The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.

The limited success in translating basic science findings into effective pain management therapies reflects, in part, the difficulty in reliably assessing pain in experimental animals. This shortcoming is particularly acute in the field of chronic, ongoing pain. Quantitative analysis of facial expressions—the grimace score—was introduced as a promising tool, however, it is thought to reliably assess only pain of short or medium duration (minutes to hours). Here, we test the hypothesis that grimace scores are a reliable metric of ongoing neuropathic pain, by testing the prediction that chronic constriction injury of the infraorbital nerve (CCI-ION) will evoke significant increases in grimace scale scores. Mice and rats were subjected to CCI-ION, and tested for changes in mechanical hypersensitivity and in grimace scores, 10 or more days after surgery. Both rats and mice with CCIION had significantly higher grimace scores, and significantly lower thresholds for withdrawal from mechanical stimuli applied to the face, compared to sham-operated animals. Fentanyl reversed the changes in rat grimace scale scores, suggesting that these scores reflect pain perception. These findings validate the grimace scale as a reliable and sensitive metric for the assessment of ongoing pain in a rodent model of chronic, trigeminal neuropathic pain.

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 lateral parabrachial (LPB) neurons from the CeA in animals of either sex. 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 after-discharges, responses that far outlast the stimulus, compared with controls. LPB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that, in both rats and mice, LPB 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 naive 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.

The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We hypothesized that PB hyperactivity influences chronic pain behavior after trigeminal nerve injury in rats. Following induction of neuropathic pain using the chronic constriction injury of the infraorbital nerve (CCI-ION) model, rats displayed spontaneous markers of pain and mechanical hyperalgesia extending beyond the receptive field of the injured nerve. PB neurons recorded from rats with CCI-ION displayed amplified activity, manifesting as significantly longer responses to sensory stimuli, compared to shams. These findings suggest that chronic neuropathic pain involves PB hyperactivity.

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.