Signaling Pathways in Sensitization: Toward a Nociceptor Cell Biology

Hucho, Tim; Levine, John D.

doi:10.1016/j.neuron.2007.07.008

Cited by 417 publications

(385 citation statements)

References 129 publications

(172 reference statements)

Supporting

Mentioning

372

Contrasting

Unclassified

Order By: Relevance

“…Here, noxious punctate stimulation of C-nociceptors induces secondary mechanical hyperalgesia mediated by A-nociceptors (7) and innocuous dynamic mechanical stimuli (gentle stroking) provokes nonnociceptor A-fiber-mediated pain (108). Cellular mechanisms underlying this complicated response involve both peripheral and central processes (14,38,105,107) and require nociceptor input, particularly A-MH and C-MH fibers (19,91,105). After a burn, A-MH fibers (most likely type I) mediate primary heat hyperalgesia in glabrous skin (9).…”

Section: Adaptive and Maladaptive Shifts In Pain Thresholdmentioning

confidence: 99%

Nociceptors: the sensors of the pain pathway

Dubin

Patapoutian²

2010

J. Clin. Invest.

1,070

856

View full text Add to dashboard Cite

Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.

show abstract

Section: Adaptive and Maladaptive Shifts In Pain Thresholdmentioning

confidence: 99%

Nociceptors: the sensors of the pain pathway

Dubin

Patapoutian²

2010

J. Clin. Invest.

1,070

856

View full text Add to dashboard Cite

show abstract

“…An important requirement for the interaction between EETs, TSPO activity, and StARD1 expression may be the presence of elevated cAMP because expression and phosphorylation of StARD1 is greatly enhanced upon gonadotropic hormone stimulation, which increases intracellular cAMP levels (42,43). Separately, the maintenance of hyperalgesia in inflammatory and neuropathic pain states is known to be largely regulated by the activation of the cAMP signaling pathway (44)(45)(46). In the brain, intracellular cAMP level is known to rise rapidly in response to inflammation mainly because the cox-2 product PGE 2 activates E-prostanoid receptors and initiates a cascade of events beginning with stimulation of adenylate cylase (47).…”

Section: Eets and Sehis Redirect Elevated Camp To An Analgesicmentioning

confidence: 99%

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Inceoglu¹,

Jinks

Ulu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

172

218

View full text Add to dashboard Cite

During inflammation, a large amount of arachidonic acid (AA) is released into the cellular milieu and cyclooxygenase enzymes convert this AA to prostaglandins that in turn sensitize pain pathways. However, AA is also converted to natural epoxyeicosatrienoic acids (EETs) by cytochrome P450 enzymes. EET levels are typically regulated by soluble epoxide hydrolase (sEH), the major enzyme degrading EETs. Here we demonstrate that EETs or inhibition of sEH lead to antihyperalgesia by at least 2 spinal mechanisms, first by repressing the induction of the COX2 gene and second by rapidly up-regulating an acute neurosteroid-producing gene, StARD1, which requires the synchronized presence of elevated cAMP and EET levels. The analgesic activities of neurosteroids are well known; however, here we describe a clear course toward augmenting the levels of these molecules. Redirecting the flow of pronociceptive intracellular cAMP toward up-regulation of StARD1 mRNA by concomitantly elevating EETs is a novel path to accomplish pain relief in both inflammatory and neuropathic pain states.cAMP ͉ inflammatory pain ͉ steroidogenesis

show abstract

“…The proinflammatory cytokine interleukin (IL)-1β directly sensitizes nociceptors, leading to transient hyperalgesia (2,3). Peripheral injection of other inflammatory mediators such as prostaglandin E 2 (PGE 2 ) also increases the sensitivity of nociceptors and the response to painful stimuli (4). Moreover, there is evidence that proinflammatory cytokines such as IL-1β and tumor necrosis factor (TNF)-α contribute to the genesis of neuropathic pain (5,6).…”

Section: Introductionmentioning

confidence: 99%

G Protein-Coupled Receptor Kinase 6 Acts as a Critical Regulator of Cytokine-Induced Hyperalgesia by Promoting Phosphatidylinositol 3-Kinase and Inhibiting p38 Signaling

Eijkelkamp

Heijnen

Carbajal

et al. 2012

Mol Med

View full text Add to dashboard Cite

The molecular mechanisms determining magnitude and duration of inflammatory pain are still unclear. We assessed the contribution of G protein-coupled receptor kinase (GRK)-6 to inflammatory hyperalgesia in mice. We showed that GRK6 is a critical regulator of severity and duration of cytokine-induced hyperalgesia. In GRK6 -/-mice, a significantly lower dose (100 times lower) of intraplantar interleukin (IL)-1β was sufficient to induce hyperalgesia compared with wild-type (WT) mice. In addition, IL-1β hyperalgesia lasted much longer in GRK6 -/-mice than in WT mice (8 d in GRK6 -/-versus 6 h in WT mice). Tumor necrosis factor (TNF)-α-induced hyperalgesia was also enhanced and prolonged in GRK6 -/-mice. In vitro, IL-1β-induced p38 phosphorylation in GRK6 -/-dorsal root ganglion (DRG) neurons was increased compared with WT neurons. In contrast, IL-1β only induced activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway in WT neurons, but not in GRK6 -/-neurons. In vivo, p38 inhibition attenuated IL-1β-and TNF-α-induced hyperalgesia in both genotypes. Notably, however, whereas PI 3-kinase inhibition enhanced and prolonged hyperalgesia in WT mice, it did not have any effect in GRK6-deficient mice. The capacity of GRK6 to regulate pain responses was also apparent in carrageenan-induced hyperalgesia, since thermal and mechanical hypersensitivity was significantly prolonged in GRK6 -/-mice. Finally, GRK6 expression was reduced in DRGs of mice with chronic neuropathic or inflammatory pain. Collectively, these findings underline the potential role of GRK6 in pathological pain. We propose the novel concept that GRK6 acts as a kinase that constrains neuronal responsiveness to IL-1β and TNF-α and cytokine-induced hyperalgesia via biased cytokine-induced p38 and PI 3-kinase/Akt activation.

show abstract

Signaling Pathways in Sensitization: Toward a Nociceptor Cell Biology

Cited by 417 publications

References 129 publications

Nociceptors: the sensors of the pain pathway

Nociceptors: the sensors of the pain pathway

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

G Protein-Coupled Receptor Kinase 6 Acts as a Critical Regulator of Cytokine-Induced Hyperalgesia by Promoting Phosphatidylinositol 3-Kinase and Inhibiting p38 Signaling

Contact Info

Product

Resources

About