Parabrachial Complex: A Hub for Pain and Aversion

Chiang, Michael; Bowen, Anna J; Schier, Lindsey A.; Tupone, Domenico; Uddin, Olivia; Heinricher, Mary M.

doi:10.1523/jneurosci.1162-19.2019

Cited by 188 publications

(184 citation statements)

References 92 publications

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“…We did this by infusing gabazine, a GABAA receptor antagonist, into LPB of naïve rats. Consistent with previous reports (Han et al, 2015;Barik et al, 2018;Chiang et al, 2019) this procedure appeared to be aversive to most animals, often resulting in either freezing or escape behaviors. This made it difficult for us to quantify pain-related behaviors in most of these animals.…”

Section: Pharmacological Disinhibition Of Pbsupporting

confidence: 90%

“…We confirmed these findings using a different retrograde tracer, FluoroGold™ (FG). By making discrete iontophoretic injections of FG, we were better able to restrict our injections to those portions of the PB that have been previously implicated in processing and relaying nociceptive information (Cechetto et al, 1985;Roeder et al, 2016;Chiang et al, 2019). Further, while the CTB experiments in the rat were performed in male Sprague-Dawley rats, FG tracing was done in Sprague-Dawley and Wistar rats of both sexes.…”

Section: Retrograde Tracingmentioning

confidence: 99%

“…PB has extensive, often reciprocal connections with brainstem, medulla and forebrain structures, and it plays key roles in functions such as satiety and appetite, sleep and arousal, cardiovascular function, and fluid homeostasis (Hajnal et al, 2009;Martelli et al, 2013;Davern, 2014). Importantly, PB plays a particularly prominent role in pain processing (Gauriau and Bernard, 2002;Roeder et al, 2016Roeder et al, , 2016Uddin et al, 2018;Chiang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Raver

Uddin

et al. 2020

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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 PB neurons from the central nucleus of the amygdala (CeA). 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 afterdischarges-responses that far outlast the stimulus-compared to controls. PB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that-in both rats and mice-PB 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 naïve 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.We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin and corticotropin-releasing hormone expressing neurons in the central nucleus of the amygdala that project to the parabrachial nucleus (PB). We show that this pathway regulates the activity of pain-related neurons in PB, 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.

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Section: Pharmacological Disinhibition Of Pbsupporting

confidence: 90%

Section: Retrograde Tracingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Raver

Uddin

et al. 2020

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“…The parabrachial nucleus (PB) subserves sensory, homeostatic and aversive functions (Palmiter, 2018;Chiang et al, 2019Chiang et al, , 2020, and is a critical hub for nociception (Gauriau and Bernard, 2002;Han et al, 2015). The role of PB in pain processing is highlighted by its reciprocal connections with brain regions associated with both the sensory and affective aspects of pain (Fulwiler and Saper, 1984;Jasmin et al, 1997;Chen et al, 2017) as well as with regions of descending modulatory control of nociception (Roeder et al, 2016;Chen et al, 2017;Chen and Heinricher, 2019).…”

Section: Introductionmentioning

confidence: 99%

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Cramer

Silva-Cardoso

Keller

2020

Preprint

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The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices, we find that baclofen, a GABAB receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of μ-opioid peptide receptors with DAMGO had similar effects, while the κ-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 antagonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABAB mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. Together, these results demonstrate that signaling pathways known to modulate nociception, alter synaptic transmission and neuronal excitability in the lateral parabrachial nucleus and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain.

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“…Dura manipulation in humans during neurosurgery is often painful 10 and dura irritation is considered an initiating factor in migraine 11 . In rodent models, dura irritation models migraine-like symptoms 12,13 The parabrachial complex (PB) is a bilateral midbrain structure that plays important roles in pain processing, as well as many survival-related homeostatic and interoceptive functions [14][15][16][17] (reviewed by 18 ). PB's anatomical connections place it in an ideal position to modulate pain.…”

Section: Introductionmentioning

confidence: 99%

Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection

Uddin

Anderson²,

Smith³

et al. 2020

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Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation. Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) is a central region that mediates chronic pain. PB receives diverse sensory information, including a direct input from the trigeminal ganglion. We hypothesized that PB processes inputs from the dura. Using in vivo electrophysiology recordings from single units in anesthetized rats we identified 58 neurons in lateral PB that respond reliably and with short latency to electrical dura stimulation. After injecting tracer into PB, anatomical examination reveals retrogradely labeled cell bodies in the trigeminal ganglion. Neuroanatomical tract-tracing revealed a population of neurons in the trigeminal ganglion that innervate the dura and project directly to PB. These findings indicate that PB is strategically placed to process dura inputs, and suggest that it is directly involved in the pathogenesis of migraine headaches.

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Parabrachial Complex: A Hub for Pain and Aversion

Cited by 188 publications

References 92 publications

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection

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