Involvement of PKA-dependent upregulation of nNOS–CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA-induced response in rats

Jiang

et al. 2015

J Pharmacol Exp Ther

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Mas oncogene-related G protein-coupled receptor C (MrgC) is unequally expressed in sensory ganglia and has been shown to modulate pathologic pain. This study investigated the mechanism underlying the effect of MrgC receptors on inflammatory pain. Intrathecal administration of the selective MrgC receptor agonist bovine adrenal medulla 8-22 (BAM8-22) (30 nmol) inhibited complete Freund's adjuvant-evoked hyperalgesia. This was associated with the inhibition of protein kinase C-g and phosphorylated extracellular signal-regulated protein kinase in the spinal cord and/or dorsal root ganglia (DRG). The complete Freund's adjuvant injection in the hindpaw induced an increase in G q , but not G i and G s , protein in the spinal dorsal horn. This increase was inhibited by the intrathecal administration of BAM8-22. The exposure of DRG cultures to bradykinin (10 mM) and prostaglandin E2 (1 mM) increased the expression of calcitonin gene-related peptide (CGRP) and neuronal nitric oxide synthase in small-and medium-sized neurons as well as the levels of CGRP, aspartate, and glutamate in the cultured medium. The bradykinin/prostaglandin E 2 -induced alterations were absent in the presence of BAM8-22 (10 nM). These results suggest that the activation of MrgC receptors can modulate the increase in the expression of CGRP and neuronal nitric oxide synthase as well as the release of CGRP and excitatory amino acids in DRG associated with inflammatory pain. This modulation results in the inhibition of pain hypersensitivity by suppressing the expression of G q protein and protein kinase C-g and extracellular signal-regulated protein kinase signaling pathways in the spinal cord and/or DRG. The present study suggests that MrgC receptors may be a novel target for relieving inflammatory pain.

Section: Inhibition Of Inflammatory Pain By Mrgc Receptorssupporting

confidence: 87%

Activation of Mas Oncogene-Related G Protein–Coupled Receptors Inhibits Neurochemical Alterations in the Spinal Dorsal Horn and Dorsal Root Ganglia Associated with Inflammatory Pain in Rats

Jiang

et al. 2015

J Pharmacol Exp Ther

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“…Previous studies have shown that the mechanisms underlying AM's contribution to morphine tolerance involve a nociception‐facilitating property (Hong et al, ) and the recruitment of CGRP and nNOS (Hong et al, ; Wang et al, ; Wang et al, ), as well as the activation of spinal microglia and astrocytes (Zeng et al, ). We now examined if AM activity was involved in the chronic morphine‐induced alteration in Gi and Gs proteins/ μ receptor coupling.…”

Section: Discussionmentioning

confidence: 99%

“…The AM receptor complex is known to be coupled with Gs protein (Mittra and Bourreau, ). We have demonstrated that treatment with AM dose‐dependently increases PKA activity and cAMP in cultured DRG neurons (Wang et al, ), suggesting that cAMP/PKA is a downstream signalling pathway of AM bioactivity. However, the cAMP/PKA signalling pathway has been demonstrated to play an important role in the pathogenesis of morphine tolerance, as PKA activity in the spinal cord is increased following chronic morphine (Dalton et al , ) and inhibition of spinal cAMP/PKA signalling abolishes morphine‐induced antinociceptive tolerance and hyperalgesia (Tumati et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic treatment with AM increases the levels of cAMP, pCREB and pERK in the spinal dorsal horn Because the treatment with chronic AM induced a μ receptorcoupled Gi-to-Gs switch, cAMP production, a functional effect at the level of the receptor, was determined. As AM can activate cAMP/PKA signalling pathways via its own receptor (Xu and Krukoff, 2007;Ho et al, 2008;Wang et al, 2013), we first examined whether activation of μ receptors by morphine following the chronic AM pretreatment could increase cAMP production. Saline or AM (8 μg) was administered i.t.…”

Section: Figurementioning

confidence: 99%

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Contribution of adrenomedullin to the switch of G protein‐coupled μ‐opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats

