Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for opioid tolerance

doi:10.1016/0006-8993(94)90224-0

Brain Research

Volume 650, Issue 1, 4 July 1994, Pages 175-179

https://doi.org/10.1016/0006-8993(94)90224-0 Get rights and content

Abstract

The aim of this study was to determine whether chronic opioid treatment could influence the protein kinase C (PKC) activity in the rat brain. Chronic morphine (μm agonist) but not butorphanol (μ/σ/κ mixed agonist) treatment enhanced cytosolic PKC activity in the pons/medulla, but not in the cytosolic fractions of cortex and midbrain regions. Concomitant administration of the opioid receptor antagonist, naloxone, blocked the PKC upregulation by chronic morphine. Chronic administration of morphine and butorphanol produced no change in the membrane PKC activity. Antinociceptive tolerance to morphine but not to butorphanol was developed under these conditions. These results suggest that chronic morphine administration leads to an upregulation of the cytosolic PKC activity in the pons/medulla through repeated activation of μ opioid receptors and that the PKC upregulation in this specific area may contribute to the morphine tolerance.

References (25)

BellR.M.
Protein kinase C activation by diacylglycerol second messenger
Cell
(1986)
ChenL. et al.
Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a μ opioid
Neuron
(1991)
GopalakrishnaR. et al.
Factors influencing chelator-stable, detergent-extractable phorbol diester-induced membrane association of protein kinase C
J. Biol. Chem.
(1986)
HoranP. et al.
Comparative pharmacological and biochemical studies between butorphanol and morphine
Pharmacol. Biochem. Behav.
(1989)
KaczmarekL.K.
The role of protein kinase C in the regulation of ion channels and neurotransmitter release
Trends Neurosci.
(1987)
KatoH. et al.
Activation of phosphatidylinositol kinase and phosphatidylinositol-4-phosphate kinase by cAMP inSaccharomyces cerevisiae
J. Biol. Chem.
(1989)
KiefelJ.M. et al.
Medullary μ and σ opioid receptors modulate mesencephalic morphine analgesia in rats
Brain Res.
(1993)
RossiG.C. et al.
Synergic brainstem interactions for morphine analgesia
Brain Res.
(1993)
SuzukiT. et al.
Effects of nor-binaltorphimine on the development of analgesic tolerance to and physical dependence on morphine
Eur. J. Pharmacol.
(1992)
TakagiH. et al.
The nucleus reticularis gigantocellularis of the medulla oblongata is a highly sensitive site in the production of morphine analgesia in the rat
Eur. J. Pharmacol.
(1977)

YamamotoT. et al.

A selective κ-opioid agonist, U-50,488H, blocks the development of tolerance to morphine analgesia in rats

Eur. J. Pharmacol.

(1988)

ZhangL.J. et al.

Phorbol ester suppression of opioid analgesia in rats

Life Sci.

(1990)

Cited by (86)

