Converging inputs compete at the lateral parabrachial nuclei to dictate the affective-motivational responses to cold pain

Abstract

The neural mechanisms of the affective-motivational symptoms of chronic pain are poorly understood. In chronic pain, our innate coping mechanisms fail to provide relief leading to heightened manifestation of these behaviors. In laboratory animals, such as mice and rats, licking the affected areas is a behavioral coping mechanism and it is sensitized in chronic pain. Hence, we have focused on delineating the brain circuits mediating licking in mice with chemotherapy-induced peripheral neuropathy (CIPN). Mice with CIPN develop intense cold hypersensitivity and lick their paws upon contact with cold stimuli. We studied how the lateral parabrachial nucleus (LPBN) neurons facilitate licking behavior when mice are exposed to noxious thermal stimuli. Taking advantage of transsynaptic viral, optogenetic, and chemogenetic strategies, we observed that the LPBN neurons become hypersensitive to cold in mice with CIPN and facilitate licks. Further, we found that the expression of licks depends on competing excitatory and inhibitory inputs from the spinal cord and lateral hypothalamus (LHA), respectively. We anatomically traced the post-synaptic targets of the spinal cord and LHA in the LPBN and found that they synapse onto overlapping populations. Activation of this LPBN population was sufficient to promote licking due to cold allodynia. In sum, our data indicate that the nociceptive inputs from the spinal cord and information on brain states from the hypothalamus impinge on overlapping LPBN populations to modulate their activity and, in turn, regulate the elevated affective-motivational responses in CIPN.