Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs

Martin, Hervé A.; Basbaum, Allan I.; Kwiat, Geoffrey C.; Goetzl, E J; Levine, Jon D.

doi:10.1016/0306-4522(87)90360-5

Cited by 220 publications

(95 citation statements)

References 44 publications

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“…The exact mechanisms through which prostaglandins contribute to the axon reflex are unknown. There is evidence suggesting that PGI 2 and PGE 2 sensitize the primary sensory afferents and increase the basal and evoked release of the neuropeptides CGRP and substance P (11,28,38,50). This mechanism is recognized to play a role in inflammation and wound healing and is most likely responsible for the increase in CuBF as well.…”

Section: Ach-mediated Cutaneous Microcirculatory Vasodilationmentioning

confidence: 99%

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Berghoff

Kathpal

Kilo

et al. 2002

Journal of Applied Physiology

111

118

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nisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation. J Appl Physiol 92: 780-788, 2002; 10.1152/japplphysiol.01167.2000.-The relative contribution of endothelial vasodilating factors to acetylcholine (ACh)-mediated vasodilation in the forearm cutaneous microcirculation is unclear. The aims of this study were to investigate the contributions of prostanoids and cutaneous C fibers to basal cutaneous blood flow (CuBF) and ACh-mediated vasodilation. ACh was iontophoresed into the forearm, and cutaneous perfusion was measured by laser-Doppler flowmetry. To inhibit the production of prostanoids, four doses of acetylsalicylic acid (ASA; 81, 648, 972, and 1,944 mg) were administered orally. Cutaneous nerve fibers were blocked with topical anesthesia. Cyclooxygenase inhibition did not change basal CuBF or endothelium-mediated vasodilation to ACh. In contrast, ASA (972 and 1,944 mg) significantly reduced the C-fiber-mediated axon reflex in a dose-dependent fashion. Blockade of C-fiber function significantly reduced axon reflex-mediated vasodilation but did not affect basal CuBF or endothelium-dependent vasodilation. The findings suggest that prostanoids do not contribute significantly to basal CuBF or endothelium-dependent vasodilation in the forearm microcirculation. In contrast, prostanoids are mediators of the ACh-provoked axon reflex. endothelium; prostaglandin; nitric oxide; axon reflex; acetylcholine CUTANEOUS BLOOD FLOW (CuBF) is regulated by endothelial, neural, and humoral factors. The interaction between these mechanisms of blood flow control is poorly defined. Recent studies of CuBF have used the technique of laser-Doppler flowmetry in combination with the iontophoretic application of charged vasoactive agents. Acetylcholine (ACh) has been used to induce endothelium-mediated blood flow, and the direct nitric oxide (NO) donor sodium nitroprusside has been used to provoke non-endothelium-mediated blood flow. Despite the widespread use of ACh-evoked vasodilation in studies investigating vascular physiology and pathophysiology, the mechanisms responsible for its effect, particularly in the cutaneous microcirculation, are unresolved. This question has important implications. If prostaglandins do play a major role in endotheliummediated vasodilation, some effects of acetylsalicylic acid (ASA) therapy, which is extensively used for its prophylactic antiplatelet effect in patients with cardiovascular and cerebrovascular disease (17, 27), may be counterproductive. Furthermore, if prostaglandins play a major role in the C-fiber-mediated axon reflex, reduction of this reflex by cyclooxygenase inhibition may attenuate the ability to mount a neurogenic inflammatory response (4, 48). Attenuation of this important protective reflex in patients with peripheral neuropathy impairs wound healing and increases susceptibility to infection, thereby leading to cutaneous ulceration, gangrene, and ultimately amputation (3,21).Factors released by the endothelium in response to ACh include NO, vasoactive prostanoi...

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Section: Ach-mediated Cutaneous Microcirculatory Vasodilationmentioning

confidence: 99%

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Berghoff

Kathpal

Kilo

et al. 2002

Journal of Applied Physiology

111

118

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“…The proinflammatory actions of PGE 2 result, in part, from a direct action of this eicosanoid on sensory neurons. In in situ preparations, E-series prostaglandins augment the firing of sensory neurons in response to noxious stimuli (16,17). Furthermore, exposing sensory neurons in culture to PGE 2 increases cAMP content (18), increases the number of action potentials elicited by a depolarizing stimulus (19), and augments the evoked release of the neuropeptides (18,20).…”