Effect of KEPI (Ppp1r14c) deletion on morphine analgesia and tolerance in mice of different genetic backgrounds: when a knockout is near a relevant quantitative trait locus
2010, Neuroscience
Citation Excerpt :
However, morphine, unlike opioid peptides, fails to promote receptor phosphorylation, arrestin binding, endocytosis or desensitization in many circumstances (Arden et al., 1995; Keith et al., 1996, 1998; Whistler and von Zastrow, 1998; Zhang et al., 1998). Adaptations in downstream signaling pathways that include protein kinase C and protein kinase A-dependent systems provide alternative sites at which to seek additional contributions to morphine-induced tolerance and desensitization (Nestler and Tallman, 1988; Narita et al., 1994). Identification of substrates whose phosphorylation is altered in KEPI knockouts provides one avenue for identification of such downstream pathways.
We previously identified KEPI as a morphine-regulated gene using subtractive hybridization and differential display PCR. Upon phosphorylation by protein kinase C, KEPI becomes a powerful inhibitor of protein phosphatase 1. To gain insights into KEPI functions, we created KEPI knockout (KO) mice on mixed 129S6×C57BL/6 genetic backgrounds. KEPI maps onto mouse chromosome 10 close to the locus that contains the μ-opioid receptor (Oprm1) and provides a major quantitative trait locus for morphine effects. Analysis of single nucleotide polymorphisms in and near the Oprm1 locus identified a doubly-recombinant mouse with C57BL/6 markers within 1 Mb on either side of the KEPI deletion. This strategy minimized the amount of 129S6 DNA surrounding the transgene and documented the C57BL/6 origin of the Oprm1 gene in this founder and its offspring. Recombinant KEPIKO mice displayed (a) normal analgesic responses and normal locomotion after initial morphine treatments, (b) accelerated development of tolerance to analgesic effects of morphine, (c) elevated activity of protein phosphatase 1 in thalamus, (d) attenuated morphine reward as assessed by conditioned place preference. These data support roles for KEPI action in adaptive responses to repeated administration of morphine that include analgesic tolerance and drug reward.
Morphine-induced μ-opioid receptor rapid desensitization is independent of receptor phosphorylation and β-arrestins
2008, Cellular Signalling
Receptor desensitization involving receptor phosphorylation and subsequent βArrestin (βArr) recruitment has been implicated in the tolerance development mediated by μ-opioid receptor (OPRM1). However, the roles of receptor phosphorylation and βArr on morphine-induced OPRM1 desensitization remain to be demonstrated. Using OPRM1-induced intracellular Ca²⁺ ([Ca²⁺]_i)release to monitor receptor activation, as predicted, [D-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin (DAMGO), induced OPRM1 desensitization in a receptor phosphorylation- and βArr-dependent manner. The DAMGO-induced OPRM1 desensitization was attenuated significantly when phosphorylation deficient OPRM1 mutants or Mouse Embryonic Fibroblast (MEF) cells from βArr1 and 2 knockout mice were used in the studies. Specifically, DAMGO-induced desensitization was blunted in HEK293 cells expressing the OPRM1S375A mutant and was eliminated in MEF cells isolated from βArr2 knockout mice expressing the wild type OPRM1. However, although morphine also could induce a rapid desensitization on [Ca²⁺]_i release to a greater extent than that of DAMGO and could induce the phosphorylation of Ser³⁷⁵ residue, morphine-induced desensitization was not influenced by mutating the phosphorylation sites or in MEF cells lacking βArr1 and 2. Hence, morphine could induce OPRM1 desensitization via pathway independent of βArr, thus suggesting the in vivo tolerance development to morphine can occur in the absence of βArr.
Pre-treatment with a PKC or PKA inhibitor prevents the development of morphine tolerance but not physical dependence in mice
2008, Brain Research
Citation Excerpt :
Granados-Soto et al. (2000) demonstrated that a 5-day morphine infusion in rats resulted in an increased phosphorylating activity and in significantly higher levels of PKCα and PKCγ in the dorsal spinal horn. In addition, chronic morphine treatment in mice enhanced cytosolic PKC activity in the brainstem (Narita et al., 1994) and up-regulated membrane-bound PKC in the limbic forebrain including the nucleus accumbens (Narita et al., 2002). Morphine tolerance was prevented when mice were co-infused for 5 days with the antisense oligonucleotide to PKCα and morphine (Hua et al., 2002).
