Hyperalgesia by synaptic long-term potentiation (LTP): an update

Sandkühler, Jürgen; Gruber‐Schoffnegger, Doris

doi:10.1016/j.coph.2011.10.018

Cited by 164 publications

(110 citation statements)

References 85 publications

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“…At 7–21 days post colitis induction, CREB activity is increased in bladder afferent neurons which may participate in cAMP-responsive element (CRE)-dependent transcription and induce prolonged neuronal activation. Recent update on spinal LTP in facilitating nociception is extensively reviewed by (Sandkuhler and Gruber-Schoffnegger, 2012). In this study, we show that the key players in LTP in hippocampus, the PLCγ and CaMKII (Gartner et al, 2006; Yamauchi, 2005), are also associated with bladder afferent activation post colitis.…”

Section: Discussionmentioning

confidence: 99%

Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLCγ pathway

Xia

Shen

Hashmi

et al. 2016

Experimental Neurology

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Patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) often experience increased sensory responsiveness in the urinary bladder reflecting neurogenic bladder overactivity. Here we demonstrate that colitis-induced up-regulation of the phospholipase C gamma (PLCγ) pathway downstream of brain-derived neurotrophic factor (BDNF) in bladder afferent neurons in the dorsal root ganglia (DRG) plays essential roles in activating these neurons thereby leading to bladder hyperactivity. Upon induction of colitis with 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats, we found that the phosphorylation (activation) level of cAMP responsive element-binding (p-CREB) protein, a molecular switch of neuronal plasticity, was increased in specifically labeled bladder afferent neurons in the thoracolumbar and lumbosacral DRGs. In rats having reduced levels of BDNF (BDNF+/−), colitis failed to elevate CREB protein activity in bladder afferent neurons. Physiological examination also demonstrated that colitis-induced urinary frequency was not shown in BDNF+/− rats, implicating an essential role of BDNF in mediating colon-to-bladder sensory cross-sensitization. We further implemented in vivo and in vitro studies and demonstrated that BDNF-mediated colon-to-bladder sensory cross-activation involved the TrkB - PLCγ-calcium/calmodulin-dependent protein kinase II (CaMKII) cascade. In contrast, the PI3K/Akt pathway was not activated in bladder afferent neurons during colitis and was not involved in BDNF action in the DRG. Our results suggest that colon-to-bladder sensory cross-sensitization is regulated by specific signal transduction initiated by the up-regulation of BDNF in the DRG.

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Section: Discussionmentioning

confidence: 99%

Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLCγ pathway

Xia

Shen

Hashmi

et al. 2016

Experimental Neurology

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“…Chronic pain can be thought of as a type of persistent sensory memory, and increasing evidence suggests that LTP and LTD in the dorsal horn of the spinal cord and cortical areas, including the ACC 3,4 , are causally related to chronic pain. There is abundant evidence from animal models to suggest that, in the spinal cord, LTP at C fibre synapses can contribute to hyperalgesia, and that reversal of LTP by depotentiation reduces nociceptive behaviours 53 . Here, we describe the forms of synaptic plasticity that can be induced in the ACC in vitro.…”

Section: Allodyniamentioning

confidence: 99%

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

et al. 2016

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The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.

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“…First, exogenous opiate withdrawal in the spinal cord initiates de novo NMDAR-dependent LTP {Drdla, 2009 #4604;Zhou, 2010 #5167}. Second, NMDAR signaling and post-synaptic spinal neuron Ca 2+ rise are required in the induction, rather than maintenance, of spinal LTP and hyperalgesia (Weyerbacher et al, 2010, Sandkuhler and Gruber-Schoffnegger, 2012). Third, AC1 is activated by NMDAR-derived Ca 2+ and is necessary for LTP induction (Liauw et al, 2005, Wei et al, 2006).…”

Section: Cellular Dependence On Morcamentioning

confidence: 99%

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Taylor

Corder

2014

Current Topics in Behavioral Neurosciences

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Endogenous activation of μ-opioid receptors (MORs) provides relief from acute pain. Recent studies have established that tissue inflammation produces latent pain sensitization (LS) that is masked by spinal MOR signaling for months, even after complete recovery from injury and re-establishment of normal pain thresholds. Disruption with MOR inverse agonists reinstates pain and precipitates cellular, somatic and aversive signs of physical withdrawal; this phenomenon requires N-methyl-D-aspartate receptor-mediated activation of calcium-sensitive adenylyl cyclase type 1 (AC1). In this review, we present a new conceptual model of the transition from acute to chronic pain, based on the delicate balance between LS and endogenous analgesia that develops after painful tissue injury. First, injury activates pain pathways. Second, the spinal cord establishes MOR constitutive activity (MORCA) as it attempts to control pain. Third, over time, the body becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Stress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioid tone. Pain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on pain transmission: LS mediated by AC1 (which maintains accelerator), and pain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesia and latent NMDAR–AC1-mediated pain sensitization create a lasting vulnerability to develop chronic pain. Thus, chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control. An overarching long-term therapeutic goal of future research is to alleviate chronic pain by either: a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission; or b) extinguishing LS altogether.

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Hyperalgesia by synaptic long-term potentiation (LTP): an update

Cited by 164 publications

References 85 publications

Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLCγ pathway

Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLCγ pathway

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

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