Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior.

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain.

Damage to peripheral nerves causes significant remodeling of peripheral innervation and can lead to neuropathic pain. Most nociceptive primary afferents are unmyelinated (C fibers) and subdivided into peptidergic and nonpeptidergic fibers. Previous studies have found nerve injury in the trigeminal system to induce changes in small-diameter primary afferent innervation and cause significant autonomic sprouting into the upper dermis of the lower-lip skin of the rat. In this study, we used the ribosomal toxin, saporin, conjugated to the lectin IB4 to specifically ablate the nonpeptidergic nociceptive C fibers, to see if loss of these fibers was enough to induce autonomic fiber sprouting. IB4-saporin treatment led to specific and permanent ablation of the IB4-positive, P2X(3)-immunoreactive fibers and led to sprouting of parasympathetic fibers into the upper dermis, but not of sympathetic fibers. These changes were associated with significant increase in glial-derived nerve growth factor levels in the lower-lip skin. While IB4-saporin treatment had no effect on evoked mechanical thresholds when von Frey hairs were applied to the lower-lip skin, ablation of nonpeptidergic fibers in a chronic constriction injury model caused significant sympathetic and parasympathetic fiber sprouting, and led to an exacerbated pain response. This was an unexpected finding, as it has been suggested that nonpeptidergic fibers play a major role in mechanical pain, and suggests that these fibers play a complex role in the development of neuropathic pain.