Possible involvement of prolonging spinal μ-opioid receptor desensitization in the development of antihyperalgesic tolerance to μ-opioids under a neuropathic pain-like state

ArticleinAddiction Biology 18(4) · August 2011with5 Reads
DOI: 10.1111/j.1369-1600.2011.00354.x · Source: PubMed
In the present study, we investigated the possible development of tolerance to the antihyperalgesic effect of µ-opioid receptor (MOR) agonists under a neuropathic pain-like state. Repeated treatment with fentanyl, but not morphine or oxycodone, produced a rapid development of tolerance to its antihyperalgesic effect in mice with sciatic nerve ligation. Like the behavioral study, G-protein activation induced by fentanyl was significantly reduced in membranes obtained from the spinal cord of nerve-ligated mice with in vivo repeated injection of fentanyl. In β-endorphin-knockout mice with nerve ligation, developed tolerance to the antihyperalgesic effect of fentanyl was abolished, and reduced G-protein activation by fentanyl after nerve ligation with fentanyl was reversed to the normal level. The present findings indicate that released β-endorphin within the spinal cord may be implicated in the rapid development of tolerance to fentanyl under a neuropathic pain-like state.
    • "This study expanded upon these previous results in finding that morphine retained its effectiveness to reverse formalin-induced depression of ICSS during repeated treatment for 8 consecutive days. Tolerance is often observed to morphine antinociception in conventional assays of pain-stimulated behavior (Way et al., 1969; Cicero and Meyer, 1973; Morgan and Christie, 2011; Yu et al., 2014); however, the absence of antinociceptive tolerance in the present study agrees with previous studies reporting both minimal tolerance to low-dose morphine antinociception in assays of neuropathy-induced allodynia (Neil et al., 1990; Suzuki et al., 1992; Sounvoravong et al., 2004; Narita et al., 2013) and resistance to morphine tolerance in assays of painrelated ICSS depression (; Miller et al., 2015a). Moreover, these results agree with evidence for the clinical effectiveness of morphine and other opioids to treat neuropathic pain (Finnerup et al., 2015) and with evidence for sustained analgesic effects of mu opioids during chronic opioid treatment in many clinical contexts (Foley, 1995; Rosenblum et al., 2008; Harden et al., 2010; Morgan and Christie, 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32-3.2 mg/kg), ketoprofen (0.1-10 mg/kg), bupropion (3.2-32 mg/kg), and [INCREMENT]9-tetrahydrocannabinol (THC; 0.32-3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin-induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain.
    Article · Nov 2015
    • "Previous studies have demonstrated that both proinflammatory and anti-inflammatory cytokines are involved in the establishment and maintenance of morphine tolerance and neuropathic pain (Johnston et al. 2004; Schafers and Sommer 2007; Uceyler and Sommer 2008; Shen et al. 2011). Opioids-induced hyperalgesia is observed in tolerance; it is similar to the symptoms observed in neuropathic pain, where opioids also have a limited analgesic effect (Mika et al. 2004; Narita et al. 2013). Numerous studies have indicated that neuropathic pain results in reduced morphine efficacy and a more rapid development of morphine tolerance (Ossipov et al. 1995; Mayer et al. 1999; Mika et al. 2004; Przewlocki and Przewlocka 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured. Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.
    Full-text · Article · Feb 2014
    • "By analyzing the behavioral responses of rats to the morphine treatment (catalepsy, non-stereotyped activity, and stereotyped activity), these authors related MOR up-regulation in the CPu to morphine sensitization [25], as also done in the current study. The dose of morphine (20 mg/kg/day, subcutaneous) used in the present study has been demonstrated to induce tolerance to its analgesic effect ([37] and own unpublished observation), which correlate with a decrease in MOR-mediated signaling, mainly in the spinal cord [38]. However, we demonstrate in the current work that the administration of morphine produces MOR sensitization, since an increase of MOR-mediated signaling has been shown in the striosomal compartment of the CPu. "
    [Show abstract] [Hide abstract] ABSTRACT: The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine.
    Full-text · Article · Jan 2013
Show more