An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Abstract

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.

Parabrachial nucleus circuit governs neuropathic pain-like behavior

“…Since the LPBN also receives GABAergic innervation from other brain regions 28,53,54 , it was possible that light stimulation in the vGAT-ChR2 transgenic mice activated the fibers and terminals of GABAergic neurons projecting to or via the LPBN from other brain regions. To determine whether activation of the local GABAergic LPBN neurons is sufficient to inhibit neuropathic pain-like hypersensitivity, we initially injected Credependent AAV-DIO-ChR2-eYFP or AAV-DIO-eYFP virus into the LPBN of mice expressing Cre recombinase under the control of the glutamic acid decarboxylase enzyme (GAD2-ires-Cre mice) ( Fig.…”

“…It is interesting to note that GABAergic neurons only constitute~10.1% of LPBN neurons, much less than that reported in the spinal dorsal horn (~70%) 62 and in the central nucleus of the amygdala (~50.78%), but comparable to that reported in the thalamus (~10.43%) and somatosensory cortex (~8.66%) (Allen Brain Atlas, http://www. brain-map.org) in the pain transmission pathway, suggesting that glutamatergic LPBN neurons that also receive GABAergic innervation from other regions 28,54,53 are under the relatively weak control of local GABAergic neurons. Consistent with this proposal, we found that the optogenetic activation of GABAergic LPBN neurons did not affect the paw-withdraw response in naïve mice (Fig.…”

“…However, our study does not exclude the possibility that GABAergic input from other brain regions to the LPBN may also play an important role in neuropathic pain-like hypersensitivity. In this respect, it should be noted that a recent study has shown that suppressed GABAergic input from the central nucleus of the amygdala to the LPBN may contribute to chronic pain 28 .…”

“…Two ascending pathways have been described for pain transmission to higher centers. The spinothalamic tract carries sensory inputs from spinal neurons to the thalamus, which relays the information to the somatosensory cortex for processing the sensory and discriminative aspects of pain, whereas the spinoparabrachial tract transmits the pain signal to the parabrachial nucleus (PBN) 7,[14][15][16][17][18][19] , which is reported to project to the amygdala and other brain regions to transform the sensory signals into the aversive and emotional components of pain [20][21][22][23][24][25][26][27][28][29] . Furthermore, the PBN has been associated with other important sensory processes, such as itch and craniofacial affective pain, as well as aversive emotional behaviors, including aversive learning, avoidance behavior, and anorexia/hunger [30][31][32][33][34][35][36] .…”

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

“…The suppressed release of GABA may lead to the amplified activity of PB neurons, seen in chronic pain conditions (Uddin et al, 2018;Raver et al, 2020) through at least two mechanisms. Reduced GABA release may lead to reduced activation of postsynaptic GABA B receptors, resulting in dis-inhibition of PB neurons and amplifying responses to nociceptive inputs (Uddin et al, 2018;Raver et al, 2020).…”