Identifying the pathways required for coping behaviours associated with sustained pain

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 Tac1Cre and Lbx1Flpo, called Tac1Lbx1, drive pain-associated coping responses. Tac1Lbx1 neurons are required to produce persistent licking and conditioned place aversion evoked by stimuli that produce sustained pain in humans, including skin pinching and burn injury, but dispensable for all tested reflexive-defensive reactions. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1-3. 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 also 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.