We previously demonstrated that intracerebroventricular (i.c.v.) administration of protein kinase C (PKC) or protein kinase A (PKA) inhibitors reversed morphine antinociceptive tolerance in 3-day morphine-pelleted mice. The present study aimed at evaluating whether pre-treating mice with a PKC or PKA inhibitor prior to pellet implantation would prevent the development of morphine tolerance and physical dependence. Antinociception was assessed using the warm-water tail immersion test and physical dependence was evaluated by quantifying/scoring naloxone-precipitated withdrawal signs. While drug-naïve mice pelleted with a 75 mg morphine pellet for 3 days developed a 5.8-fold tolerance to morphine antinociception, mice pre-treated i.c.v. with the PKC inhibitors bisindolylmaleimide I, Go-7874 or Go-6976, or with the myristoylated PKA inhibitor, PKI-(14-22)-amide failed to develop any tolerance to morphine antinociception. Experiments were also conducted to determine whether morphine-pelleted mice were physically dependent when pre-treated with PKC or PKA inhibitors. The same inhibitor doses that prevented morphine tolerance were evaluated in other mice injected s.c. with naloxone and tested for precipitated withdrawal. The pre-treatment with PKC or PKA inhibitors failed to attenuate or block the signs of morphine withdrawal including jumping, wet-dog shakes, rearing, forepaw tremor, increased locomotion, grooming, diarrhea, tachypnea and ptosis. These data suggest that elevations in the activity of PKC and PKA in the brain are critical to the development of morphine tolerance. However, it appears that tolerance can be dissociated from physical dependence, indicating a role for PKC and PKA to affect antinociception but not those signs mediated through the complex physiological processes of withdrawal.
Determination of the role of conventional, novel and atypical PKC isoforms in the expression of morphine tolerance in mice
2007, Pain
This study comprehensively determines the role of all the major PKC isoforms in the expression morphine tolerance. Pseudosubstrate and receptors for activated C-kinase (RACK) peptides inhibit only a single PKC isoform, while previously tested chemical PKC inhibitors simultaneously inhibit multiple isoforms making it impossible to determine which PKC isoform mediates morphine tolerance. Tolerance can result in a diminished effect during continued exposure to the same amount of substance. In rodents, morphine pellets provide sustained exposures to morphine leading to the development of tolerance by 72 h. We hypothesized that administration of the PKC isoform inhibitors i.c.v. would reverse tolerance and reinstate antinociception in the tail immersion and hot plate tests from the morphine released solely from the pellet. Inhibitors to PKCα, γ and ε (100–625 pmol) dose-dependently reinstated antinociception in both tests. The PKCβ_I, β_II, δ, θ, ε, η and ξ inhibitors were inactive (up to 2500 pmol). In other mice, the degree of morphine tolerance was determined by calculating ED₅₀ and potency-ratio values following s.c. morphine administration. Morphine s.c. was 5.6-fold less potent in morphine-pelleted vs. placebo-pelleted mice. Co-administration of s.c. morphine with the inhibitors i.c.v. to either PKCα (625 pmol), γ (100 pmol) or ε (400 pmol) completely reversed the tolerance so that s.c. morphine was equally potent in both placebo- and morphine-pelleted mice. The PKCβ_I, β_II, δ, θ, ε, η and ξ inhibitors were inactive. Thus, PKCα, γ and ε appear to contribute to the expression of morphine tolerance in mice.
How important is protein kinase C in μ-opioid receptor desensitization and morphine tolerance?
2006, Trends in Pharmacological Sciences
The repeated administration of opiate drugs such as morphine results in the development of tolerance to their analgesic, rewarding (euphoric) and respiratory-depressant effects; thus, to obtain the same level of response with subsequent administrations, a greater dose must be used. Tolerance can limit the clinical efficacy of opiate drugs and enhance the social problems that are inherent in recreational opioid abuse. Surprisingly, the mechanism (or mechanisms) underlying the development of morphine tolerance remains controversial. Here, we propose that protein kinase C could have a crucial role in the desensitization of μ-opioid receptors by morphine and that this cellular process could contribute to the development and maintenance of morphine tolerance in vivo.
Phosphorylation: A molecular switch in opioid tolerance
2006, Life Sciences
Protein phosphorylation is a key posttranslational modification mechanism controlling the conformation and activity of many proteins. Increasing evidence has implicated an essential role of phosphorylation by several major protein kinases in promoting and maintaining opioid tolerance. We review some of the most recent studies on protein kinase C (PKC), cyclic AMP dependent protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase G (PKG), and G protein receptor kinase (GRK). These kinases act as the molecular switches to modulate opioid tolerance. Pharmacological interventions at one or more of the protein kinases and phosphatases may provide valuable strategies to improve opioid analgesia by attenuating tolerance to these drugs.

View all citing articles on Scopus

View full text

Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for opioid tolerance

Abstract

Cell

Neuron

J. Biol. Chem.

Pharmacol. Biochem. Behav.

Trends Neurosci.

J. Biol. Chem.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.