Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia

Taiwo, Yetunde O.; Levine, Jon D.

doi:10.1016/0306-4522(91)90255-m

Cited by 217 publications

(147 citation statements)

References 30 publications

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“…In accordance with these findings, adenylyl cyclase knock-out mice show reduced behavioral responses in several pain models (44,45) as well as a reduced response to opioids (46,47). At the cellular and molecular level the hyperalgesic effect of cAMP is mainly mediated by PKA (32). PKA phosphorylates multiple targets during central sensitization (i.e.…”

Section: Discussionsupporting

confidence: 57%

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Coste

Brenneis

Linke

et al. 2008

Journal of Biological Chemistry

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Sphingosine 1-Phosphate (S1P) modulates various cellular functions such as apoptosis, cell differentiation, and migration. Although S1P is an abundant signaling molecule in the central nervous system, very little is known about its influence on neuronal functions. We found that S1P concentrations were selectively decreased in the cerebrospinal fluid of adult rats in an acute and an inflammatory pain model. Pharmacological inhibition of sphingosine kinases (SPHK) decreased basal pain thresholds and SphK2 knock-out mice, but not SphK1 knock-out mice, had a significant decrease in withdrawal latency. Intrathecal application of S1P or sphinganine 1-phosphate (dihydro-S1P) reduced the pain-related (nociceptive) behavior in the formalin assay. S1P and dihydro-S1P inhibited cyclic AMP (cAMP) synthesis, a key second messenger of spinal nociceptive processing, in spinal cord neurons. By combining fluorescence resonance energy transfer (FRET)-based cAMP measurements with Multi Epitope Ligand Cartography (MELC), we showed that S1P decreased cAMP synthesis in excitatory dorsal horn neurons. Accordingly, intrathecal application of dihydro-S1P abolished the cAMP-dependent phosphorylation of NMDA receptors in the outer laminae of the spinal cord. Taken together, the data show that S1P modulates spinal nociceptive processing through inhibition of neuronal cAMP synthesis.The bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P) 2 is synthesized by phosphorylation of sphingosine by sphingosine kinases (SPHK) in a wide variety of cell types in response to extracellular stimuli such as nerve growth factor or vascular endothelial growth factor. S1P modulates diverse cellular functions such as apoptosis, cell differentiation, and migration either through the activation of a family of five G-protein-coupled receptors (S1P 1-5 ) or by acting as an intracellular second messenger (1-3). In the central nervous system S1P has been shown to be released by cerebellar granule cells and astrocytes (4 -6). Regarding its function in the central nervous system it is well known that S1P promotes survival of neurons and astrocytes, induces proliferation of neural progenitor cells and astrocytes, and mediates nerve growth factor (NGF)-stimulated neurite outgrowth (2, 3, 7). However, very little is known about the role of S1P in the regulation of neuronal excitability and the mechanisms that mediate these S1P functions. Recently whole cell patch clamp recordings revealed that loss of S1P 2 leads to a large increase in the excitability of neocortical pyramidal neurons (8), suggesting an inhibitory effect of S1P 2 on neuronal excitability. On the other hand, several in vitro studies show that S1P can also increase neuronal functions. For example, S1P receptor activation augments glutamate secretion in hippocampal neurons (9) and elevated intracellular S1P concentrations enhance the spontaneous neurotransmitter release at neuromuscular junctions (10). Furthermore, intra-as well as extracellularly applied S1P facilitated the NGF-induced increas...

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Section: Discussionsupporting

confidence: 57%

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Coste

Brenneis

Linke

et al. 2008

Journal of Biological Chemistry

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“…It evokes vasodilation through the activation of a cAMP-dependent pathway (44). PGI 2 is produced from arachidonic acid in a series of reactions catalyzed by enzymes that include cyclooxygenase.…”

Section: Discussionmentioning

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

109

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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“…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). The resulting inflammatory pain can be blocked by an inactive cAMP analogue, which prevents PKA activation (48). Here we confirmed that peripheral inflammation led to an increase in spinal cord levels of intracellular cAMP by quantifying 2 cAMP-responsive genes, both of which were significantly induced during the course of inflammation (Fig.…”

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.

169

218

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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

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Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia

Cited by 217 publications

References 30 publications

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

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

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

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