Article

Improvement of morphine-mediated analgesia by inhibition of beta-arrestin 2 expression in mice periaqueductal gray matter.

Department of Pharmacology, Shenyang Pharmaceutical University, P R China.
International Journal of Molecular Sciences (Impact Factor: 2.34). 04/2009; 10(3):954-63. DOI: 10.3390/ijms10030954
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
107 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating mu-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5 mg), placebo, or morphine (10 mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratories), and analgesia (cold pain test) vs. placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5 mg) elicited higher peak analgesia (105, 116 seconds latency versus 75 seconds for morphine, p<0.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5 mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus. -7.3, -7.6, and -9.4 hr∗L/min, p<0.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3 mg (n=0, 1), but not 4.5 mg (n=9). TRV130 was generally well-tolerated, and exposure was dose-proportional. Thus in this study TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.
    Pain 06/2014; · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug discovery targeting G protein-coupled receptors (GPCRs) is no longer limited to seeking agonists or antagonists to stimulate or block cellular responses associated with a particular receptor. GPCRs are now known to support a diversity of pharmacological profiles, a concept broadly referred to as functional selectivity. In particular, the concept of ligand bias, whereby a ligand stabilizes subsets of receptor conformations to engender novel pharmacological profiles, has recently gained increasing prominence. This review discusses how biased ligands may deliver safer, better tolerated, and more efficacious drugs, and highlights several biased ligands that are in clinical development. Biased ligands targeting the angiotensin II type 1 receptor and the μ opioid receptor illustrate the translation of the biased ligand concept from basic biology to clinical drug development.
    Trends in Pharmacological Sciences 05/2014; · 9.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: G protein-coupled receptors (GPCRs), in recent years, have been shown to signal via multiple distinct pathways. Furthermore, biased ligands for some receptors can differentially stimulate or inhibit these pathways versus unbiased endogenous ligands or drugs. Biased ligands can be used to gain a deeper understanding of the molecular targets and cellular responses associated with a GPCR, and may be developed into therapeutics with improved efficacy, safety and/or tolerability. Here we review examples and approaches to pathway validation that establish the relevance and therapeutic potential of distinct pathways that can be selectively activated or blocked by biased ligands.
    Current Opinion in Pharmacology 05/2014; 16C:108-115. · 4.23 Impact Factor

Preview (3 Sources)

Download
1 Download
Available from