Nociceptive stimuli activate the hypothalamus-habenula circuit to inhibit the mesolimbic reward system and cocaine seeking-behaviors.

Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here we show that the LH-LHb pathway is necessary for nociceptive modulation of this system using male Sprague-Dawley rats. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail-pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail-pinch increased activity of GABA neurons in ventral tegmental area (VTA), decreased extracellular DA level in the nucleus accumbens ventrolateral shell in intact rats and reduced cocaine-increased DA concentration, which was blocked by disruption of the LH. Furthermore, tail-pinch attenuated cocaine-induced locomotor activity, 22- and 50-kHz ultrasonic vocalizations, and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement. SIGNIFICANCE STATEMENT: The lateral habenula (LHb) and the lateral hypothalamus (LH) have been implicated in processing nociceptive signals and modulating dopamine (DA) release in the mesolimbic DA system. Here we show that the LH-LHb pathway is critical for nociception-induced modulation of mesolimbic DA release and cocaine reinstatement. Nociceptive stimulation alleviates extracellular DA release in the mesolimbic DA system, cocaine-induced psychomotor activities, and reinstatement of cocaine-seeking behaviors through the LH-LHb pathway. These findings provide novel evidence for sensory modulation of mesolimbic DA system and drug addiction.