Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system

Taiwo, Yetunde O.; Bjerknes, L.; Goetzl, Edward J.; Levine, Jon D.

doi:10.1016/0306-4522(89)90280-7

Cited by 227 publications

(164 citation statements)

References 18 publications

Supporting

Mentioning

152

Contrasting

Unclassified

Order By: Relevance

“…The data indicated that acute inflammation with IS resulted in a decrease in the PWL and PWT in the behavioral studies and this is consistent with previous studies using acute inflammatory mediators (Taiwo et al, 1987;Taiwo et al, 1989;Simone et al, 1989b;Gilchrist et al, 1996). Sensitization to heat was confirmed at the single fiber level, with CMH units showing a decrease in threshold and an increase in discharge rate in response to IS.…”

Section: Differences In Mechanisms Underlying Thermal Vs Mechanical Ssupporting

confidence: 90%

“…modulation of second messenger pathways. In this regard, Group II mGluRs inhibit a forskolin-stimulated cAMP pathway (Tanabe et al, 1992), a pathway activated by many inflammatory mediators leading to hyperalgesia (Taiwo et al 1989(Taiwo et al , 1991Yang and Gereau, 2002). Group II mGluRs may reduce peripheral glutamate release.…”

Section: Peripheral Site Of Action For the Group II Agonistmentioning

confidence: 99%

See 1 more Smart Citation

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

Zhou

Carlton

2008

Neuroscience

View full text Add to dashboard Cite

Several lines of evidence indicate that Group II metabotropic glutamate receptor (mGluR) activation can depress sensory transmission. We have reported the expression of Group II mGluRs on unmyelinated axons, many of which were presumed to be nociceptors, in the rat digital nerve (Carlton et al., 2001b). The goals of the present study are to further our understanding of Group II modulation of nociceptor processing in the periphery, documenting behavioral changes using inflammatory models and documenting, for the first time, cutaneous single fiber activity following exposure to a Group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and antagonist LY341495 (LY). The data indicate that peripheral Group II mGluR activation does not depress nociceptive behaviors or nociceptor fiber responses in the non-sensitized state (i.e. following brief nociceptive mechanical or thermal stimulation) but can depress these responses when nociceptors are sensitized by exposure to formalin or inflammatory soup. Group II mGluR agonist-induced inhibition can be blocked by a selective Group II antagonist. Peripheral Group II mGluR-induced inhibition evoked in these studies occurs through activation of local receptors and not through spinal or supraspinal mechanisms. The data indicate that administration of selective Group II agonists may be potent therapeutic agents for prevention of peripheral sensitization and for treatment of inflammatory pain. KeywordsGroup II mGluR; pain; APDC; LY341495; formalin; inflammation; inflammatory soup Glutamate and glutamate receptors play an important role in peripheral pain mechanisms in animals (Carlton, 2001;Carlton et al., 2003) and humans (McNearney et al., 1999;McNearney et al., 2000;Cairns et al., 2001;Alfredson et al., 2001;Alfredson and Lorentzon, 2002;Svensson et al., 2003;Cairns et al., 2003). To date, ionotropic glutamate receptors (iGluRs) including N-methyl-D-aspartate (NMDA) and non-NMDA receptors are implicated in peripheral cutaneous pain mechanisms Bleakman et al., 2006).More recent studies indicate that metabotropic glutamate receptors (mGluRs) can modulate peripheral nociceptor function. In contrast to iGluRs, which are ligand-gated ion channel receptors, mGluRs mediate their function via G-protein coupled receptors which trigger Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2009 June 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript intracellular second-messenger systems (Pin and Duvoisin, 1995). Accordin...

show abstract

Section: Differences In Mechanisms Underlying Thermal Vs Mechanical Ssupporting

confidence: 90%

Section: Peripheral Site Of Action For the Group II Agonistmentioning

confidence: 99%

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

Zhou

Carlton

2008

Neuroscience

View full text Add to dashboard Cite

show abstract

“…It has been demonstrated that intrathecally applied cAMP-analogues as well as the adenylyl cyclase activator forskolin produce an enhanced response to noxious stimuli (hyperalgesia) (28) while inhibitors of cAMP-phosphodiesterases prolong hyperalgesia (28,29). Moreover, agents that decrease cAMP levels, such as opioids and adenosine, inhibit hyperalgesia (30,31).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Coste

Brenneis

Linke

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

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.

169

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

Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system

Cited by 227 publications

References 18 publications

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

Group II metabotropic glutamate receptor activation attenuates peripheral sensitization in inflammatory states

Sphingosine 1-Phosphate Modulates Spinal Nociceptive Processing

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

Contact Info

Product

Resources

About