Mechanisms of Opioid-Induced Tolerance and Hyperalgesia

Department of Pharmaceutics, University of Washington Seattle, Seattle, Washington, United States
Pain Management Nursing (Impact Factor: 1.53). 10/2007; 8(3):113-21. DOI: 10.1016/j.pmn.2007.02.004
Source: PubMed


Opioid tolerance and opioid-induced hyperalgesia are conditions that negatively affect pain management. Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a decrease of the drug's effects over time. Opioid-induced hyperalgesia occurs when prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus. Complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying opioid tolerance. Pain facilitatory mechanisms in the central nervous system are known to contribute to opioid-induced hyperalgesia. Recent research indicates that there may be overlap in the two conditions. This article reviews known and hypothesized pathophysiologic mechanisms surrounding these phenomena and the clinical implications for pain management nurses.

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    • "Opioids have been used to alleviate moderate to severe pain. Although opioids are potent analgesics, treatment of opioids can also cause a state of nociceptive sensitization, often referred to as opioid-induced hyperalgesia and allodynia [10] [11]. There is strong evidence to implicate the importance of N-methyl- D-aspartate (NMDA) receptors to the induction and maintenance of central and peripheral sensitization in these pain hypersensitivities [12]. "
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    ABSTRACT: Background In this study, we investigated the effects of locally (intraplantar) applied remifentanil, a μ opioid receptor agonist, to the paws and tested whether locally N-methyl d-aspartate (NMDA) receptors agonist or antagonist can modify remifentanil-induced effects in diabetic rats. Methods Effects of locally (intraplantar) remifentanil, NMDA and MK801 or their combinations were investigated by measuring the latencies, thresholds and two biochemical parameters (malondialdehyde (MDA) and nitric oxide (NO)), in streptozotocin induced diabetic rats. Results Diabetic rats exhibited hyperalgesia and allodynia and remifentanil treatment aggravated the hyperalgesia and allodynia. The hyperalgesic and allodynic effects of remifentanil decreased in diabetic rats as compared to healthy rats. MK801 suppressed the hyperalgesic and allodynic actions of remifentanil in diabetic rats. However, hyperalgesic and allodynic actions of NMDA increased in diabetic rats. In contrast to age matched group, the combination of NMDA and remifentanil did not produce synergistic actions in diabetic rats. The levels of MDA and NO in the paw tissues of the diabetic rats significantly increased. MK801 significantly decreased NO levels, but not MDA, in diabetic rats. Conclusions The hyperalgesic and allodynic actions of locally treated remifentanil may decrease in diabetic conditions. Increases in NMDA receptors activation, reactive oxygen species production and NO release may modify the sensitivity to remifentanil in diabetes induced neuropathic pain states.
    Pharmacological reports: PR 12/2014; 66(6):1065–1072. DOI:10.1016/j.pharep.2014.07.004 · 1.93 Impact Factor
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    • "Although OIH has been well characterized in animal models [3-14] and clinical reviews/reports [8,15-19], OIH treatment in patients is difficult [19], in part because increasing opioid doses exacerbate OIH symptoms. The mechanisms underlying development and maintenance of OIH appear to have complicated central [6,16,20] and peripheral [13,21] components, but the transient receptor potential vanilloid type 1 receptor (TRPV1) appears to play a key role in the development and/or maintenance of OIH [13], especially in primary afferent neurons [21]. "
