypothesis: CeM–RVLM circuits may be implicated in sudden unexpected death in epilepsy by melanocortinergic–sympathetic signaling

“…The understanding of neuroanatomical sympathetic circuitry and neuronal connections in the CeM and RVLM is important in studying the possible mechanism of CeM-RVLM circuits. We had characterized the projection from the kidney to the CeM and RVLM in the adult transgenic mouse line expressing green fluorescent protein (GFP) under the control of the MC4R promoter by using retrograde transsynaptic tracing techniques of pseudorabies virus (PRV)-614 [8,[23][24][25][26][27][28][29][30]. We found that injection of PRV-614 into the kidney resulted in retrograde infection of neurons in the RVLM and CeM through the sympathetic pathway ( Fig.…”

Hypothesis: The central medial amygdala may be implicated in sudden unexpected death in epilepsy by melanocortinergic–sympathetic signaling

“…Melanocortin-4 receptor (MC4R) signaling plays a pivotal role in the central regulation of energy homeostasis via regulation of the sympathetic and the parasympathetic nervous system [16][17][18][19][20][21][22][23][24][25][26][27]. We had characterized projections from the kidney to the amygdala in adult male MC4R-green fluorescent protein (GFP) transgenic mice by using PRV-614.…”

Effects of melanocortin‐4 receptor (MC4R) antagonist on neuropathic pain hypersensitivity in rats – A systematic review and meta‐analysis

“…The melanocortin system has been implicated in pain and nociception [2–6]. Melanocortins are natural peptides derived from the precursor molecule pro‐opiomelanocortin (POMC), which is present in the nervous system.…”