Descending modulation of pain: the GABA disinhibition hypothesis of analgesia

Lau, Benjamin K.; Vaughan, Christopher W.

doi:10.1016/j.conb.2014.07.010

Cited by 233 publications

(189 citation statements)

References 40 publications

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“…PAG projections to rostral ventromedial medulla (RVM) initiate descending modulation of incoming pain signals via RVM projections to spinal cord (Lau and Vaughan, 2014). This PAG-RVM-spinal pathway mediates the analgesic effects of opioids and cannabinoids, as well as stressinduced analgesia.…”

Section: Discussionmentioning

confidence: 99%

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

Itoga

Hellard

Whitaker

et al. 2016

Neuropsychopharmacol

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Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stressinduced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.

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Section: Discussionmentioning

confidence: 99%

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

Itoga

Hellard

Whitaker

et al. 2016

Neuropsychopharmacol

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“…Ascending nociception is blocked at the spinal cord level through inhibition of the spinal dorsal horn neurons. Activation of this pathway by higher centers is the basis for stress induced analgesia through the activation of MOR and cannabinoid receptors [13].…”

Section: Periaqueductal Graymentioning

confidence: 99%

The Neurobiology of Pain Perception in Normal and Persistent Pain

2015

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Pain is a significant national burden in terms of patient suffering, expenditure and lost productivity. Understanding pain is fundamental to improving evaluation, treatment and innovation in the management of acute and persistent pain syndromes. Pain perception begins in the periphery, and then ascends in several tracts, relaying at different levels. Pain signals arrive in the thalamus and midbrain structures which form the pain neuromatrix, a constantly shifting set of networks and connections that determine conscious perception. Several cortical regions become active simultaneously during pain perception; activity in the cortical pain matrix evolves over time to produce a complex pain perception network. Dysfunction at any level has the potential to produce unregulated, persistent pain.

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“…Eicosanoid-based control of GABA release and neuronal excitability was initially described within the PAG for MOPr agonists. Therein, HPETE production by morphine reduced local release of GABA, most plausibly through the modulation of presynaptic voltage-gated K + channels on GABAergic terminals (Vaughan et al, 1997;Lau and Vaughan, 2014). As a result of the reduction in extracellular GABA, PAG neurons projecting to the rostral medulla enhanced analgesia by morphine (Vaughan et al, 1997;Lau and Vaughan, 2014).…”

Section: D-opioid Receptors and Phospholipase Signalingmentioning

confidence: 99%

“…Therein, HPETE production by morphine reduced local release of GABA, most plausibly through the modulation of presynaptic voltage-gated K + channels on GABAergic terminals (Vaughan et al, 1997;Lau and Vaughan, 2014). As a result of the reduction in extracellular GABA, PAG neurons projecting to the rostral medulla enhanced analgesia by morphine (Vaughan et al, 1997;Lau and Vaughan, 2014). Interestingly, unlike MOPr in the PAG and DOPr in the NRM Pan, 2010, 2012), activation of PAG DOPr was not associated with presynaptic modulation of K + conductance, instead inducing postsynaptic hyperpolarization of local somata via inward rectifying K + channels (Vaughan et al, 2003).…”

Section: D-opioid Receptors and Phospholipase Signalingmentioning

confidence: 99%