Crain SM, Shen KF. Acute thermal hyperalgesia elicited by low dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid analgesia

Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Brain Research (Impact Factor: 2.84). 02/2001; 888(1):75-82. DOI: 10.1016/S0006-8993(00)03010-9
Source: PubMed


Our previous electrophysiologic studies on nociceptive types of dorsal root ganglion (DRG) neurons in culture demonstrated that extremely low fM-nM concentrations of morphine and many other bimodally-acting mu, delta and kappa opioid agonists can elicit direct excitatory opioid receptor-mediated effects, whereas higher (microM) opioid concentrations evoked inhibitory effects. Cotreatment with pM naloxone or naltrexone (NTX) plus fM-nM morphine blocked the excitatory effects and unmasked potent inhibitory effects of these low opioid concentrations. In the present study, hot-water-immersion tail-flick antinociception assays at 52 degrees C on mice showed that extremely low doses of morphine (ca. 0.1 microg/kg) can, in fact, elicit acute hyperalgesic effects, manifested by rapid onset of decreases in tail-flick latency for periods >3 h after drug administration. Cotreatment with ultra-low-dose NTX (ca. 1-100 pg/kg) blocks this opioid-induced hyperalgesia and unmasks potent opioid analgesia. The consonance of our in vitro and in vivo evidence indicates that doses of morphine far below those currently required for clinical treatment of pain may become effective when opioid hyperalgesic effects are blocked by coadministration of appropriately low doses of opioid antagonists. This low-dose-morphine cotreatment procedure should markedly attenuate morphine tolerance, dependence and other aversive side-effects.

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    • "Systemic administration of morphine has been shown to elicit not only analgesia but it may also enhance sensitivity to pain in rodents (Celerier et al., 2000; Crain and Shen, 2001; Laulin et al., 2002; Van Elstraete et al., 2005) as well as in human subjects (Andrews, 1943). "
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    ABSTRACT: Morphine-induced hyperalgesia is a pharmacological phenomenon often hindering its prolonged applications in the clinic. It has been shown that systemic administration of morphine induced a hyperalgesic response at an extremely low dose. Extracellular signal-regulated kinase (ERK) pathway contributes to pain sensitization, and its phosphorylation under pain conditions results in the induction and maintenance of pain hypersensitivity. The present study was designed to determine whether low dose morphine treatment in mice could influence the spinal activity of ERK. The data showed that morphine (1µg/kg) induced a marked increase in ERK phosphorylation. Intrathecal pre-treatment with a selective mitogen-activated and extracellular signal-regulated kinase (MEK) inhibitor PD98059, attenuated morphine-associated thermal hyperalgesia. Morphine exposure increased phosphorylation of c-JUN, that was prevented by the inhibition of ERK pathway. In addition, double immunofluorescence studies revealed that, p-ERK and p-c-JUN are localized on neurons of the spinal dorsal horn expressing µ receptors. These data suggest that ERK contributes to the morphine-induced hyperalgesia by regulating the activation of c-JUN. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 07/2015; 764. DOI:10.1016/j.ejphar.2015.07.022 · 2.53 Impact Factor
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    • "dosing (Crain and Shen, 2001; Kayser et al., 1987; Levine et al., 1979; Li et al., 2001). The neural mechanisms that underlie hyperalgesic effects are poorly understood, but are dependent on the concentration of the drug and the duration of exposure (Crain and Shen, 2000; Rubovitch et al., 2003). "
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    ABSTRACT: The μ-opioid receptor (MOR) is the primary target for opioid analgesics. MOR induces analgesia through the inhibition of second messenger pathways and the modulation of ion channels activity. Nevertheless, cellular excitation has also been demonstrated, and proposed to mediate reduction of therapeutic efficacy and opioid-induced hyperalgesia upon prolonged exposure to opioids. In this mini-perspective, we review the recently identified, functional MOR isoform subclass, which consists of six transmembrane helices (6TM) and may play an important role in MOR signaling. There is evidence that 6TM MOR signals through very different cellular pathways and may mediate excitatory cellular effects rather than the classic inhibitory effects produced by the stimulation of the major (7TM) isoform. Therefore, the development of 6TM and 7TM MOR selective compounds represent a new and exciting opportunity to better understand the mechanisms of action and the pharmacodynamic properties of a new class of opioids. Copyright © 2014. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2014; 62. DOI:10.1016/j.pnpbp.2014.11.009 · 3.69 Impact Factor
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    • "The co-administration of ultra-low dose opioid antagonists in opioid pain management has emerged as a potentially promising practical approach to minimising the adverse effects that can limit the use of these analgesics and may also enhance analgesia. In vitro (Crain and Shen, 1990, 1992) and animal studies (Crain and Shen, 2001; Powell et al., 2002; Shen and Crain, 1997; Terner et al., 2006) and, limited but conflicting human reports (Cepeda et al., 2002, 2004; Chindalore et al., 2005; Gear et al., 2000; Hamann and Sloan, 2007) have suggested that the addition of an opioid antagonist in ultra-low doses (0.001–0.1 lg/kg) (Crain and Shen, 2000) can potentiate the analgesic effect of opioids. Recently, a putative site for this action of opioid antagonists has been identified on filamin A, a structural protein that may interact with the opioid receptor (Wang et al., 2008; Wang and Burns, 2009). "
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    ABSTRACT: Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects.
    European journal of pain (London, England) 03/2011; 15(3):293-8. DOI:10.1016/j.ejpain.2010.07.009 · 2.93 Impact Factor
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