Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala

Itoga, Christy A.; Hellard, Emily A. Roltsch; Whitaker, Annie M.; Lu, Yi-Ling; Schreiber, Allyson L.; Baynes, Brittni B; Baiamonte, Brandon A.; Richardson, H. G.; Gilpin, Nicholas W.

doi:10.1038/npp.2016.44

Cited by 52 publications

(52 citation statements)

References 47 publications

(52 reference statements)

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“…Rats that displayed a <10 sec decrease in time spent in the predator odor-paired chamber were classified as ‘Non-Avoiders’. The 10s cut-off for Avoiders and Non-Avoiders is consistent with previous publications from our lab (e.g., Edwards et al, 2013; Itoga et al, in press; Whitaker & Gilpin, 2015). By not using a median split, our criterion for separating those two groups remains identical across studies.…”

Section: Methodssupporting

confidence: 90%

“…By not using a median split, our criterion for separating those two groups remains identical across studies. This 10-s cut-off has been used to show differences between groups in alcohol drinking (Edwards et al, 2013), nociception (Itoga et al, in press), and the corticosterone response to stress (Whitaker & Gilpin, 2015). …”

Section: Methodsmentioning

confidence: 99%

“…Non-Avoiders show no difference in appetitive conditioning and are able to acquire operant conditioning at the same rate as Avoiders prior to stress exposure (Edwards et al, 2013). Furthermore, these animals do not differ in baseline alcohol self-administration, anxiety-like behavior (Edwards et al, 2013), or nociception (Itoga et al., in press) prior to stress.…”

Section: Introductionmentioning

confidence: 94%

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Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context

Schreiber

Baynes

et al. 2017

Neuropharmacology

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Post-traumatic stress disorder affects 7.7 million Americans. One diagnostic criterion is avoidance of stimuli related to the traumatic stress. Using a predator odor stress conditioned place avoidance (CPA) model, rats can be divided into groups based on stress reactivity, measured by avoidance of the odor-paired context. Avoider rats, which show high stress reactivity, exhibit avoidance of stress-paired context and escalated alcohol drinking. Here, we examined the role of corticotropin-releasing factor (CRF), a neuropeptide that promotes anxiety-like behavior, in mediating post-stress avoidance and escalated alcohol drinking. CRF is expressed in the medial prefrontal cortex (mPFC). The dorsal and ventral sub-regions of mPFC (dmPFC and vmPFC) have opposing roles in stress reactivity and alcohol drinking/seeking. We hypothesized that CRF-CRFR1 signaling in the vmPFC contributes to stress-induced avoidance and escalated alcohol self-administration. In Experiment 1, adult male Wistar rats were exposed to predator odor stress in a CPA paradigm, indexed for avoidance of odor-paired context, and brains processed for CRF-immunoreactive cell density in vmPFC and dmPFC. In Experiment 2, rats were tested for avoidance of a context repeatedly paired with intra-vmPFC CRF infusions. In Experiment 3, rats were stressed, indexed, and tested for the effects of intra-vmPFC CRFR1 antagonism on avoidance and alcohol self-administration. Post-stress, Avoiders exhibited higher CRF cell density in vmPFC, but not dmPFC. Intra-vmPFC CRF infusion produced conditioned place avoidance. Intra-vmPFC CRFR1 antagonism reversed avoidance of odor-paired context, but did not alter post-stress alcohol self-administration. These findings suggest that vmPFC CRF-CRFR1 signaling mediates avoidance of stimuli paired with traumatic stress.