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    ABSTRACT: Despite advances in understanding the signaling mechanisms involved in the development and maintenance of chronic pain, the pharmacologic treatment of chronic pain has seen little advancement. Agonists at the mu opioid receptor (MOPr) continue to be vital in the treatment of many forms of chronic pain, but side-effects limit their clinical utility and range from relatively mild, such as constipation, to major, such as addiction and dependence. Additionally, chronic activation of MOPr results in pain hypersensitivity known as opioid-induced hyperalgesia (OIH), and we have shown recently that recruitment of beta-arrestin2 to MOPr, away from transient potential vanilloid receptor type 1 (TRPV1) in primary sensory neurons contributes to this phenomenon. The delta opioid receptor (DOPr) has become a promising target for the treatment of chronic pain, but little is known about the effects of chronic activation of DOPr on nociceptor sensitivity and OIH. Here we report that chronic activation of DOPr by the DOPr-selective agonist, SNC80, results in the sensitization of TRPV1 and behavioral signs of OIH via beta-arrestin2 recruitment to DOPr and away from TRPV1. Conversely, chronic treatment with ARM390, a DOPr-selective agonist that does not recruit beta-arrestin2, neither sensitized TRPV1 nor produced OIH. Interestingly, the effect of SNC80 to sensitize TRPV1 is species-dependent, as rats developed OIH but mice did not. Taken together, the reported data identify a novel side-effect of chronic administration of beta-arrestin2-biased DOPr agonists and highlight the importance of potential species-specific effects of DOPr agonists.
    Molecular Pain 08/2014; 10(1):50. DOI:10.1186/1744-8069-10-50 · 3.65 Impact Factor
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    • "Opiate analgesics are the classical first line treatment for strong and persistent pain, but their effectiveness in long-term treatment is limited by the emergence of tolerance (Colpaert 2002; DuPen, Shen et al. 2007; Bekhit 2010; Joseph, Reichling et al. 2010). This morphine-resistant condition is thought to arise over time and involve a dysfunction of µ-opioid receptor (MOR)-and dopamine (DA)-receptor mediated cAMP/PKA second messenger pathways in the brain (Suzuki, Kishimoto et al. 2001; Schmidt, Tambeli et al. 2002; Fazli-Tabaei, Yahyavi et al. 2006; Zhang, Zhang et al. 2008; Le Marec, Marie-Claire et al. 2011; Enoksson, Bertran-Gonzalez et al. 2012; Zhang, Zhang et al. 2012). "
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    ABSTRACT: Dopamine (DA) modulates spinal reflexes, including nociceptive reflexes, in part via the D3 receptor subtype. We have previously shown that mice lacking the functional D3 receptor (D3KO) exhibit decreased paw withdrawal latencies from painful thermal stimuli. Altering the DA system in the CNS, including D1 and D3 receptor systems, reduces the ability of opioids to provide analgesia. Here, we tested if the increased pain sensitivity in D3KO might result from a modified µ-opioid receptor (MOR) function at the spinal cord level. As D1 and D3 receptor subtypes have competing cellular effects and can form heterodimers, we tested if the changes in MOR function may be mediated in D3KO through the functionally intact D1 receptor system. We assessed thermal paw withdrawal latencies in D3KO and wild type (WT) mice before and after systemic treatment with morphine, determined MOR and phosphorylated MOR (p-MOR) protein expression levels in lumbar spinal cords, and tested the functional effects of DA and MOR receptor agonists in the isolated spinal cord. In vivo, a single morphine administration (2 mg/kg) increased withdrawal latencies in WT but not D3KO, and these differential effects were mimicked in vitro, where morphine modulated spinal reflex amplitudes (SRAs) in WT but not D3KO. Total MOR protein expression levels were similar between WT and D3KO, but the ratio of phosphorylated MOR (pMOR)/total MOR was higher in D3KO. Blocking D3 receptors in the isolated WT cord precluded morphine’s inhibitory effects observed under control conditions. Lastly, we observed an increase in D1 receptor protein expression in the lumbar spinal cord of D3KO. Our data suggest that the D3 receptor modulates the MOR system in the spinal cord, and that a dysfunction of the D3 receptor can induce a morphine-resistant state. We propose that the D3KO mouse may serve as a model to study the onset of morphine resistance at the spinal cord level, the primary processing site of the nociceptive pathway.
    Frontiers in Neural Circuits 05/2014; 8(62). DOI:10.3389/fncir.2014.00062 · 3.60 Impact Factor
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