Ethanol withdrawal induces hyperalgesia mediated by PKCε

Dina, Olayinka A.; Messing, Robert O.; Levine, Jon D.

doi:10.1111/j.1460-9568.2006.04886.x

Cited by 77 publications

(88 citation statements)

References 58 publications

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“…The mismatch ODN sequence, 5′-GCC AGC G CG ATC TT T CGC CC-3′, corresponds to the PKCε subunit antisense sequence with 2 bases mismatched (indicated in bold typeface). We have previously shown that (at a dose of 40 μg) antisense ODN with this sequence decreases PKCε protein in dorsal root ganglia [19,19,23,52,53,60]. A search of EMBL and NCBI GenBank Rattus norvegicus databases to PKCε identified no homologous sequences.…”

Section: Methodsmentioning

confidence: 99%

Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

Green

Chen

Álvarez

et al. 2011

Pain

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100

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Chronic pain in adults has been associated with early-life stress. To examine the pronociceptive effect of early-life stress, we evaluated cutaneous and muscle nociception and activity in muscle nociceptors in an animal model of neonatal stress, limited bedding, in the rat. In this model, litters are exposed to limited bedding between postnatal days 2 – 9 (neonatal limited bedding, NLB) and controls to standard bedding. In adult NLB-treated rats, mechanical nociceptive threshold in skeletal muscle was ficantly lower (~22%) than in controls. Furthermore, administration of prostaglandin E2 (PGE2) in skin as well as produced markedly prolonged hyperalgesia, an effect prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase CΣ (PKCε), a second messenger in nociceptors that has been implicated in the induction and maintenance of chronic pain. In electrophysiological studies, mechanical threshold of muscle nociceptors was reduced by ~31% and conduction velocity significantly increased (~28%). These findings indicate that neonatal stress induces apersistent hyperalgesia and nociceptor sensitization manifest in the adult and that the second messenger PKCε may be a target against which therapies might be directed to treat a chronic pain syndrome that is associated with early-life traumatic stress.

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Section: Methodsmentioning

confidence: 99%

Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

Green

Chen

Álvarez

et al. 2011

Pain

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100

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“…Pain sensitivity after alcohol administration is associated with altered levels of PKCγ in the cytoplasm of rat motor neurons [71]. In related work, withdrawal-induced hyperalgesia was reversibly inhibited with PKCε oligodeoxynucleotide antisense [72]. Morphine tolerance studies in rats show that PKCγ expression increases substantially after eight days of morphine treatment [73].…”

Section: Pkcγ and Pkcε In Neural Tissuesmentioning

confidence: 99%

Protein kinase C as a stress sensor

Barnett

Madgwick

Takemoto

2007

Cellular Signalling

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While there are many reviews which examine the group of proteins known as protein kinase C (PKC), the focus of this article is to examine the cellular roles of two PKCs that are important for stress responses in neurological tissues (PKCγ and ε) and in cardiac tissues (PKCε). These two kinases, in particular, seem to have overlapping functions and interact with an identical target, connexin 43 (Cx43), a gap junction protein which is central to proper control of signals in both tissues. While PKCγ and PKCε both help protect neural tissue from ischemia, PKCε is the primary PKC isoform responsible for responding to decreased oxygen, or ischemia, in the heart. Both do this through Cx43.It is clear that both PKCγ and PKCε are necessary for protection from ischemia. However, the importance of these kinases has been inferred from preconditioning experiments which demonstrate that brief periods of hypoxia protect neurological and cardiac tissues from future insults, and that this depends on the activation, translocation, or ability for PKCγ and/or PKCε to interact with distinct cellular targets, especially Cx43.This review summarizes the recent findings which define the roles of PKCγ and PKCε in cardiac and neurological functions and their relationships to ischemia/reperfusion injury. In addition, a biochemical comparison of PKC γ and PKC ε and a proposed argument for why both forms are present in neurological tissue while only PKC ε is present in heart, are discussed. Finally, the biochemistry of PKCs and future directions for the field are discussed, in light of this new information.

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“…According to the Substance Abuse and Mental Health Services Administration (SAMHSA), in 2013, about 17 million or 7.2 percent of Americans reportedly had an AUD (SAMHSA, 2013). Chronic alcohol exposure can cause neuronal degeneration in the peripheral and central nervous systems (Egli et al, 2012; Mellion et al, 2011; Obernier et al, 2002) resulting in painful small fiber peripheral neuropathy (Dina et al, 2006; Edwards et al, 2012). The hallmarks of neuropathic pain are allodynia (pain responses to normally innocuous stimuli) and hyperalgesia (a heightened reponses to noxious stimuli).…”

Section: Introductionmentioning

confidence: 99%

“…Protein kinase Cε (PKCε), an intracellular protein kinase, is associated with the alcoholic neuropathy and mechanical hyperalgesia (Dina et al, 2000, 2006; Joseph and Levine, 2010; Shumilla et al, 2005). However, it is difficult to develop truly PKC isoform-selective inhibitors (Roffey et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

Alongkronrusmee

Chiang

Rijn

2016

Drug and Alcohol Dependence

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Background As a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA. Methods To study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia. Results We created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3 g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice. Conclusions DORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal.

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Ethanol withdrawal induces hyperalgesia mediated by PKCε

Cited by 77 publications

References 58 publications

Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

Protein kinase C as a stress sensor

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

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