Low‐dose morphine induces hyperalgesia through activation of G<sub>αs</sub>, protein kinase C, and l‐type Ca<sup>2+</sup> channels in rats

Esmaeili‐Mahani, Saeed; Shimokawa, Noriaki; Javan, Mohammad; Maghsoudi, Nader; Motamedi, Fereshteh; Koibuchi, Noriyuki; Ahmadiani, Abolhasan

doi:10.1002/jnr.21489

Cited by 31 publications

(17 citation statements)

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“…Several lines of evidence indicate the importance of this pathway for mu receptor signaling: (1) Mu opioid receptors increase inositol (1,4,5)triphosphate formation in a pertussis toxin-reversible manner [21]; (2) genetic deletion of PLC β3 [32] or PKCε [17] in mice enhances morphine analgesia; and (3) a small molecule inhibitor of Gβγ-dependent PLC increases morphine analgesia [3, 15]. Furthermore, the hyperalgesia induced by ultra-low dose morphine is mediated by the PLC-PKC pathway [2, 6, 8]. Thus, a pro-nociceptive system is activated through mu opioid receptors and PLC-PKC pathways.…”

Section: Discussionmentioning

confidence: 99%

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Lee

Baiamonte

Spano³

et al. 2011

Neuroscience Letters

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Rhes, the Ras Homolog Enriched in Striatum, is an intermediate-size GTP binding protein.Although its full functions are not yet known, it has been shown to affect signaling and behaviors mediated by G protein-coupled receptors. Here we have tested whether Rhes affects behaviors mediated by opioid receptors. Wild type and rhes-deficient mice were administered morphine and tested for analgesia in formalin and tail flick tests. Rhes −/− mice showed significantly enhanced analgesia in both tests relative to rhes +/+ mice. Furthermore, rhes −/− mice did not display tolerance to repeated morphine administration and displayed significantly less withdrawal than rhes +/+ mice. These findings indicate that Rhes is involved in behaviors mediated by mu opioid receptors and in the adaptive response to repeated morphine administration. KeywordsRASD2; opioid; tolerance; analgesia; dependence; GTP-binding protein Rhes (Ras Homolog Enriched in Striatum, RASD2) is a GTP-binding protein that is highly expressed in the striatum of rodents and has a high degree of homology with the Ras superfamily of small GTPase proteins [7]. It was originally characterized by using subtractive hybridization for genetic sequences differentially expressed in striatum [7,29]. The rhes gene codes for a 266 amino acid protein of intermediate size between Ras-like GTPases and α subunits of heterotrimeric G proteins. Rhes is most closely related to AGS1/ Dexras1, showing 62% identity [7]. Both proteins contain an elongated C-terminus, defining them as the founding members of a novel subfamily of the Ras superfamily [7]. Furthermore, both genes are regulated by hormones, rhes by thyroid hormone and AGS1/ dexras1 by dexamethasone [11,30].In vitro investigations of Rhes have shown its ability to attenuate Gs and, more recently, Gi/ o signaling after agonist stimulation of G protein coupled receptors (GPCR). In PC12 cells,

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Section: Discussionmentioning

confidence: 99%

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Lee

Baiamonte

Spano³

et al. 2011

Neuroscience Letters

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“…Opioids in ordinary (analgesic) doses have an inhibitory effect on calcium channels, but could activate these channels in very low doses which elicit a hyperalgesic property (Esmaeili-Mahani et al, 2008). Therefore, it seems logical that olive leaf extract with calcium channel blockade activity could block morphine-induced hyperalgesia and also potentiate morphine analgesia.…”

Section: Experimental Groupsmentioning

confidence: 99%

“…Due to the fact that calcium influx blockade is essential for normal opioid receptor signaling, Ca 2+ channel antagonists have been shown to elevate antinociceptive effect of morphine (Fukuizumi et al, 2003;Esmaeili-Mahani et al, 2005) and suppress morphineinduced hyperalgesia (Esmaeili-Mahani et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Olive (Olea europaea L.) leaf extract elicits antinociceptive activity, potentiates morphine analgesia and suppresses morphine hyperalgesia in rats

Esmaeili‐Mahani

Rezaeezadeh-Roukerd

Esmaeilpour

et al. 2010

Journal of Ethnopharmacology

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“…Rather, PKC-mediated desensitization appears to be a secondary mechanism to reduce persistent MOR activation when GRK phosphorylation, arrestin binding, and/or endocytosis are inhibited or fail, as in the case of morphine. Furthermore, although analgesic doses of morphine do not activate PKC in naive animals, chronic morphine treatment has been shown to increase coupling of the MOR to pronociceptive PKC-dependent signaling pathways 32,33. PKC-dependent tolerance to DAMGO, a synthetic analogue of endogenous enkephalin, is only observed when endocytosis is inhibited,34 and similarly, deletion of arrestin is required to unmask PKC-dependent tolerance to morphine in the spinal cord 15.…”

Section: Persistent Mor Desensitization and Tolerancementioning

confidence: 99%

How to design an opioid drug that causes reduced tolerance and dependence

Berger

Whistler

2010

Annals of Neurology

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Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance.Opioids have been used to treat pain for well over 5,000 years. 1 Before the 19th century, the drug of choice was opium, the resin released from the seed pods of the opium poppy. The potency of opium varied greatly from batch to batch, making it impossible to standardize dosage and greatly increasing the risk of overdose. The purification of morphine from opium in 1803 finally solved this problem and greatly improved the safety of using opioids; however, once drug doses were easily quantifiable, the problem of tolerance, defined as the need for higher doses of drug to achieve the same effect, became increasingly apparent. Tolerance was frequently accompanied by physical dependence, the need for continued drug use to prevent somatic and affective withdrawal symptoms, and in some cases by addiction.Scientists have assumed, or at least hoped, that the biological mechanisms mediating opioid analgesia are distinct from, and can be divorced from, those mediating tolerance, dependence, and addiction, and from the time of morphine's discovery, they have tried to develop opioids with a reduced propensity to cause these negative sequelae of prolonged opioid use. Two hundred years later, however, morphine is still a mainstay of modern pain management, and Many attempts to develop a better opioid have been based on flawed or incomplete hypotheses of tolerance development. As a case in point, both heroin and sustained release oxycodone (trade name OxyContin), today 2 of the most highly sought after opioid drugs of ...

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Low‐dose morphine induces hyperalgesia through activation of G_αs, protein kinase C, and l‐type Ca²⁺ channels in rats

Cited by 31 publications

References 48 publications

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Olive (Olea europaea L.) leaf extract elicits antinociceptive activity, potentiates morphine analgesia and suppresses morphine hyperalgesia in rats

How to design an opioid drug that causes reduced tolerance and dependence

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Low‐dose morphine induces hyperalgesia through activation of Gαs, protein kinase C, and l‐type Ca2+ channels in rats

Cited by 31 publications

References 48 publications

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Olive (Olea europaea L.) leaf extract elicits antinociceptive activity, potentiates morphine analgesia and suppresses morphine hyperalgesia in rats

How to design an opioid drug that causes reduced tolerance and dependence

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Low‐dose morphine induces hyperalgesia through activation of G_αs, protein kinase C, and l‐type Ca²⁺ channels in rats