Pain modulates dopamine neurons via a spinal–parabrachial–mesencephalic circuit

Yang, Hong-Chang; Jong, Johannes de; Cerniauskas, Ignas; Peck, James R.; Lim, Byung Kook; Gong, Hui; Lammel, Stephan

doi:10.1038/s41593-021-00903-8

Cited by 65 publications

(80 citation statements)

References 73 publications

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“…Similarly, we previously reported that SNr neurons innervated by the STN partially mediate hyperalgesia in parkinsonian mice 20 . Contrary to these studies 20,61 , but similar to another study 37 , we observed that stimulation of SNr neurons led to analgesic effects. These results suggest that SNr neurons are diverse in terms of their involvement in pain perception, depending on which neural pathway they belong to.…”

Section: Discussionsupporting

confidence: 59%

“…Previous studies have reported that SNr neurons respond diversely to various pain modalities and that using pharmacological or electrical neuromodulation to inhibit the STN or stimulate the SNr produces analgesic effects 60 . A recent study demonstrated that SNr neurons receiving direct nociceptive signals from excitatory neurons in the LPB are essential for pain perception 61 . Similarly, we previously reported that SNr neurons innervated by the STN partially mediate hyperalgesia in parkinsonian mice 20 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…In agreement with previous studies, mechanical stimulation of the cast-immobilized hind limb induced a decrease in dopamine levels in the NAcSh. Recently, the role of lateral parabrachial neurons in the pons, which consist of the ascending nociceptive pathway and receive input from the spinal cord, in the inhibition of VTA dopamine neurons and dopamine release in the NAcSh in response to noxious stimuli has been reported ( Yang et al, 2021 ). It is possible that lateral parabrachial neurons are involved in the inhibition of the VTA-NAc dopamine pathway under conditions of mechanical hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of dopamine neurotransmission in the nucleus accumbens in immobilization-induced hypersensitivity

et al. 2022

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Cast immobilization causes sensory hypersensitivity, which is also a symptom of neuropathic pain and chronic pain. However, the mechanisms underlying immobilization-induced hypersensitivity remain unclear. The present study investigated the role of dopamine neurotransmission in the nucleus accumbens shell (NAcSh) of rats with cast immobilization-induced mechanical hypersensitivity using in vivo microdialysis. Cast immobilization of the hind limb decreased the paw withdrawal threshold (PWT). Mechanical stimulation of the cast-immobilized hind limb induced a decrease in dopamine in the NAcSh, and this decrease was associated with the upregulation of presynaptic D2-like receptors. A D2-like receptor antagonist infused into the NAcSh reversed the decrease in PWT in rats with cast immobilization, whereas a D2-like receptor agonist infused into the NAcSh induced a decrease in PWT in control rats. In addition, the expression of the D2 receptor (Drd2) mRNA in the NAcSh was increased by cast immobilization. Importantly, systemic administration of the D2-like receptor antagonist reversed the decrease in PWT in rats with cast immobilization. As dopamine levels regulated by presynaptic D2-like receptors did not correlate with the PWT, it is presumed that the D2-like receptor antagonist or agonist acts on postsynaptic D2-like receptors. These results suggest that immobilization-induced mechanical hypersensitivity is attributable to the upregulation of postsynaptic D2-like receptors in the NAc. Blockade of D2-like receptors in the NAcSh is a potential therapeutic strategy for immobilization-induced hypersensitivity.

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“…The autonomic and arousal components of the itch pathway can be potentially mediated by the bi-directional communication between the PBN and the insular cortex (Grady et al, 2020 ). Through its direct projections to the VTA, PBN can modulate scratch-induced reward and itch-induced aversion (Coizet et al, 2010 ; Yuan et al, 2018 ; Su et al, 2019 ; Yang et al, 2021 ). The activation of PBN neurons corresponds to bouts of scratching, implying that the motor output of scratching can be driven or mediated by PBN neurons.…”

Section: Pbn As a Gateway To Understanding Itch Processing In The Brainmentioning

confidence: 99%

The Spino-Parabrachial Pathway for Itch

Shah

Barik

2022

Front. Neural Circuits

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Itch-induced scratching is an evolutionarily conserved behavioral response that protects organisms from potential parasites/irritants in their immediate vicinity. How the exposure to a pruritogen is translated to the perception of itch and how that perception drives scratching directed towards the site of exposure remains poorly understood. In this review, we focus on the recent findings that shed light on the neural pathways in the brain that underlie itch-induced scratching. We compare the molecularly defined itch pathways with the known pain circuits as they have anatomical and functional overlap. We review the roles played by the neurons in the spinoparabrachial pathway—comprising of the neurons in the spinal cord and the parabrachial nucleus (PBN), which acts as a hub for transmitting itch information across the brain. Lastly, we deliberate on scratching as a behavioral measure of the intensity of itch and its implication in unraveling the underlying supraspinal mechanisms. In summary, we provide a resource on the recent advances and discuss a path forward on our understanding of the neural circuits for itch.

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Pain modulates dopamine neurons via a spinal–parabrachial–mesencephalic circuit

Cited by 65 publications

References 73 publications

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

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

Dysregulation of dopamine neurotransmission in the nucleus accumbens in immobilization-induced hypersensitivity

The Spino-Parabrachial Pathway for Itch

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