Cortical Regulation of Nociception of the Trigeminal Nucleus Caudalis

Abstract

Pain perception is strongly influenced by descending pathways from "higher" brain centers that regulate the activity of spinal circuits. In addition to the extensively studied descending system originating from the medulla, the neocortex provides dense anatomical projections that directly target neurons in the spinal cord and the spinal trigeminal nucleus caudalis (SpVc). Evidence exists that these corticotrigeminal pathways may modulate the processing of nociceptive inputs by SpVc, and regulate pain perception. We demonstrate here, with anatomical and optogenetic methods, and using both rats and mice (of both sexes), that corticotrigeminal axons densely innervate SpVc, where they target and directly activate inhibitory and excitatory neurons. Electrophysiological recordings reveal that stimulation of primary somatosensory cortex potently suppresses SpVc responses to noxious stimuli and produces behavioral hypoalgesia. These findings demonstrate that the corticotrigeminal pathway is a potent modulator of nociception and a potential target for interventions to alleviate chronic pain. Many chronic pain conditions are resistant to conventional therapy. Promising new approaches to pain management capitalize on the brain's own mechanisms for controlling pain perception. Here we demonstrate that cortical neurons directly innervate the brainstem to drive feedforward inhibition of nociceptive neurons. This corticotrigeminal pathway suppresses the activity of these neurons and produces analgesia. This corticotrigeminal pathway may constitute a therapeutic target for chronic pain.

Anatomical aspects of corticotrigeminal projections to the medullary dorsal horn

“…The trigeminal complex receives descending projections from various sensory cortical regions, including the somatosensory, primary auditory, and primary visual cortices [40][41][42][43][44][45][46][47][48][49][50][51]. In addition to these sensory cortices, other cortical regions, such as the motor and peduncular cortical neurons, also send their axons to the Sp5C [45,52].…”

“…Projections from the facial region in S1 to the Sp5C principally target the marginal zone (lamina I) and substantia gelatinosa (lamina II) [41,44,45,51] but also target laminae III-V [47,56]. In addition to the rostrocaudal somatotopic organization of the trigeminal complex, there is somatotopy in the Sp5C corresponding to the region in S1 [49]: regions in S1 responding to stimulation of the lingual nerve, mental nerve, infraorbital nerve, and frontal nerve are rostrocaudally arranged in S1, and each S1 region projects to the most medial superficial layer, medial deep layer, middle superficial and deep layer, and lateral deep layer in Sp5C, respectively.…”

“…The physiological function of the projections from the somatosensory cortex to the Sp5C has been explored in cats [5] and rats [51,56,57]. Sessle et al (1981) estimated the effect of electrical stimulation of the somatosensory cortex on nociception by conducting electromyogram recordings in the digastric muscle during tooth pulp or infraorbital nerve stimulation (jaw-opening reflex), combined with extracellular recordings in Sp5C neurons [5].…”

“…Gojyo et al demonstrated that stimulation of S2, but not S1, reduced c-Fos expression in response to formalin injection into the lower lip [56]. Recently, some mechanisms for the suppressive role of the somatosensory cortex in trigeminal nociception have been clarified by optogenetics [51]. Descending glutamatergic projections from S1 to the Sp5C primarily terminate on inhibitory neurons rather than on excitatory neurons.…”

The Impact of Optogenetics on Regenerative Medicine

“…Light-mediated manipulation of G protein subunits of ChR2 and NpHR proteins can activate or inhibit the receptors of injured neurons. The sequencing of the RNA can promote novel research targeting such protein chains able to control the pain with optogenetic tools [46].…”