<i>In vivo</i>
            activation of a mutant μ-opioid receptor by antagonist: Future direction for opiate pain treatment paradigm that lacks undesirable side effects

Law, Ping Yee; Yang, Jesse W.; Guo, Xiaohong; Loh, Horace H.

doi:10.1073/pnas.0334906100

Cited by 24 publications

(6 citation statements)

References 26 publications

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“…for 4 days. These results resembled the previous MORS196A knock-in mice study, morphine could elicit the antinociceptive effect and induced tolerance [2]. Our findings indicate that morphine can activate the exogenously delivered and expressed mutant MOR receptor in spinal cord and induces tolerance in MOR-KO mice.…”

Section: Discussionsupporting

confidence: 91%

“…Antagonists also activated the G-protein-coupled inwardly rectifying potassium channel 1 (GIRK1) in Xenopus oocytes co-expressing the S196A mutant and the GIRK1 channel. The ability of opioid antagonists to activate MORS196A in vitro was also shown in vivo [ 2 ],. Morphine was equally antinociceptive in homozygous MORS196A knock-in mice and in wild-type mice.…”

Section: Introductionmentioning

confidence: 99%

“…Morphine was equally antinociceptive in homozygous MORS196A knock-in mice and in wild-type mice. Naloxone and naltrexone were also antinociceptive but did not cause tolerance or physical dependence in the MORS196A knock-in mice [ 2 ]. We recently [ 3 ] investigated the efficiency of using double-stranded adeno-associated virus type 2 (dsAAV2) vectors to deliver the MORS196A-enhanced green fluorescence protein (EGFP) gene into the sacral spinal cord of healthy wild type Imprinting Control Region (ICR) mice.…”

Section: Introductionmentioning

confidence: 99%

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Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Hsin

Han

et al. 2010

J Biomed Sci

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BackgroundOpioid analgesics such as morphine and meperidine have been used to control moderate to severe pain for many years. However, these opioids have many side effects, including the development of tolerance and dependence after long-term use, which has limited their clinical use. We previously reported that mutations in the mu-opioid receptors (MOR) S196L and S196A rendered them responsive to the opioid antagonist naloxone without altering the agonist phenotype. In MORS196A knock-in mice, naloxone and naltrexone were antinociceptive but did not cause tolerance or physical dependence. In this study we delivery this mutated MOR gene into pain related pathway to confirm the possibility of in vivo transfecting MORS196A gene and using naloxone as a new analgesic agent.MethodsThe MOR-knockout (MOR-KO) mice were used to investigate whether morphine and naloxone could show antinociceptive effects when MORS196A gene was transfected into the spinal cords of MOR-KO mice. Double-stranded adeno-associated virus type 2 (dsAAV2) was used to deliver the MORS196A-enhanced green fluorescence protein (EGFP) gene by microinjected the virus into the spinal cord (S2/S3) dorsal horn region. Tail-flick test was used to measure the antinociceptive effect of drugs.ResultsMorphine (10 mg/kg, s.c.) and naloxone (10 mg/kg, s.c.) had no antinociceptive effects in MOR-KO mice before gene transfection. However, two or three weeks after the MOR-S196A gene had been injected locally into the spinal cord of MOR-KO mice, significant antinociceptive effects could be induced by naloxone or morphine. On the other hand, only morphine but not naloxone induced significant tolerance after sub-chronic treatment.ConclusionTransfecting the MORS196A gene into the spinal cord and systemically administering naloxone in MOR-KO mice activated the exogenously delivered mutant MOR and provided antinociceptive effect without causing tolerance. Since naloxone will not activate natural MOR in normal animals or humans, it is expected to produce fewer side effects and less tolerance and dependence than traditional opioid agonists do.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Hsin

Han

et al. 2010

J Biomed Sci

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“…In this mutant receptor, in which the conserved Ser residue in TM4 (S4.54) was substituted with either Leu or Ala, classical opiate antagonists such as naloxone or naltrexone activated the receptor without altering the agonist activity (74). Naloxone and naltrexone produced antinociceptive responses in a S4.54A substitution knockin mouse without eliciting any of the chronic effects such as tolerance and dependence (75).…”

Section: Alternative Approaches To Reduce Side Effects Via Receptor Amentioning

confidence: 99%

Opioid receptors: toward separation of analgesic from undesirable effects

Law

Reggio

Loh

2013

Trends in Biochemical Sciences

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The use of opioid analgesics for pain has always been hampered by their many side effects; in particular, the addictive liability associated with chronic use. Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor heterooligomers. This review discusses the potential for receptor splice variant- and the hetero-oligomer-based discovery of new opioid analgesics. We also examine an alternative approach of using receptor mutants for pain management. Finally, we discuss the role of the biased agonism observed and the recently reported opioid receptor crystal structures in guiding the future development of opioid analgesics

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“…Our unique MOR mutant, MORS196A is such a RASSL , in which opioid antagonists naloxone or naltrexone inhibited forskolin-stimulated adenylyl cyclase activity or activation of Kir3.1 channels (Claude et al, 1996). The in vivo activity of this mutant MOR was demonstrated by the S196A knock-in mice or by dsAAV2-mediated delivery of the mutant MOR at the dorsal horn area of ICR mouse, where naloxone or naltrexone produced antinociceptive effects without tolerance and dependence development (Chen et al, 2007; Yang et al, 2003). …”

Section: Introductionmentioning

confidence: 99%

Naloxone can act as an analgesic agent without measurable chronic side effects in mice with a mutant mu‐opioid receptor expressed in different sites of pain pathway

Chou

Kao

Tao

et al. 2012

Synapse

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Midbrain periaqueductal gray (PAG) and spinal cord dorsal horn are major action sites of opioid analgesics in the pain pathway. Our previous study has shown that opioid antagonists activate MORS196A‐CSTA (a mutant of mu‐opioid receptor) as full agonists in vitro cell models and naloxone showed antinociceptive effects after the expression of MORS196A‐CSTA in the spinal cord in mice. The purpose of this study is to investigate the site‐directed antinociceptive effects of naloxone in mice injected with dsAAV‐MORS196A‐CSTA‐EGFP at spinal cord or at periaqueductal gray. MORS196A‐CSTA‐EGFP was administered to ICR mice using dsAAV as vector. We measured MORS196A‐CSTA‐EGFP expression by detecting the EGFP visualization with a fluorescence microscope. The antinociceptive effect of naloxone was determined by tail‐flick test and hot plate test. Drug rewarding effect was evaluated by the conditioned place preference test. Naloxone (10 mg/kg, s.c.) elicited both supraspinal and spinal antinociceptive responses in mice injected with the virus at PAG while only spinal antinociceptive response was observed in mice injected with virus at dorsal horn region. Chronic naloxone treatment did not induce physical dependence or rewarding effect in mice injected with MORS196A‐CSTA‐EGFP in spinal cord or PAG. These data suggest that the observed naloxone‐induced antinociceptive response is the consequence of the local expression of MORS196A‐CSTA at specific sites of pain pathway. Injection of such MOR mutant and the systemic administration of naloxone can be a new strategy in the management of chronic pain without the various side effects associated with the use of morphine. Synapse, 2012. © 2012 Wiley Periodicals, Inc.

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In vivo activation of a mutant μ-opioid receptor by antagonist: Future direction for opiate pain treatment paradigm that lacks undesirable side effects

Cited by 24 publications

References 26 publications

Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Opioid receptors: toward separation of analgesic from undesirable effects

Naloxone can act as an analgesic agent without measurable chronic side effects in mice with a mutant mu‐opioid receptor expressed in different sites of pain pathway

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