A nigro–subthalamo–parabrachial pathway modulates pain-like behaviors

Abstract

The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNrGABA) and glutamatergic neurons in the STN (STNGlu) and the lateral parabrachial nucleus (LPBGlu), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNrGABA neurons and strengthening of the STN–LPB glutamatergic projection. Reversing the dysfunction in the SNrGABA-STNGlu-LPBGlu pathway attenuated activity of LPBGlu neurons and mitigated pain-like behaviors. Therefore, the SNrGABA-STNGlu-LPBGlu pathway regulates pathological pain and is a potential target for pain management.

Plasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice

“…For optogenetic manipulations 65 , 68 , 473-nm and 598-nm laser generators (Newdoon, Hangzhou, China) were used to generate light to activate ChR2 and NpHR respectively. For optogenetic stimulation of ChR2-transfected neurons or their terminals, blue light (473 nm, 20 Hz, 4 mW) was delivered to the optical fiber implanted in the VP or BLA through a patch cable.…”

“…Neuropathic pain mouse model Spared nerve injury (SNI) was performed according to previous reports 7 , 65 . Mice were anesthetized with an intraperitoneal injection of sodium pentobarbital (40 mg/kg), the fur in the operation area from the knee to the hip was shaved, and the skin was sterilized with 75% alcohol.…”

“…The von Frey filaments ranged in force from 0.008 g to 4 g were used to measure mechanical threshold with an up-down method 7 , 65 , 72 . In brief, the first fiber (0.4 g) was applied to the hind paw until the fiber bent, and then held in place for 2 s. If this did not elicit a withdrawal response, the next higher force fiber was applied.…”

“…In this test, mice with transfection of either eYFP or NpHR in VP ChAT neurons and with implantation of optical fibers in the VP were subjected to sham or SNI surgery. Four weeks after surgery, the conditioned place preference (CPP) was performed on these mice according to a previous study 65 with some modifications (Supplementary Fig. S 6 ).…”

“…Male mice were anesthetized with an intraperitoneal injection of sodium pentobarbital (40 mg/kg) and stabilized in a stereotaxic apparatus (RWD Life Science Co., Shenzhen, China) with a heating pad. The surgery was performed as described previously 7,33,64,65 . After the mice were deeply anesthetized, confirmed by the loss of response to tail pinch, the fur on the head was shaved and the skin was thoroughly sterilized with 75% ethanol.…”