Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response

Chiang, Michael; Nguyen, Eileen; Canto-Bustos, Martha; Papale, Andrew E.; Oswald, Anne-Marie M.; Ross, Sarah E.

doi:10.1016/j.neuron.2020.03.014

Cited by 156 publications

(170 citation statements)

References 226 publications

(349 reference statements)

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“…We find that KOP agonists preferentially suppress synaptic release at GABAergic synapses and leave glutamatergic signaling relatively intact. This bias towards suppression of inhibition may facilitate propagation of nociceptive signals to higher brain centers such as the amygdala (Chiang et al, 2020). The reported lack of a postsynaptic effect of KOP receptors on PB neuronal excitability (Christie and North, 1988), which we also observed here, further supports a faciliatory role for PB KOPs in nociceptive signaling.…”

Section: Mop and Kop Have Mixed Effects On Pb Excitabilitysupporting

confidence: 82%

“…Similar to MOP agonists, KOP agonists are widely expressed throughout the brain, including PB (Mansour et al, 1994), where they play a critical role in mediating the aversive aspects of nociception (Chiang et al, 2020). The association between KOP signaling and aversive behavioral effects, such as dysphoria and respiratory depression (Pfeiffer et al, 1986;Roth et al, 2002;Wadenberg, 2003;Land et al, 2008;Tejeda et al, 2013), have limited the therapeutic use of exogenous agonists, despite their ability to mediate analgesia with less risk of abuse (Wang et al, 2010).…”

Section: Mop and Kop Have Mixed Effects On Pb Excitabilitymentioning

confidence: 99%

“…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%

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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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Section: Mop and Kop Have Mixed Effects On Pb Excitabilitysupporting

confidence: 82%

Section: Mop and Kop Have Mixed Effects On Pb Excitabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Cramer

Silva-Cardoso

Keller

2020

Preprint

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“…Recent studies have shown that the lateral PBN receives direct nociceptive inputs from projection neurons within the spinal dorsal horn (Barik et al, 2020;Chiang et al, 2020;Choi et al, 2020;Deng et al, 2020). The dorsolateral PBN (PBdl) receives predominantly nociceptive inputs from the spinal cord and then projects to multiple limbic structures, such as the PAG, VMH, and ILN, thereby producing emotional and physiological changes in response to pain signals (Chiang et al, 2020;Deng et al, 2020). Although the PBdl does not directly project to the amygdala, it indirectly sends pain signals to the CeA through the PBel (Deng et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, CGRP PBel neurons are critical for relaying aversive unconditioned stimuli to the CeA during aversive fear learning (Han et al, 2015). It has been shown that these neurons receive direct inputs from dynorphin neurons in the PBdl (Chiang et al, 2020), and a recent study has shown that spinal projection neurons that express GPR83 directly innervate CGRP PBel neurons to relay noxious signals (Choi et al, 2020). Therefore, it is clear that CGRP PBel neurons relay nociceptive information from the PBdl and the spinal cord to the CeA.…”

Section: Discussionmentioning

confidence: 99%

Unified neural pathways that gate affective pain and multisensory innate threat signals to the amygdala

Kang

Liu

et al. 2020

Preprint

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Perception of aversive sensory stimuli such as pain and innate threat cues is essential for animal survival. The amygdala is critical for aversive sensory perception, and it has been suggested that multiple parallel pathways independently relay aversive cues from each sensory modality to the amygdala. However, a convergent pathway that relays multisensory aversive cues to the amygdala has not been identified. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafasicular thalamic nucleus (SPFp) are necessary and sufficient for affective-motivational pain perception by forming a spino-thalamo-amygdaloid pain pathway. In addition, we find that this thalamic CGRP pain pathway, together with well-known parabrachio-amygdaloid CGRP pain pathway, is critical for the perception of multisensory innate threat cues. The discovery of unified pathways that collectively gate aversive sensory stimuli from all sensory modalities may provide critical circuit-based insights for developing therapeutic interventions for affective pain- and innate fear-related disorders.

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Efferent projections of Vglut2, Foxp2, and Pdyn parabrachial neurons in mice

Huang

Grady

Peltekian

et al. 2020

J of Comparative Neurology

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The parabrachial nucleus (PB) is a complex structure located at the junction of the midbrain and hindbrain. Its neurons have diverse genetic profiles and influence a variety of homeostatic functions. While its cytoarchitecture and overall efferent projections are known, we lack comprehensive information on the projection patterns of specific neuronal subtypes in the PB. In this study, we compared the projection patterns of glutamatergic neurons here with a subpopulation expressing the transcription factor Foxp2 and a further subpopulation expressing the neuropeptide Pdyn. To do this, we injected an AAV into the PB region to deliver a Cre-dependent anterograde tracer (synaptophysin-mCherry) in three different strains of Cre-driver mice. We then analyzed 147 neuroanatomical regions for labeled boutons in every brain (n = 11). Overall, glutamatergic neurons in the PB region project to a wide variety of sites in the cerebral cortex, basal forebrain, bed nucleus of the stria terminalis,

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Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response

Cited by 156 publications

References 226 publications

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Unified neural pathways that gate affective pain and multisensory innate threat signals to the amygdala

Efferent projections of Vglut2, Foxp2, and Pdyn parabrachial neurons in mice

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