Summary The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain 1 – 4 . Projection neurons (PNs) of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery channel through these spinal PNs en route to the brain. However, the organizational logic of the anterolateral pathway remains elusive. Here, we show that two PN populations that express structurally related GPCRs, TACR1 and GPR83, form parallel ascending circuit modules that cooperate to convey tactile, thermal and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons (PBN L ). Axons of Tacr1 - and Gpr83 -expressing spinoparabrachial (SPB) neurons innervate distinct sets of PBN L subnuclei, and strong optogenetic stimulation of their axon terminals induces distinct escape behaviors and autonomic responses. Moreover, Gpr83 -expressing SPB neurons are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Remarkably, the valence associated with activation of Gpr83 -expressing SPB neurons is either positive or negative depending on stimulus intensity. These findings reveal anatomically, physiologically, and functionally distinct SPB tract subdivisions that underlie affective aspects of touch and pain.

The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain1-4. Projection neurons (PNs) of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery channel through these spinal PNs en route to the brain.However, the organizational logic of the anterolateral pathway remains elusive. Here, we show that two PN populations that express structurally related GPCRs, TACR1 and GPR83, form parallel ascending circuit modules that cooperate to convey tactile, thermal and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons (PBNL).Axons of Tacr1-and Gpr83-expressing spinoparabrachial (SPB) neurons innervate distinct sets of PBNL subnuclei, and strong optogenetic stimulation of their axon terminals induces distinct escape behaviors and autonomic responses. Moreover, Gpr83-expressing SPB neurons are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high-and low-threshold primary mechanosensory neurons. Remarkably, the valence associated with activation of Gpr83-expressing SPB neurons is either positive or negative depending on stimulus intensity. These findings reveal anatomically, physiologically, and functionally distinct SPB tract subdivisions that underlie affective aspects of touch and pain.