Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent opioid analgesia.
ABSTRACT 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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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; · 4.03 Impact Factor
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ABSTRACT: Neuropeptide FF1 and FF2 receptors (NPFF1-R and NPFF2-R), and their endogenous ligand NPFF, are one of only several systems responsible for mediating opioid-induced hyperalgesia, tolerance and dependence. Currently, no small molecules displaying good affinity or selectivity for either subtype have been reported, to decipher the role of NPFF2-R as it relates to opioid-mediated analgesia, for further exploration of NPFF1-R, or for medication development for either subtype. We report the first non-peptide small molecule scaffold for NPFF1,2-R, the guanidino-piperidines, and SAR studies resulting in the discovery of a NPFF1 agonist (7b, Ki: 487 ± 117 nM), a NPFF1 antagonist (46, Ki: 81 ± 17 nM) and a NPFF2 partial antagonist (53a, Ki: 30 ± 5 nM), which serve as leads for the development of pharmacological probes and potential therapeutic agents. Testing of 46 alone was without effect in the mouse 48°C warm-water tail-withdrawal test, but pretreatment with 46 prevented NPFF-induced hyperalgesia.Journal of Medicinal Chemistry 09/2014; · 5.48 Impact Factor
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ABSTRACT: Morphine-3ß-D-glucuronide (M3G), a primary morphine metabolite, evokes hyperalgesia in mice and rats and putatively mediates hyperalgesia associated with morphine (MOR) administration. However, M3G does not act via opioid receptors and its locus of activity in the CNS is unknown. Here we assessed the density of neurons immunoreactive for c-Fos, an immediate early gene regulated by neuronal activity, in the periaqueductal gray (PAG), a midbrain region critical to pain modulation, in male CD-1 mice after MOR and M3G exposure. Mice were injected with acute doses of MOR or M3G following a pre-injection of saline (SAL) or the opioid antagonist naltrexone (NTX), perfused 3 hours later, and labeled for c-Fos using immunohistochemistry. Labeled image stacks taken from the PAG were then analyzed on a confocal microscope for the number of neurons showing c-Fos expression. Relative to controls, significant but similar increases in the mean density of PAG c-Fos immunoreactive neurons were observed in mice pre-injected with SAL then M3G or morphine. However, NTX pre-injection blocked this increase in MOR but not M3G injected mice. The data demonstrate for the first time a CNS locus for M3G activity. Consistent with previous observations, this M3G activity is not mediated by opioid receptors.Physiology & Behavior 03/2014; · 3.03 Impact Factor