Distinct basolateral amygdala excitatory inputs mediate the somatosensory and aversive-affective components of pain

Pain is a multidimensional perception that includes unpleasant somatosensory and affective experiences; however, the underlying neural circuits that mediate different components of pain remain elusive. Although hyperactivity of basolateral amygdala glutamatergic (BLA(Glu)) neurons is required for the somatosensory and emotional processing of pain, the precise excitatory inputs to BLA(Glu) neurons and their roles in mediating different aspects of pain are unclear. Here, we identified two discrete glutamatergic neuronal circuits in male mice: a projection from the insular cortex glutamatergic (IC(Glu)) to BLA(Glu) neurons, which modulates both the somatosensory and affective components of pain, and a projection from the mediodorsal thalamic nucleus (MD(Glu)) to BLA(Glu) neurons, which modulates only the aversive-affective component of pain. Using whole-cell recording and fiber photometry, we found that neurons within the IC→BLA and MD→BLA pathways were activated in mice upon inflammatory pain induced by injection of complete Freund’s adjuvant (CFA) into their paws. Optical inhibition of the IC(Glu)→BLA pathway increased the nociceptive threshold and induced behavioral place preference in CFA mice. In contrast, optical inhibition of the MD(Glu)→BLA pathway did not affect the nociceptive threshold but still induced place preference in CFA mice. In normal mice, optical activation of the IC(Glu)→BLA pathway decreased the nociceptive threshold and induced place aversion, while optical activation of the MD(Glu)→BLA pathway only evoked aversion. Taken together, our results demonstrate that discrete IC(Glu)→BLA and MD(Glu)→BLA pathways are involved in modulating different components of pain, provide insights into its circuit basis, and better our understanding of pain perception.