Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter

Department of Pharmacology, Shenyang Pharmaceutical University, P R China.
International Journal of Molecular Sciences (Impact Factor: 2.86). 04/2009; 10(3):954-63. DOI: 10.3390/ijms10030954
Source: PubMed


Morphine is a well-known mu-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of beta-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of beta-arrestin2 was proven by overexpression or knockdown of its homology beta-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting beta-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance.

  • Source
    • "This intracellular overlap between the MOR and DA systems, along with evidence that D1, but not D2 receptors are involved in mediating the behavioral responses to morphine by acting to recruit GRK and ß-arrestin to the MOR (Urs et al., 2011) and that blocking ß-arrestin expression has been shown to enhance morphine-mediated analgesia (Li et al., 2009), has led to the model proposed in Figure 7. According to our model, activation of the D3 receptor leads in WT to a reduction of adenylate cyclase (AC) activity, which will result in a reduction of cAMP levels and decreased cAMP-mediated signaling, in a manner that is synergistic to the MOR in response to its ligand. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · May 2014 · Frontiers in Neural Circuits
  • Source
    • "The Authors regulation is known to be agonist specific, so that regulatory events recruited by morphine differ from those induced by other opioids (Burford et al., 1998; McPherson et al., 2010). In particular , it was recently shown that morphine promotes interaction of OPRM1 only with b-arrestin2 and not b-arrestin1 (Groer et al., 2007, 2011; Li et al., 2009) and that this interaction is sufficient to induce OPRM1 internalization, but not receptor ubiquitination and subsequent degradation (Groer et al., 2011). To check whether these features of OPRM1 regulation can account for the observed suppression of TRPM8 current by morphine, we examined the possibility of direct interaction between the two proteins and their plasmalemmal trafficking. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stimulation of μ-opioid receptors (OPRMs) brings powerful pain relief, but it also leads to the development of tolerance and addiction. Ensuing withdrawal in abstinent patients manifests itself with severe symptoms, including cold hyperalgesia, often preventing addicted patients from successfully completing the rehabilitation. Unsurprisingly, OPRMs have been a central point of many studies. Nonetheless, a satisfactory understanding of the pathways leading to distorted sensory responses during opiate administration and abstinence is far from complete. Here, we present a mechanism that leads to modulation by OPRMs of one of the sensory responses, thermosensation. Activation of OPRM1 leads to internalization of a cold-sensor TRPM8, which can be reversed by a follow-up treatment with the inverse OPRM agonist naloxone. Knockout of TRPM8 protein leads to a decrease in morphine-induced cold analgesia. The proposed pathway represents a universal mechanism that is probably shared by regulatory pathways modulating general pain sensation in response to opioid treatment.
    Full-text · Article · Jul 2013 · Cell Reports
  • Conference Paper: Applying TQM to R&D
    [Show abstract] [Hide abstract]
    ABSTRACT: Summary form only given. The author attempts to explain how to effectively apply TQM (total quality management) to R&D through the use of a new, integrative model for key TQM and R&D processes. Drawing upon basic management theories, the literature, the author's 15 years of experience as an engineer and R&D executive, and ongoing research with several R&D organizations, the model relates the general concept of TQM with the Hoshin planning, process improvement, and new product development processes. The author has examined implications for applying TQM to R&D, suggesting the problems and the benefits, and how to overcome the shortcomings through a more comprehensive view of TQM that employs innovation as much as improvement and maintenance
    No preview · Conference Paper · Nov 1991
Show more