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.
    No preview · Article · Jul 2015 · European journal of pharmacology
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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.
    Full-text · Article · Dec 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "Biphasic dose–response relationships have been demonstrated in animals and humans following administration of opioids (Jacquet and Lajtha, 1973). Beyond the analgesic effect exerted by morphine at analgesic doses, acute thermal hyperalgesia has been demonstrated by different authors after morphine administration to rodents at extremely low doses (Kayser et al., 1987;Crain and Shen, 2001). Memory and the process of learning in mammals are affected by opioid agonists , which interfere with these processes and produce amnesia. "
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    ABSTRACT: Bimodal dose–response relationships have been demonstrated in animals and humans following morphine administration. We examined if systemic administration of morphine, in extremely low (μg) and high (mg, analgesic) doses, changed the learning process. In the social learning test, an adult rat investigates a juvenile. The juvenile is submitted to a second encounter after a few days and investigation by the adult should be reduced. Morphine was administered before the first encounter between rats, and the critical test was performed 24, 72 or 168 h later, when animals were re-exposed to each other, in the absence of morphine. Low doses of morphine, comparable with endogenous brain concentrations, enhanced long-term memory recognition; while high doses did the reverse, indicating the adult failed to recognize the juvenile. Recognition of a familiar rat appeared to be mediated within the brain accessory olfactory bulb (AOB) by an opioid system intrinsic to the olfactory system through μ-opioid receptors (MORs). At this supraspinal site, the PLC/PKC signalling pathway was activated by extremely low morphine doses. Morphine treatment administration may either disrupt or facilitate social memory, depending on the dose, extending to memory formation the bimodal effects of morphine previously shown in pain. Social memory formation elicited by extremely low morphine doses, was mediated within the AOB by an opioid system, intrinsic to the olfactory system through MORs.
    Preview · Article · Nov 2012 · British Journal of Pharmacology
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