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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 (SNr^GABA) and glutamatergic neurons in the STN (STN^Glu) and the lateral parabrachial nucleus (LPB^Glu), 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 SNr^GABA neurons and strengthening of the STN-LPB glutamatergic projection. Reversing the dysfunction in the SNr^GABA-STN^Glu-LPB^Glu pathway attenuated activity of LPB^Glu neurons and mitigated pain-like behaviors. Therefore, the SNr^GABA-STN^Glu-LPB^Glu pathway regulates pathological pain and is a potential target for pain management.

SUBMITTER: Jia T

PROVIDER: S-EPMC9755217 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Jia Tao T Wang Ying-Di YD Chen Jing J Zhang Xue X Cao Jun-Li JL Xiao Cheng C Zhou Chunyi C

Nature communications 20221215 1

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 ST ...[more]

PMID: 36522327

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Project description:The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to lateral parabrachial (LPB) neurons from the CeA in animals of either sex. Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges, responses that far outlast the stimulus, compared with controls. LPB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that, in both rats and mice, LPB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin, and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.SIGNIFICANCE STATEMENT We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin, and corticotropin-releasing hormone-expressing neurons in the CeA that project to the parabrachial nucleus. We show that this pathway regulates the activity of pain-related neurons in parabrachial nucleus, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

Dataset Information

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

Publications

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

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