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Section: Methodssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context

Schreiber

Baynes

et al. 2017

Neuropharmacology

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“…Long lasting inflammatory and neuropathic pain increases CRF expression in the CeAmy [14-16]. CRF release in the CeAmy causes hypersensitivity via CRF1 receptor and analgesia via CRF2 receptor [17-19]. While low doses of endogenous CRF in CeAmy increase pain sensitivity [20], high doses of exogenous CRF are analgesic [21].…”

Section: Introductionmentioning

confidence: 99%

Contribution of amygdala CRF neurons to chronic pain

Andreoli

Marketkar

Dimitrov

2017

Experimental Neurology

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We investigated the role of amygdala corticotropin-releasing factor (CRF) neurons in the perturbations of descending pain inhibition caused by neuropathic pain. Forced swim increased the tail-flick response latency in uninjured mice, a phenomenon known as stress-induced analgesia (SIA) but did not change the tail-flick response latency in mice with neuropathic pain caused by sciatic nerve constriction. Neuropathic pain also increased the expression of CRF in the central amygdala (CeAmy) and ΔFosB in the dorsal horn of the spinal cord. Next, we injected the CeAmy of CRF-cre mice with cre activated AAV-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) vectors. Activation of CRF neurons by DREADD/Gq did not affect the impaired SIA but inhibition of CRF neurons by DREADD/Gi restored SIA and decreased allodynia in mice with neuropathic pain. The possible downstream circuitry involved in the regulation of SIA was investigated by combined injections of retrograde cre-virus (CAV2-cre) into the locus ceruleus (LC) and cre activated AAV-diphtheria toxin (AAV-FLEX-DTX) virus into the CeAmy. The viral injections were followed by a sciatic nerve constriction ipsilateral or contralateral to the injections. Ablation of amygdala projections to the LC on the side of injury but not on the opposite side, completely restored SIA, decreased allodynia and decreased ΔFosB expression in the spinal cord in mice with neuropathic pain. The possible lateralization of SIA impairment to the side of injury was confirmed by an experiment in which unilateral inhibition of the LC decreased SIA even in uninjured mice. The current view in the field of pain research attributes the process of pain chronification to abnormal functioning of descending pain inhibition. Our results demonstrate that the continuous activity of CRF neurons brought about by persistent pain leads to impaired SIA, which is a symptom of dysregulation of descending pain inhibition. Therefore, an over-activation of amygdala CRF neurons is very likely an important contributing factor for pain chronification.

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“…Similarly, injecting mice with alcohol immediately after removal from the conditioning chamber produces a CPA that is observed in wild-type and Ucn1 knockout mice (Giardino et al 2011), suggesting that Ucn1 signaling via CRFR1 may not mediate the aversive and/or negative reinforcing effects of alcohol (i.e., perhaps this effect is mediated by CRF signaling). In support of this, rats show a conditioned place aversion to a chamber paired with CRF infused into the ventricles, the vmPFC, or the CeA (Cador et al 1992; Itoga et al 2016; Schreiber et al 2017), which suggests that excess brain CRF signaling is aversive, and may support the notion that CRF mediates the aversive effects of alcohol.…”

Section: 4 Brain Region-specific Crfr1 and Crfr2 Effects On Alcoholmentioning

confidence: 68%

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

Schreiber

Gilpin

2018

Handbook of Experimental Pharmacology

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Alcohol use is pervasive in the United States. In the transition from nonhazardous drinking to hazardous drinking and alcohol use disorder, neuroadaptations occur within brain reward and brain stress systems. One brain signaling system that has received much attention in animal models of excessive alcohol drinking and alcohol dependence is corticotropin-releasing factor (CRF). The CRF system is composed of CRF, the urocortins, CRF-binding protein, and two receptors - CRF type 1 and CRF type 2. This review summarizes how acute, binge, and chronic alcohol dysregulates CRF signaling in hypothalamic and extra-hypothalamic brain regions and how this dysregulation may contribute to changes in alcohol reinforcement, excessive alcohol consumption, symptoms of negative affect during withdrawal, and alcohol relapse. In addition, it summarizes clinical work examining CRF type 1 receptor antagonists in humans and discusses why the brain CRF system is still relevant in alcohol research.

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Traumatic Stress Promotes Hyperalgesia via Corticotropin-Releasing Factor-1 Receptor (CRFR1) Signaling in Central Amygdala

Cited by 52 publications

References 47 publications

Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context

Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context

Contribution of amygdala CRF neurons to chronic pain

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

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