Identification of pathways required for sustained pain-associated coping behaviors

Abstract

Animals and humans display two types of responses to noxious stimuli. The first includes reflexive-defensive responses to prevent or limit injury. A well-known example is the quick withdrawal of one’s hand touching a hot object. When the first-line response fails to prevent tissue damage (e.g., a finger is burnt), the resulting pain invokes a second-line coping response, such as licking the injured area to soothe suffering. However, the underlying neural circuits driving these two strings of behaviors remain poorly understood. Here we show that in mice, spinal neurons marked by coexpression of Tુ ^Cre and Lbx1 ^Flpo, called Tac1 ^Lbx1, drive pain-related coping responses. Ablation of Tac1 ^Lbx1 neurons led to loss of persistent licking and conditioned aversion evoked by stimuli that produce sustained pain in humans, including skin pinching and burn injury, without affecting all tested reflexive-defensive reactions. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei ^{1– 3} . Consistently, spinal Tac1 lineage neurons are connected to medial thalamic nuclei, via direct projections and indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal levels is applied to primary sensory neurons. For example, in response to noxious mechanical stimuli, Mrgprd ⁺ and TRPV1 ⁺ nociceptors are required to elicit reflexive and coping responses, respectively. Our studies therefore reveal a fundamental subdivision within the cutaneous somatosensory system. The implications for translational success from preclinical pain studies will be discussed.