Possible mechanism of antinociception induced by motor cortex stimulation: a virally mediated transsynaptic tracing study in spinally transected transgenic mouse model

Previous theories considered that the main cause of motor cortex stimulation (MCS)-induced antinociception was due to opioid participation in periaqueductal gray (PAG). However, recent evidence indicated that melanocortinergic signaling in PAG plays an important role in neuropathic pain. A number of studies verified that the neurotropic pseudorabies virus (PRV) provided a highly specific method of mapping the motor and sympathetic pathways innervating a variety of targets. The goal of the present study was to elucidate whether the sympathetic neuronal circuitry existed among MC, PAG and spinal cord by PRV-614 injection to the left gastrocnemius muscle in MC4R-GFP transgenic mouse. To prevent PRV-614 from being transmitted to MC, PAG and spinal cord via motor circuitry, a spinal transection was performed just below the L2 level, which is caudal to the majority of sympathetic preganglionic neurons innervating the muscle, but rostral to the gastrocnemius motoneurons. We found that injections of PRV-614 into the gastrocnemius muscle resulted in retrograde infection of neurons in the ipsilateral intermediolateral cell column (IML) of spinal cord, PAG and MC. In addition, PRV-614/MC4R-GFP dual labeled neurons were detected in the IML of spinal cord, PAG and MC. Based on all these findings, we speculate that MC may primarily involve in sympathetic regulation of PAG and spinal cord. In conclusion, our data indicate that the melanocortinergic projection from the MC to the PAG and spinal cord is an integral component of the central command pathway that regulates sympathetic function, suggesting that stimulation of the MC may influence sympathetic function in PAG and spinal cord by melanocortinergic pathway. This work was supported by grants from National Natural Science Foundation of Hubei Province (No. 2013CFB121 to H.X.), Special Fund of Fundamental Scientific Research Business Expense for Higher School of Central Government (2012 TS060 to H.X). Previous theories considered that the main cause of motor cortex stimulation (MCS)-induced antinociception was due to opioid participation in periaqueductal gray (PAG). However, recent evidence indicated that melanocortinergic signaling in PAG plays an important role in neuropathic pain. A number of studies verified that the neurotropic pseudorabies virus (PRV) provided a highly specific method of mapping the motor and sympathetic pathways innervating a variety of targets. The goal of the present study was to elucidate whether the sympathetic neuronal circuitry existed among MC, PAG and spinal cord by PRV-614 injection to the left gastrocnemius muscle in MC4R-GFP transgenic mouse. To prevent PRV-614 from being transmitted to MC, PAG and spinal cord via motor circuitry, a spinal transection was performed just below the L2 level, which is caudal to the majority of sympathetic preganglionic neurons innervating the muscle, but rostral to the gastrocnemius motoneurons. We found that injections of PRV-614 into the gastrocnemius muscle resulted in retrograde infection of neurons in the ipsilateral intermediolateral cell column (IML) of spinal cord, PAG and MC. In addition, PRV-614/MC4R-GFP dual labeled neurons were detected in the IML of spinal cord, PAG and MC. Based on all these findings, we speculate that MC may primarily involve in sympathetic regulation of PAG and spinal cord. In conclusion, our data indicate that the melanocortinergic projection from the MC to the PAG and spinal cord is an integral component of the central command pathway that regulates sympathetic function, suggesting that stimulation of the MC may influence sympathetic function in PAG and spinal cord by melanocortinergic pathway. This work was supported by grants from National Natural Science Foundation of Hubei Province (No. 2013CFB121 to H.X.), Special Fund of Fundamental Scientific Research Business Expense for Higher School of Central Government (2012 TS060 to H.X).