Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model

Barnes, Nicholas S. Adamson; Mitchell, Vanessa; Kazantzis, Nicholas P.; Vaughan, Christopher W.

doi:10.1111/bph.13337

Cited by 50 publications

(47 citation statements)

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“…Moreover, simultaneous inhibition of these enzymes produces enhanced antinociceptive effects in these assays (Long et al, 2009b; Adamson Barnes et al, 2016). The present study reports similar findings, as shown by anti-allodynic effects in the carrageenan and CCI assays and thermal antinociception in the tail withdrawal assay, though SA-57 did not elevate paw withdrawal latencies in the contralateral paw of CCI mice.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, combined inhibition of FAAH and MAGL results in enhanced antinociceptive effects compared with single inhibition of these enzymes. One such dual inhibitor, JZL195 produces augmented antinociceptive effects in mouse models of acute thermal, visceral (Sakin et al, 2015), inflammatory (Long et al, 2009b; Anderson et al, 2014) and neuropathic (Adamson Barnes et al, 2016) pain. Additionally, the combination of a high dose of the FAAH inhibitor PF3845 and a low dose of the MAGL inhibitor JZL184 produces augmented antinociceptive effects in inflammatory and neuropathic pain assays (Ghosh et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

et al. 2017

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Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

et al. 2017

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“…After arrival, each group of four animals was acclimatized to their holding cages and testing devices (except for the open field) over an initial 4–5 day period. We first examined the time course of action of a near maximal dose of morphine, but not WIN55212, as this has been characterized in our recent study (Adamson Barnes et al , ). In these experiments, animals underwent pain and side effect testing (except open field), and then CCI surgery.…”

Section: Methodsmentioning

confidence: 99%

Opioid and cannabinoid synergy in a mouse neuropathic pain model

Kazantzis

Casey

Seow

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEClinical studies have reported that pan-cannabinoid receptor agonists may have efficacy in neuropathic pain states and that this might be enhanced by co-administration with opioids. While cannabinoid-opioid analgesic synergy has been demonstrated in animal models of acute pain, it has not been examined in neuropathic pain models. We examined the effect of combination treatment with cannabinoid and opioid receptor agonists on allodynia and side effects in a nerve injury-induced neuropathic pain model. EXPERIMENTAL APPROACHC57BL/6 mice were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of morphine and the pan-cannabinoid receptor agonist, WIN55212, on allodynia and side effects were examined at 7-10 days post-CCI surgery. Isobolographic analysis was used to determine whether the effects of the combination were synergistic. KEY RESULTSThe opioid agonist morphine reduced CCI-induced mechanical and cold allodynia and produced motor incoordination, in a dosedependent manner. WIN55212 reduced CCI-induced allodynia and produced motor incoordination, catalepsy and sedation, in a dose-dependent manner, as we have observed previously. When administered together, WIN55212 and morphine reduced allodynia in a synergistic manner but had only an additive effect on motor incoordination. CONCLUSIONS AND IMPLICATIONSThese findings indicate that administration of a combination of a non-selective opioid and cannabinoid receptor agonist synergistically reduces nerve injury-induced allodynia, while producing side effects in an additive manner. This suggests that this combination treatment has an improved anti-allodynic potency and therapeutic index in a neuropathic pain model. AbbreviationsCCI, chronic constriction injury; MPE, maximum possible effect; PWT, paw withdrawal threshold; THC, Δ 9

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“…Systemic administration of JZL195 produces greater cannabimimetic effects than full inhibition of MAGL or FAAH alone (Long et al, 2009b), but unlike synthetic cannabinoid agonists, the effective dose for antinociception is significantly lower than that producing unwanted side-effects, indicating a potential therapeutic window (Adamson Barnes et al, 2016). Similarly, a recent study employed full FAAH inhibition with partial MAGL inhibition via co-administration of PF-3845 and JZL184 (Ghosh et al, 2015), producing a synergistic augmentation of antinociceptive potency in models of neuropathic and inflammatory pain, in the absence of cannabimimetic side effects, and with an apparent lack of tolerance and dependence following chronic dosing.…”

Section: Blockade Of Ec Metabolism As An Analgesic Approach: Past mentioning

confidence: 99%

The cannabinoid system and pain

et al. 2017

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Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1 receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain.

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Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model

Cited by 50 publications

References 42 publications

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

Opioid and cannabinoid synergy in a mouse neuropathic pain model

The cannabinoid system and pain

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