The parabrachial to central amygdala pathway is critical to injury-induced pain sensitization in mice

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. However, the functional significance of this pathway in the modulation of the somatosensory component of pain was recently challenged by studies showing that spinal nociceptive neurons do not target CeA-projecting PBN cells and that manipulations of this pathway have no effect on reflexive-defensive somatosensory responses to peripheral noxious stimulation. Here, we showed that activation of CeA-projecting PBN neurons is critical to increase both stimulus-evoked and spontaneous nociceptive responses following an injury 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 increased the expression of the neuronal activity marker Fos in CeA-projecting PBN neurons and that chemogenetic inactivation of these cells decreased behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we showed that chemogenetic activation of CeA-projecting PBN neurons is sufficient to induced bilateral hypersensitivity without injury. Together, our results indicate that the PBN→CeA pathway is a key modulator of pain-related behaviors that can increase reflexive-defensive and affective-motivational responses to somatosensory stimulation in injured states without affecting nociception under normal physiological conditions.

GABA Release From Central Amygdala Neurotensin Neurons Differentially Modulates Reward and Consummatory Behavior in Male and Female Mice

“…This effect, akin to drinking, was driven by the males. Finally, we investigated pain and mechanosensory behaviors as CeA neurons have been implicated in such behaviors in previous studies [18,19]. We find that CeA Nts ::vGAT-shRNA mice show increased thermal nociception, however this was driven by the female mice.…”

“…Pain can be a driver of negative affect, which can potentiate misuse of substances such as alcohol [41,42]. The CeA is known to be a region involved in the regulation of pain and related behaviors [17,18,[43][44][45]. Therefore, we investigated pain and sensory behaviors across all groups and sexes as these behaviors could be relevant in the context of alcohol use.…”

“…Pain can be a driver of negative affect, which can potentiate misuse of substances such as alcohol [39,40]. The CeA is known to be involved in the regulation of pain and related behaviors [18,19,[41][42][43]. Additionally, previous work from our lab has revealed that neurons in the CeA Nts population also express some genetic markers relevant to pain such as dynorphin, somatostatin, and PKCΔ [7].…”

“…Because of the well-established role of the CeA in pain behaviors [18,19], we evaluated mechanical, heat nociception and cold sensitivity across all groups and sexes. There were no differences between groups in mechanical hypersensitivity in the von Frey assay (Fig.…”

ParabrachialCalcaneurons drive nociplasticity

“…The PBN is composed of approximately a dozen molecularly defined glutamatergic neuron subtypes and a minor population of GABAergic neurons (Pauli et al 2022). Non-specific activation of the PBN glutamatergic neurons can elicit painful phenotypes such as allodynia, while inhibition of those neurons or activation of the GABAergic neurons can inhibit painful phenotypes (Torres-Rodriguez et al, 2023; Zhou et al, 2023; Sun et al, 2020; Chiang et al, 2019). The roles that molecularly defined subsets of PBN neurons contribute to pain sensation is also being explored.…”