Reduced development of tolerance to the analgesic effects of morphine and clonidine in PKCγ mutant mice

Zeitz, Karla P.; Malmberg, Annika B.; Gilbert, Heather; Basbaum, Allan I.

doi:10.1016/s0304-3959(01)00353-0

Cited by 111 publications

(96 citation statements)

References 37 publications

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“…With the method of [ The results indicate a strong correlation between PKC and morphine tolerance, which was later confirmed by a wide range of other studies (8)(9)(10)(11). The present study was performed to explore the role of PKC in morphine tolerance at the spinal level of rats, especial in the development and maintenance of morphine tolerance.…”

supporting

confidence: 66%

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Jin

2009

ACS Chem. Neurosci.

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The present study was performed to investigate the possible role of protein kinase C (PKC) in morphine tolerance at spinal levels of rats. Intrathecal injection of 10 μg of morphine induced increases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in rats. After intrathecal injections of 10 μg of morphine (twice a day) lasted for 5 days, the antinociceptive effects induced by intrathecal injections of morphine decreased significantly in rats. Interestingly, we found that there were significant increases in the content of PKC in the dorsal horn of the spinal cord and the dorsal root ganglion, but not in the ventral horn of the spinal cord, in rats with morphine tolerance determined by Western blot, suggesting that PKC is involved in morphine tolerance at spinal levels of rats. Furthermore, our results demonstrated that chronic intrathecal injection of the PKC inhibitor significantly inhibited the development of morphine tolerance. Moreover, we found that the maintenance of morphine tolerance was blocked by intrathecal administration of a PKC inhibitor in rats, and the inhibitory effects of the PKC inhibitor on morphine tolerance lasted for more than two days. Taken together, the present study clearly showed that PKC is involved in morphine tolerance at the spinal level of rats and that intrathecal administration of a PKC inhibitor can block the development and maintenance of morphine tolerance.Keywords: Development of morphine tolerance, dorsal root ganglion, hindpaw withdrawal latency, maintenance of morphine tolerance, PKC, spinal cord M orphine still proves to be clinically indispensible in treating moderate to severe pain. However, the development of tolerance, antinociceptive effect produced by a given dose of morphine declined over time (1-3), largely limits its extensive application. Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinases, has been demonstrated to play an important role in cellular signal transduction. PKC can be activated upon external stimulation of cells by various ligands including growth factors, hormones, and neurotransmitters (4-6).With the method of [ The results indicate a strong correlation between PKC and morphine tolerance, which was later confirmed by a wide range of other studies (8-11). The present study was performed to explore the role of PKC in morphine tolerance at the spinal level of rats, especial in the development and maintenance of morphine tolerance. Results and DiscussionInfluence of Morphine Tolerance on the Expression of PKC at the Spinal Level of RatsTo investigate the role of PKC in morphine tolerance at the spinal level, rats received intrathecal administration of 10 μg of morphine twice a day for 5 days to produce morphine tolerance. Another group of rats without any treatment was as the control group (n=8).As shown in Figure 1, there were significant increases in the content of PKC (n=5; F=6.34; P<0.05) in the dorsal horn of the spinal cord in rats with morphine tolerance compared wit...

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supporting

confidence: 66%

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Jin

2009

ACS Chem. Neurosci.

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“…In more recent work, it was demonstrated that PKCγ contributes to the induction of tolerance to morphine. PKCγ knock out mice had similar nocioceptive processing regardless of morphine treatment [74]. In other work, PKCγ knock out mice treated with morphine did not exhibit spinal cord astroglial hypertrophy or proliferation which is normally associated with development of morphine tolerance [75].…”

Section: Pkcγ and Pkcε In Neural Tissuesmentioning

confidence: 72%

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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“…Morphine tolerance was prevented when mice were co-infused for 5 days with the antisense oligonucleotide to PKC and morphine (Hua et al, 2002). A similar attenuated morphine tolerance was observed in PKC null mutant mice, suggesting that the level of PKC available for kinase phosphorylation is critical to the development of antinociceptive tolerance (Zeitz et al, 2001). We have recently used pseudosubstrate and RACK (receptors for activated C-kinase) peptides inhibitors that can inhibit only a single PKC isoform, and we demonstrated that the PKC , and but not the PKC I , II , , , , and isoforms appear to contribute to the expression of morphine tolerance in mice (Smith et al, 2007).…”

Section: Prevention Of Morphine Antinociceptive Tolerance By Pkc Inhimentioning

confidence: 73%

Pre-treatment with a PKC or PKA inhibitor prevents the development of morphine tolerance but not physical dependence in mice

et al. 2008

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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 naloxoneprecipitated 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.

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Reduced development of tolerance to the analgesic effects of morphine and clonidine in PKCγ mutant mice

Cited by 111 publications

References 37 publications

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Protein kinase C as a stress sensor

Pre-treatment with a PKC or PKA inhibitor prevents the development of morphine tolerance but not physical dependence in mice

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