The parabrachial to central amygdala circuit is a key mediator of injury-induced pain sensitization

Abstract

The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic transmission in the parabrachial nucleus (PbN) to central amygdala (CeA) pathway has been reported in rodent models of persistent pain. At the behavioral level, the PbN→CeA pathway has been proposed to serve as a general alarm system to potential threats that modulates pain-related escape behaviors, affective-motivational (but not somatosensory) responses to painful stimuli, aversion, and threat memory. Increased sensitivity to previously innocuous somatosensory stimulation is a hallmark of chronic pain. Whether the PbN→CeA circuit contributes to heightened sensitivity to somatosensory stimulation following an injury, however, remains unknown. Here, we demonstrate that activation of CeA-projecting PbN neurons contributes to injury-induced behavioral hypersensitivity but not baseline nociception in male and female mice. Using optogenetic assisted circuit mapping, we confirmed a functional excitatory projection from PbN→CeA that is independent of the genetic or firing identity of CeA cells. We then showed that peripheral noxious stimulation increases the expression of the neuronal activity marker c-Fos in CeA-projecting PbN neurons and chemogenetic inactivation of these cells reduces behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we show that chemogenetic activation of CeA-projecting PbN neurons is sufficient to induce bilateral hypersensitivity without injury. Together, our results demonstrate that the PbN→CeA pathway is a key modulator pain-related behaviors that can amplify responses to somatosensory stimulation in pathological states without affecting nociception under normal physiological conditions.

Brain nuclei and neural circuits in neuropathic pain and brain modulation mechanisms of acupuncture: a review on animal-based experimental research

“…Most GABAergic input to the LPB is derived from and innervated by CeA ( Torres-Rodriguez et al, 2023 ). In the NP model, enhanced activity of LPB neurons is associated with a decrease in inhibitory GABAergic input, and activation of this pathway inhibits pain behavior ( Raver et al, 2020 ).…”

Divergent changes in PBN excitability in a mouse model of neuropathic pain

“…von Frey testing Sciatic cuff group: In a subset of animals von Frey testing was performed 7 days after surgery as previously described (Torres-Rodriguez et al, 2023). Male mice were habituated in the von Frey apparatus in a red-lit room for 2 hr prior to testing.…”

“…PBN circuitry: outputs and intra-PBN signaling Specific PBN outputs have been linked to particular aspects of aversion and nocifensive responses. These include projections from PBN to the CeA (Allen et al, 2023;Chen et al, 2018;Chiang et al, 2020;Liu et al, 2022;Torres-Rodriguez et al, 2023), bed nucleus of the stria terminalis (Chen et al, 2018;Chiang et al, 2020), ventral tegmental area (Yang et al, 2021), reticular formation (Barik et al, 2018), periaqueductal gray (Chiang et al, 2020), substantia innominata (Bowen et al, 2020), and various hypothalamic (Bowen et al, 2020;Chiang et al, 2020) and thalamic nuclei (Bowen et al, 2020;Deng et al, 2020). One possible consequence of increased lPBN excitability could be increased output onto these targets, leading to increased nociception and nocifensive behaviors.…”

Converging inputs compete at the lateral parabrachial nuclei to dictate the affective-motivational responses to cold pain

“…These neurons express the gene encoding the neuropeptide, substance P or Tac1, and primarily project to the lateral parabrachial nucleus (LPBN). LPBN neurons that receive spinal inputs in turn target several areas in the mid and forebrain regions involved in emotion and motivation, including the hypothalamus, thalamus, insula, and amygdala 68,74,80 , making it a critical conduit for transmitting pain information across the brain and mediating affective responses to pain, including licking behavior 12,81,89,22,5 . Indeed, activating LPBN neurons with strong projections to the intralaminar thalamus promotes licking in response to sustained noxious mechanical and chemical stimuli 5,27 .…”