Differential Neuronal Activation of Nociceptive Pathways in Neuropathic Pain After Spinal Cord Injury

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Neuropathic pain, a prevalent complication following spinal cord injury (SCI), severely impairs the life quality of patients. No ideal treatment exists due to incomplete knowledge on underlying neural processes. To explore the SCI-induced effect on nociceptive circuits, the protein expression of c-Fos was analyzed as an indicator of neuronal activation in a rat contusion model exhibiting below-level pain. Additional stimuli were delivered to mimic the different peripheral sensory inputs in daily life. Following noxious rather than innocuous or no stimulation, a greater number of spinal dorsal horn (DH) neurons were activated after SCI, mainly in the deep DH. SCI facilitated the activation of excitatory but not inhibitory DH neurons. Moreover, excitatory interneurons expressing protein kinase C gamma (PKCγ) in laminae II–III, which are known to play a role in mechanical allodynia after peripheral nerve injury, responded in larger amounts to both innocuous and noxious stimulation following SCI. Accordingly, more spinal projection neurons in lamina I were activated. Within supraspinal nuclei processing pain, differentially enhanced activation in response to noxious stimulation was detected after SCI, with a significant increase in the locus coeruleus and medial thalamus, a slight increase in the periaqueductal gray and dorsal raphe, and no change in the lateral parabrachial nucleus or primary sensory cortex. These findings indicated differential hyperexcitability along the sensory neuroaxis following SCI, with a particular emphasis on the involvement of specific neuron subtypes, such as spinal PKCγ interneurons and locus coeruleus noradrenergic neurons, which may serve as crucial targets for potential therapies.Graphical Rats exhibiting pain like behavior after spinal cord injury showed increased engagement of specific subtypes of spinal excitatory neurons and enhanced activity in supraspinal nuclei. The figure was created using Figdraw 2.0.