Section: Prostaglandin E 2 Receptors (Ep Receptors)mentioning

confidence: 99%

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

Southall¹,

Vasko

2001

Journal of Biological Chemistry

168

150

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Although a number of prostaglandin E 2 (PGE 2 ) receptor subtypes have been cloned, limited studies have been performed to elucidate subtypes that subserve specific actions of this eicosanoid, in part because of a paucity of selective receptor antagonists. Using reverse transcription-polymerase chain reaction (PCR) and antisense oligonucleotides, we examined which prostaglandin E 2 receptor (EP receptor) subtypes are expressed in sensory neurons and which mediate the PGE 2 -induced increase in cAMP production and augmentation of peptide release. Reverse transcription-PCR of cDNA isolated from rat sensory neurons grown in culture revealed PCR products for the EP1, EP2, EP3C, and EP4 receptor subtypes but not the EP3A or EP3B. Preexposing neuronal cultures for 48 h to antisense oligonucleotides of EP3C and EP4 mRNA diminished expression of the respective receptors by ϳ80%, abolished the PGE 2 -stimulated production of cAMP, and blocked the ability of PGE 2 to augment release of immunoreactive substance P and calcitonin gene-related peptide. Pretreating with individual antisense against the EP2, EP3C, or EP4 receptors or combinations of missense oligonucleotides had no effect on PGE 2 -induced activity. Treatment with antisense to EP3C and EP4 receptor subtypes did not alter the ability of forskolin to increase cAMP or enhance peptide release. These results demonstrate that sensory neurons are capable of expressing multiple EP receptor subtypes but that only the EP3C and EP4 receptors mediate PGE 2 -induced sensitization of sensory neurons. Prostaglandin E 2 receptors (EP receptors)1 have been classified into four general subtypes, EP1, EP2, EP3, and EP4, based on cloning and pharmacological manipulations (1, 2). These receptors are G-protein-coupled, and binding of agonists results in activation of various transduction cascades depending on the receptor subtype activated and the cells being studied. Activation of the EP1 receptor in kidney tubule cells increases the concentration of intracellular calcium, phosphoinositol turnover, and PKC activity (3, 4). EP2 and EP4 receptors are coupled through G s (1) to increase intracellular cAMP in a number of preparations (5-8). The EP3 receptor undergoes post-transcriptional RNA splicing to produce multiple EP3 isoforms, and activation of these splice variants can increase calcium mobilization or either stimulate or inhibit cAMP production (9 -11). Because subtypes of the EP receptor can be linked to different transduction cascades in different types of cells, it is critical to determine which receptors and receptorassociated signal transduction pathways are responsible for specific physiological actions of E-series prostaglandins.Although PGE 2 has a number of diverse physiological actions (12), its role in pain and inflammation is of primary importance. Indeed, both the analgesic and the anti-inflammatory actions of the nonsteroidal anti-inflammatory drugs are attributed to their ability to inhibit prostaglandin synthesis (13). In addition, PGE 2 is produced at sites of ...

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“…Interestingly, there are several similarities between BK-and capsaicin-induced responses. For example, the depolarization of sensory neurons caused by BK or capsaicin is highly correlated (Martin et al, 1987) and the thermal hyperalgesia produced by BK in wild-type mice is absent in mice lacking TRPV1 (Chuang et al, 2001). Therefore, in the present study, we sought to investigate the role played by TRPV1 receptors in the nociceptive response induced by peripheral activation of kinin B 2 receptor in vivo.…”

Section: Introductionmentioning

confidence: 99%

Contribution of vanilloid receptors to the overt nociception induced by B₂ kinin receptor activation in mice

Ferreira

Silva

Calixto

2004

British J Pharmacology

169

101

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1 The vanilloid receptor (TRPV1) is viewed as a molecular integrator of several nociceptive stimuli. In the present study, we have investigated the role played by TRPV1 in the nociceptive response induced by the peripheral activation of kinin B 2 receptor in mice. 2 The intraplantar (i.pl.) administration of bradykinin (BK) and the selective B 2 agonist Tyr 8 -BK, or the vanilloid agonists resiniferatoxin and capsaicin, into the mouse paw induced a dose-related overt nociception of short duration. The B 2 receptor antagonist Hoe 140 inhibited BK-induced, but not capsaicin-induced, nociceptive response. On the other hand, the TRPV1 antagonist capsazepine inhibited both capsaicin-and BK-mediated nociception. 3 Repeated injections of BK or capsaicin produced desensitization to their nociceptive response. Capsaicin desensitization greatly reduced BK-induced nociception, but in contrast, the desensitization to BK increased the capsaicin response. 4 Administration of low doses of capsaicin or acidified saline did not produce nociception when administered alone, but caused a pronounced effect when administered in association with a subthreshold dose of BK. Moreover, the degeneration of the subset of primary afferent fibers, sensitive to capsaicin, abolished both capsaicin-and BK-induced nociception. 5 The inhibition of phospholipase C (PLC), protein kinase C or phospholipase A 2 markedly decreased the nociception caused by BK, but not that of capsaicin. BK administration increased leukotriene B 4 levels in the injected paw. Likewise, BK-induced overt nociception was decreased by lipoxygenase (LOX) inhibition. 6 These results demonstrate that BK produces overt nociception mediated by TRPV1 receptor stimulation, via PLC pathway activation and LOX product formation.

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Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs

Cited by 220 publications

References 44 publications

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

Contribution of vanilloid receptors to the overt nociception induced by B₂ kinin receptor activation in mice

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Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs

Cited by 220 publications

References 44 publications

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

Prostaglandin Receptor Subtypes, EP3C and EP4, Mediate the Prostaglandin E2-induced cAMP Production and Sensitization of Sensory Neurons

Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice

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Contribution of vanilloid receptors to the overt nociception induced by B₂ kinin receptor activation in mice