In Vivo Characterization of MMP-2200, a Mixed δ/μ Opioid Agonist, in Mice

Lowery, John J.; Raymond, Tyler; Giuvelis, Denise; Bidlack, Jean M.; Polt, Robin; Bilsky, Edward J.

doi:10.1124/jpet.110.172866

Cited by 76 publications

(109 citation statements)

References 33 publications

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“…Following determination of the fentanyl dose-effect function (0.00032 – 0.01 mg/kg/infusion), a range of doses of the delta/mu opioid agonist MMP-2200 (0.032–1 mg/kg/infusion) was tested. Given that MMP-2200 has a much slower onset than fentanyl, and similar onset and duration of action as morphine (Elmagbari et al, 2004; Lowery et al, 2011), a range of doses of morphine (0.01–0.32mg/kg/infusion) was also tested. The primary dependent variable for drug self-administration was number of drug infusions.…”

Section: Methodsmentioning

confidence: 99%

“…Glycosylation of these peptides has been shown to increase blood-brain barrier penetration in vitro and systemic bioavailability in vivo (Polt et al 1994; Bilsky et al 2000; Elmagbari et al 2004). Although these glycosylated delta/mu agonists demonstrate broad-spectrum analgesic efficacy under inflammatory and neuropathic pain conditions (Lowery et al 2011; Giuvelis et al, unpublished findings), their potential side effects have not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

“…Based on plasma stability and bioavailability, a lead analgesic candidate, MMP-2200, was selected for further therapeutic and side effect profiling in mice (Lowery et al 2011). We found that MMP-2200 had potent and efficacious anti-nociceptive activity in mice, with reduced locomotor activation, tolerance, and dependence.…”

Section: Introductionmentioning

confidence: 99%

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The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence

Stevenson

Luginbuhl

Dunbar

et al. 2015

Pharmacology Biochemistry and Behavior

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Previous work in our laboratories provides preclinical evidence that mixed-action delta/mu receptor glycopeptides have equivalent efficacy for treating pain with reduced side effect profiles compared to widely used mu agonist analgesics such as morphine. This study evaluated the rewarding and reinforcing effects of a lead candidate, mixed-action delta/mu agonist MMP-2200, using a conditioned place preference assay as well as a drug self-administration procedure in rats. In place conditioning studies, rats underwent a 2-week conditioning protocol and were then tested for chamber preference. Rats receiving MMP-2200, at previously determined analgesic doses, could not distinguish between the drug and saline-paired chamber, whereas rats receiving the opioid agonist morphine showed a strong preference for the morphine-paired chamber. In self-administration studies, rats were trained to respond for the high efficacy mu opioid receptor agonist fentanyl on an FR5 schedule of reinforcement. Following complete dose-response determinations for fentanyl, a range of doses of MMP-2200 as well as morphine were tested. Relative to the mu agonist morphine, MMP-2200 maintained a significantly lower number of drug infusions. To begin investigating potential molecular mechanisms for the reduced side effect profile of MMP-2200, we also examined βarrestin2 (βarr2) recruitment and chronic MMP-2200 induced cAMP tolerance and super-activation at the human delta and mu receptors in vitro. MMP-2200 efficaciously recruited βarr2 to both receptors, and induced cAMP tolerance and super-activation equivalent to or greater than morphine at both receptors. The in vivo findings suggest that MMP-2200 may be less reinforcing than morphine but may have some abuse potential. The reduced side effect profile cannot be explained by reduced βarr2 recruitment or reduced cAMP tolerance and superactivation at the monomeric receptors in vitro.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence

Stevenson

Luginbuhl

Dunbar

et al. 2015

Pharmacology Biochemistry and Behavior

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“…Indeed, an improved antinociception and a low propensity to tolerance development were reported for ligands possessing mixed MOR-DOR opioid activity. These pharmacological effects have been described for the DOR antagonist-MOR agonist peptidic ligands KSK-103 and UFP-505 (Purington et al, 2011;Balboni et al, 2010), as well as for the MOR-DOR peptidic agonists MMP2200 and BVD03 (Lowery et al, 2011;Vandormael et al, 2011). We previously identified a compound based on the 6,7-benzomorphan structure, 3-[(2R,6R,11R)-8-hydroxy-6, 11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2 H)-yl]-N-phenylpropanamide (LP1, Fig.…”

Section: Introductionmentioning

confidence: 95%

Antinociceptive profile of LP1, a non-peptide multitarget opioid ligand

et al. 2012

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“…DADLE ([D-Ala2, D-Leu5]-enkephalin) is considered the prototype selective agonist that has been used to evaluate DOR mediated effects. DOR activation was found to control inflammatory (4,5) as well as neuropathic pain (6,7) , treat/prevent migraine attacks (8) , enhance the analgesic potency of mu receptor agonists while reducing tolerance and dependence (9) , attenuate hyperalgesia (10) , modulate urinary bladder functions (11) and promote locomotion through differential signalling pathways (12) . On the other hand, DOR antagonists have been found to reduce alcohol seeking and abuse (13) .…”

Section: Introductionmentioning

confidence: 99%

Promising Therapeutic Agents: Delta Opioid Receptor Agonists

Bazzari

2017

IAM

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Adequate characterization of the endogenous opioid system's peptides and receptors; in addition to, the development of highly selective ligands, have improved research approaches and understanding the roles of this system. DeltaOpioid Receptor (DOR) was found to exhibit distinctive pharmacological profile and tissue distribution compared to other opioid receptors. Hence, DOR has been extensively investigated in the last decade as a potential target in the treatment of various disorders. Research findings indicate high potential of DOR agonists in the modulation of brain as well as cardiovascular system functions. DOR activation was found to display cytoprotective effects against ischemia/reperfusion injury in neurons and cardiomyocytes. DOR affects cellular functions on the level of gene expression, ion channels, enzymatic activity and membrane-receptors functions through multiple signaling pathways and second messenger systems. Moreover, DOR has been implicated in mood disorders; in vivo administration of DOR agonists and enkephalinase inhibitors had significant anxiolytic and antidepressant effects. More recent research findings have shown consistent and statistically significant results on DOR activation beneficial effects in cardiac conditioning, neural ischemia protection, anxiety and depression management. Further advances in research would potentially reveal the exact molecular mechanisms underlying DOR functions in relation to receptor subtypes and signaling pathways.

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In Vivo Characterization of MMP-2200, a Mixed δ/μ Opioid Agonist, in Mice

Abstract: We have previously reported the chemistry and antinociceptive properties of a series of glycosylated enkephalin analogs (glycopeptides) exhibiting approximately equal affinity and efficacy at ␦ opioid receptors (DORs) and opioid receptors (MORs).

Cited by 76 publications

References 33 publications

The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence

The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence

Antinociceptive profile of LP1, a non-peptide multitarget opioid ligand

Promising Therapeutic Agents: Delta Opioid Receptor Agonists

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