Substance P and peripheral inflammatory hyperalgesia

Nakamura-Craig, Meire; Smith, T.W.

doi:10.1016/0304-3959(89)90078-x

Cited by 88 publications

(37 citation statements)

References 43 publications

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“…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%

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

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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...

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Section: Sp Augments M Current In Sensory Neurons Via Oxidativesupporting

confidence: 85%

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

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“…In this test, the end point is a behavioral response, the freezing reaction. The constant-pressure rat-paw test over the years has been instrumental in many original observations (2,4,6,48,49). The drugs were tested by connection to a 100-ml Hamilton microsyringe.…”

Section: Experimental Protocol For Acute and Persistent Hypernociceptmentioning

confidence: 99%

Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K ⁺ channel pathway

Sachs

Cunha

Ferreira

2004

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

172

120

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The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K ؉ channels (K ATP ؉ ). This channel is known to be open either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was shown that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive effect of morphine and dipyrone on acute hypernociception and of dipyrone on persistent hypernociception. It was also shown that, in both models, KT5823 prevented the peripheral antinociceptive effect of an analogue of cGMP, the nitric oxide (NO) donor (S-nitroso-Nacetyl-D,L-penicilamine). However, in acute hypernociception, KT5823 did not prevent the peripheral antinociceptive effect of diazoxide (a direct K ATP ؉ opener). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E 2 (PGE2, 100 ng) into the rat paw for 14 days. After cessation of PGE 2 injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. T he suggestion that the main mechanism of action of aspirin and aspirin-like drugs is due to the prevention of nociceptor sensitization (development of hyperalgesia) is now broadly accepted (1). In contrast with specific cyclooxygenase (COX)-1 and -2 inhibitors, some analgesics, such as morphine, dipyrone, diclofenac, and keterolac are able to directly block ongoing nociceptor sensitization, as shown by its blockade of acute prostaglandin E 2 -(PGE 2 ) induced hypernociception in rat hind paws (2-5). In 1979, the peripheral antinociceptive effect of opioids was discovered; this discovery led to the understanding that hypernociception (induced by inflammation or directly by inflammatory mediators) was essential for the manifestation of peripheral hypernociception (2, 6). In these studies, it was shown that the analgesic action of encephalin derivatives that did not cross the blood-brain barrier (e.g., BW180c and Tyr-D-Ala-GlyPhe) was achieved when the drugs were given systemically. At that time and based on these observations, the possibility of developing strong peripheral analgesics was suggested, a suggestion recently rediscovered by Stein et al. (7). These pioneering observations were confirmed over the next decade by Ferreira and coworkers (8-10) and by other scientists, notably Smith and coworkers (11-16). More recently, other groups have become interested in this area (17)(18)(19).Our serendipitous discovery of the opiates' peripheral antinociceptive activity was a corollary of the observation that morphine inhibited the activation of adenylyl cyclase (20), because we had proposed that inflammatory hyperalgesia was due to stimulation of the neuronal adenosine cAMP͞Ca 2ϩ pathway (21). In this work, following the idea that in several biological systems guanosine cGMP has the opposite effect of cAMP (22)...

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“…These are distributed differentially throughout both the central nervous system (CNS) and peripheral tissues where they regulate a wide variety of physiological processes including smooth muscle contraction, inflammation, perception of pain, secretion, neurotransmission, and proliferation (Nilsson et al, 1985;Grandordy et al, 1988;Nakamura-Craig and Smith, 1989;Rogers et al, 1989;Mayer et al, 1990;Reid et al, 1990). Neurokinin actions are mediated by three pharmacologically distinct cell-surface receptors classified as NK-1, NK-2, and NK-3 that display limited selectivity toward SP, NKA, and NKB, respectively.…”

Section: Introductionmentioning

confidence: 99%

Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways.

Eistetter¹,

Church²,

Mills³

et al. 1991

Cell Regul

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Neurokinins are a family of neuropeptides with widespread distribution mediating a broad spectrum of physiological actions through three distinct receptor subtypes: NK-1, NK-2, and NK-3. We investigated some of the second messenger and cellular processes under control by the recombinant bovine NK-2 receptor stably expressed in Chinese hamster ovary cells. In this system the NK-2 receptor displays its expected pharmacological characteristics, and the physiological agonist neurokinin A stimulates several cellular responses. These include 1) transient inositol 1 ,4,5-trisphosphate (OP3) formation and Ca21 mobilization, 2) increased out put of arachidonic acid and prostaglandin E2 (PGE2J, 3) enhanced cyclic AMP (cAMP) generation, 4) increased de novo DNA synthesis, and 5) an induction of the "immediate early" genes c-fos and c-jun. Although NK-2 receptor-mediated IP3 formation involves activation of a pertussis toxin-insensitive Gprotein, increased cAMP production is largely a secondary response and can be at least partially attributed to autocrine stimulation by endogenously generated eicosanoids, particularly PGE2. This is the first demonstration that a single recombinant neurokinin receptor subtype can regulate, either directly or indirectly, multiple signal transduction pathways and suggests several potential important mediators of neurokinin actions under physiological conditions.

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Substance P and peripheral inflammatory hyperalgesia

Cited by 88 publications

References 43 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

Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K ⁺ channel pathway

Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways.

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Substance P and peripheral inflammatory hyperalgesia

Cited by 88 publications

References 43 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

Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K + channel pathway

Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways.

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Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K ⁺ channel pathway