Neurokinin-1 Receptor Enhances TRPV1 Activity in Primary Sensory Neurons via PKCε: A Novel Pathway for Heat Hyperalgesia

Zhang, Hua; Cang, Chunlei; Kawasaki, Yuki; Liang, Lingli; Zhang, Yu‐Qiu; Ji, Ru-Rong; Zhao, Zhi‐Qi

doi:10.1523/jneurosci.0496-07.2007

Cited by 173 publications

(180 citation statements)

References 63 publications

(83 reference statements)

Supporting

Mentioning

160

Contrasting

Unclassified

Order By: Relevance

“…We therefore tested the peripheral effects of SP on the excitability of nociceptive neurons in vivo and compared them with the effects of BK. First we confirmed the previously characterized (7,39) hyperalgesic effect induced by plantar injection of SP. In accordance with previous studies, the latency of hind paw withdrawal at the presentation of a thermal stimulus was decreased significantly after plantar injection of 10 μM SP in saline (50 μL; 0.5 nmol per site) (Fig.…”

Section: Sp Augments M Current In Sensory Neurons Via Oxidativesupporting

confidence: 85%

“…To quantify the population of nociceptive neurons in rat DRG and TG which express functional NKR, we used the phenomenon of TRPV1 sensitization by SP (7,8). We focused our study on the small-diameter DRG neurons (20-30 μM), which we characterized in detail in our previous study (12); 60-70% of these neurons express TRPV1 (12).…”

Section: Functional Expression Of Nkr In Mammalian Sensory Neuronsmentioning

confidence: 99%

“…Sensitization of CAP responses by SP was suggested to be mediated by the action of PKC on TRPV1 (7,8), suggesting that DAG is released upon SP application. Therefore, we next determined whether the IP 3 -Ca 2+ branch of the G q/11 signaling cascade is activated also.…”

Section: Functional Expression Of Nkr In Mammalian Sensory Neuronsmentioning

confidence: 99%

“…9). Nevertheless, it is accepted that peripherally acting SP sensitizes TRPV1 in nociceptors, an effect underlying inflammatory hyperalgesia; the SP-induced TRPV1 sensitization was shown to be mediated by PKC (7,8). There is no consensus regarding the effect of SP on sensory neuron excitability and neurotransmitter release, and both positive (10) and negative (11) feedback effects have been suggested.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Linley¹,

Ooi

Pettinger³

et al. 2012

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

108

View full text Add to dashboard Cite

Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and G i/o proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as second messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca 2+ stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca 2+ stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.G protein coupled receptors | inflammatory pain | intracellular signaling | KCNQ | M current E xcitation of peripheral terminals of sensory neurons is a primary event in somatosensation, including pain. A large proportion of sensory neurons (mostly TRPV1 + damage-sensing or "nociceptive" neurons) produce neuropeptides such as substance P (SP), which are released in response to nociceptive stimulation both at spinal cord synapses and in the periphery (1). In the spinal cord SP acts as an excitatory neurotransmitter or cotransmitter (2, 3), whereas peripheral SP release is thought to underlie the inflammatory response known as "neurogenic inflammation" (4). Many peripheral nociceptors also express receptors for SP [neurokinin receptors (NKR) 1-3 (NK1-3)]; this expression may suggest paracrine or autocrine actions of this peptide. However, the nature of such actions is controversial, and the molecular events triggered by NKR in peripheral nociceptors are not well established. The NKR traditionally are classed as G q/11 -coupled G protein-coupled receptors (GPCR) that activate phospholipase C (PLC), with subsequent hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and release of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG) (5, 6). Common downstream steps of G q/11 signaling include IP 3 -mediated release of Ca 2+ from intracellular stores and DAG-mediated activation of PKC. However, it was hitherto unknown whether NKR in peripheral sensory neurons couple fully to this signaling cascade, because a lack of coupling between NKR and Ca 2+ release in dorsal root ganglia (DRG) neurons has been noted (ref. 7 and 8, but cf. ref. 9). Nevertheless, it is accepted that peripherally act...

show abstract

Section: Sp Augments M Current In Sensory Neurons Via Oxidativesupporting

confidence: 85%

Section: Functional Expression Of Nkr In Mammalian Sensory Neuronsmentioning

confidence: 99%

Section: Functional Expression Of Nkr In Mammalian Sensory Neuronsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Linley¹,

Ooi

Pettinger³

et al. 2012

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

108

View full text Add to dashboard Cite

show abstract

“…A more likely scenario is that several linoleic acid metabolites contribute to TRPV1 activation. It is also possible that other factors capable of sensitizing TRPV1 (15)(16) were coreleased under these conditions. Thus, the resultant TRPV1 agonist activity could be an entourage effect of several lipids acting in concert.…”

Section: Discussionmentioning

confidence: 99%

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Patwardhan¹,

Scotland

Akopian³

et al. 2009

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

196

191

View full text Add to dashboard Cite

Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9-and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.inflammation ͉ pain T ransient receptor potential vanilloid 1 (TRPV1) plays a pivotal role in many pain models, leading to the development of hyperalgesia and/or allodynia (1-2). TRPV1 is expressed in the peripheral as well as central nervous systems (CNS) including several areas involved in nociceptive transmission (3). Numerous studies have demonstrated that peripheral TRPV1 is activated by noxious heat and protons and is regulated by endogenous ligands (2), contributing to peripheral mechanisms of heat hyperalgesia (4). However, TRPV1 is also expressed in the CNS, where comparatively little is known about the role of this receptor in mediating central pain mechanisms.Recent studies have used TRPV1 antagonists to evaluate the role of CNS TRPV1 in inflammatory hyperalgesia. Interestingly, the systemic/spinal administration of TRPV1 antagonists blocks inflammation-induced heat hyperalgesia, as well as mechanical allodynia (5-6). These findings were unexpected since TRPV1 is not activated by mechanical stimuli, suggesting that spinal TRPV1 activation leads to central sensitization to both thermal and mechanical stimuli (7-8). Based upon these observations, we hypothesized that the afferent barrage resulting from peripheral tissue injury leads to generation of endogenous TRPV1 ligands in the spinal cord that activate TRPV1 in the CNS resulting in central sensitization. Results Depolarization of Spinal Cord Results in the Release of EndogenousTRPV1 Ligands. To evaluate the hypothesis that endogenous TRPV1 agonists are released from spinal cord neurons, freshly isolated male rat spinal cords w...

show abstract

Biochemical Pharmacology of TRPV1: Molecular Integrator of Pain Signals

Surowy

Kym

Reilly

2010

Vanilloid Receptor TRPV1 in Drug Discovery

View full text Add to dashboard Cite

Neurokinin-1 Receptor Enhances TRPV1 Activity in Primary Sensory Neurons via PKCε: A Novel Pathway for Heat Hyperalgesia

Cited by 173 publications

References 63 publications

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Biochemical Pharmacology of TRPV1: Molecular Integrator of Pain Signals

Contact Info

Product

Resources

About