Elsevier

Brain Research

Volume 723, Issues 1–2, 3 June 1996, Pages 61-69
Brain Research

Relevance of phosphorylation state to opioid responsiveness in opiate naive and tolerant/dependent tissue

https://doi.org/10.1016/0006-8993(96)00217-XGet rights and content

Abstract

This laboratory previously reported that the μ-selective opiate receptor agonist, sufentanil, produces a naloxone-reversible, concentration-dependent facilitation or inhibition of the stimulated formation of cAMP in the myenteric plexus. Chronic in vivo exposure to morphine results not only in the loss of inhibitory opioid responsiveness but in the reversal of inhibition to enhancement. The present study demonstrates, in tolerant/dependent as well as opiate naive tissue, that the state of phosphorylation is a critical determinant of the balance between positive and negative opioid modulation of stimulated cAMP formation. In vitro treatment of chronic morphine-treated preparations with inhibitors of protein kinases, abolishes the previously observed reversal of opioid inhibition to enhancement and restores sufentanil inhibitory responsiveness. The established kinase-type selectivity profile of the inhibitors employed suggests the involvement of protein kinase C (PKC) in the tolerant-associated reversal from opioid inhibition to enhancement of cAMP formation. Conversely, treatment of opiate naive tissue with the protein phosphatase inhibitor okadaic acid or a phorbol ester activator of protein kinase C, phorbol 12-myristate 13-acetate (PMA), not only attenuates sufentanil inhibition of evoked cAMP formation but reverses it to a facilitation (as occurs following chronic in vivo morphine exposure). This effect of PMA is abolished by the PKC-selective inhibitor chelerythrine. Moreover, the longitudinal muscle myenteric plexus content of PKC α and PKC β is substantially elevated following chronic morphine treatment. These results underscore the relevance of opioid bimodality to the manifestation of tolerance/dependence and suggest that augmented phosphorylation (mediated at least in part via PKC) is a critical determinant of some of the sequelae of chronic morphine exposure.

References (31)

Cited by (31)

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    2009, International Review of Neurobiology
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    Tolerance and physical dependence have been correlated with changes in the intracellular cAMP signal transduction cascade. Elements of the cascade found to be altered include G-proteins, adenylate cyclase, protein kinase A (PKA), and its target CREB (cAMP response element-binding) (Nestler et al., 1994; Wang and Gintzler, 1997; Wang et al., 1996). The activity of CREB is regulated by phosphorylation and opiates have been shown to alter phosphorylation of CREB protein.

  • Chronic morphine-induced loss of the facilitative interaction between vasoactive intestinal polypeptide and δ-opioid: Involvement of protein kinase C and phospholipase Cβs

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    These results indicate that the VIP–DPDPE multiplicative enhancement of spinal cAMP formation is subject to opioid tolerance, which is consistent with the previously observed ability of chronic systemic morphine to produce cross-tolerance with δ-opioid receptor-mediated antinociception [45]. In order to explore the involvement of PKC phosphorylation in the chronic morphine-induced loss of the VIP–DPDPE facilitative interaction, we assessed whether or not it could be mitigated by acute in vitro treatment with the highly selective PKC inhibitor chelerythrine [25] as previously utilized [41,42]. In in vivo chronic morphine-exposed spinal tissue that had been treated in vitro with chelerythrine, basal levels of cAMP were 8.48±0.76 pmol/mg protein, comparable to values obtained in the absence of opioid.

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Mildred Rivera is an Aaron Diamond Foundation Fellow.

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