Zeng

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEChronic exposure to morphine increases spinal adrenomedullin (AM) bioactivity resulting in the development and maintenance of morphine tolerance. This study investigated the possible involvement of AM in morphine-evoked alteration in μ-opioid receptor-coupled G proteins. EXPERIMENTAL APPROACHAgents were administered intrathecally (i.t.) in rats. Nociceptive behaviours and cumulative dose-response of morphine analgesia were assessed. Neurochemicals in the spinal dorsal horn were assayed by immunoprecipitation, Western blot analysis and ELISA. KEY RESULTSIntrathecal injection of AM (8 μg) for 9 days decreased and increased the levels of μ receptor-coupled Gi and Gs proteins respectively. Morphine stimulation (5 μg) after chronic treatment with AM also induced an increase in cAMP production in the spinal dorsal horn. Co-administration of the selective AM receptor antagonist AM 22-52 inhibited chronic morphine-evoked switch of G protein-coupled μ receptor from Gi to Gs. Chronic exposure to AM increased the phosphorylation of cAMP-responsive element-binding protein (CREB) and ERK. Co-administration of the PKA inhibitor H-89 (5 μg) or MEK1 inhibitor PD98059 (1 μg) reversed the AM-induced thermal/mechanical hypersensitivity, decline in morphine analgesic potency, switch of G proteincoupled μ receptor and increase in cAMP. CONCLUSIONS AND IMPLICATIONSThe present study supports the hypothesis that an increase in AM activity in the spinal dorsal horn contributes to the switch of the μ receptor-coupled G protein from Gi to Gs protein via the activation of cAMP/PKA/CREB and ERK signalling pathways in chronic morphine use. AbbreviationsAM, adrenomedullin; IPP, immunoprecipitation; MPE, maximum possible efffect; MEK, MAP kinase kinase; TFL, tail flick latency; TRPV1, Transient receptor potential vanilloid 1

“…The cAMP‐dependent protein kinase A family (PKAs) (Dina, Chen, Reichling, & Levine, ; Gu, Wang, Li, & Huang, ; Hu & Gereau, ; Kawasaki et al, ; Wang, Ruan, Hong, Chabot, & Quirion, ), protein kinase C family (PKCs) (Gu et al, ; Guo et al, ; He & Wang, ; Kawasaki et al, ; Zhu, Xu, Cuascut, Hall, & Oxford, ), and Src family kinases (SFKs) (Guo et al, ; Kawasaki et al, ; Mickle, Shepherd, Loo, & Mohapatra, ) have been found to play important roles in the regulation of neuroplasticity that is associated with the formation and persistence of pain hypersensitivity. The effects of PKA or PKC activation either alone or together in spinal dorsal horn neurons can be reduced by the inhibition of Src (Kawasaki et al, ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the firing activity by PKA‐PKC‐Src family kinases in cultured neurons of hypothalamic arcuate nucleus

Sun

J of Neuroscience Research

et al. 2019

The cAMP‐dependent protein kinase A family (PKAs), protein kinase C family (PKCs), and Src family kinases (SFKs) are found to play important roles in pain hypersensitivity. However, more detailed investigations are still needed in order to understand the mechanisms underlying the actions of PKAs, PKCs, and SFKs. Neurons in the hypothalamic arcuate nucleus (ARC) are found to be involved in the regulation of pain hypersensitivity. Here we report that the action potential (AP) firing activity of ARC neurons in culture was up‐regulated by application of the adenylate cyclase activator forskolin or the PKC activator PMA, and that the forskolin or PMA application‐induced up‐regulation of AP firing activity could be blocked by pre‐application of the SFK inhibitor PP2. SFK activation also up‐regulated the AP firing activity and this effect could be prevented by pre‐application of the inhibitors of PKCs, but not of PKAs. Furthermore, we identified that forskolin or PMA application caused increases in the phosphorylation not only in PKAs at T197 or PKCs at S660 and PKCα/βII at T638/641, but also in SFKs at Y416. The forskolin or PMA application‐induced increase in the phosphorylation of PKAs or PKCs was not affected by pre‐treatment with PP2. The regulations of the SFK and AP firing activities by PKCs were independent upon the translocation of either PKCα or PKCβII. Thus, it is demonstrated that PKAs may act as an upstream factor(s) to enhance SFKs while PKCs and SFKs interact reciprocally, and thereby up‐regulate the AP firing activity in hypothalamic ARC neurons.