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The Monoacylglycerol Lipase Inhibitor KML29 with Gabapentin Synergistically Produces Analgesia in Mice

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The Monoacylglycerol Lipase Inhibitor KML29 with Gabapentin Synergistically Produces Analgesia in Mice Clinical and Translational Science Institute Centers 12-1-2017 The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice Molly S. Crowe West Virginia University Catheryn D. Wilson University of Arkansas for Medical Sciences Emma Leishman Indiana University - Bloomington Paul L. Prather University of Arkansas for Medical Sciences Heather B. Bradshaw Indiana University - Bloomington See next page for additional authors Follow this and additional works at: https://researchrepository.wvu.edu/ctsi Part of the Medicine and Health Sciences Commons Digital Commons Citation Crowe, Molly S.; Wilson, Catheryn D.; Leishman, Emma; Prather, Paul L.; Bradshaw, Heather B.; Banks, Matthew L.; and Kinsey, Steven G., "The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice" (2017). Clinical and Translational Science Institute. 716. https://researchrepository.wvu.edu/ctsi/716 This Article is brought to you for free and open access by the Centers at The Research Repository @ WVU. It has been accepted for inclusion in Clinical and Translational Science Institute by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Authors Molly S. Crowe, Catheryn D. Wilson, Emma Leishman, Paul L. Prather, Heather B. Bradshaw, Matthew L. Banks, and Steven G. Kinsey This article is available at The Research Repository @ WVU: https://researchrepository.wvu.edu/ctsi/716 British Journal of British Journal of Pharmacology (2017) 174 4523–4539 4523 BJP Pharmacology RESEARCH PAPER The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesiainmice Correspondence Steven G. Kinsey, Department of Psychology, West Virginia University, P.O. Box 6040 Morgantown, WV 26506, USA. E-mail: [email protected] Received 24 April 2017; Revised 25 August 2017; Accepted 14 September 2017 Molly S Crowe1,2, Catheryn D Wilson3,EmmaLeishman4, Paul L Prather3, Heather B Bradshaw4, Matthew L Banks5 and Steven G Kinsey1 1Department of Psychology, West Virginia University, Morgantown, WV,USA,2Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA, 3Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA, 4Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA, and 5Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA BACKGROUND AND PURPOSE Gabapentin is commonly prescribed for nerve pain but may also cause dizziness, sedation and gait disturbances. Similarly, inhibition of the endogenous cannabinoid enzyme monoacylglycerol lipase (MAGL) has antinociceptive and anti-inflammatory properties but also induces sedation in mice at high doses. To limit these side effects, the present study investigated the analgesic effects of coadministering a MAGL inhibitor with gabapentin. EXPERIMENTAL APPROACH Mice subjected to the chronic constriction injury model of neuropathic pain were administered the MAGL inhibitor KML29 À À (1–40 mg·kg 1, i.p.), gabapentin (1–50 mg·kg 1, i.p.) or both compounds. Mice were tested for mechanical and cold allodynia. The function and expression of cannabinoid CB1 receptors in whole brain homogenates and lipid profile of spinal cords were assessed after repeated drug administration. KEY RESULTS The combination of low-dose KML29:gabapentin additively attenuated mechanical allodynia and synergistically reduced cold allodynia. The CB1 antagonist, rimonabant, partially reversed the anti-allodynic effects of KML29:gabapentin in me- chanical allodynia but not cold allodynia. The anti-allodynic effects of KML29:gabapentin did not undergo tolerance in mechanical allodynia after repeated administration but produced mild tolerance in cold allodynia. High dose KML29 alone reduced CB1 re- ceptor expression and function, but KML29:gabapentin reduced the density of CB1 receptors but did not alter their function. KML29:gabapentin influenced additional signalling pathways (including fatty acids) other than the pathways activated by a higher dose of either drug alone. CONCLUSION AND IMPLICATIONS These data support the strategy of combining MAGL inhibition with a commonly prescribed analgesic as a therapeutic approach for attenuating neuropathic pain. Abbreviations 2-AG, 2-arachidonylglycerol; 2-LG, 2-linoleoyl glycerol; anandamide, arachidonoylethanolamine; CB receptor, cannabi- noid receptor; CCI, chronic constriction injury; CI, confidence interval; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAEs, N-acylethanolamines; NAGly, N-arachidonoyl glycine; PEA, N-palmitoyl ethanolamine; TRPV, transient receptor potential cation channel subfamily V; Zadd, predicted additive ED50 values; Zmix,experimentally derived ED50 values © 2017 The British Pharmacological Society DOI:10.1111/bph.14055 MSCroweetal. BJP Introduction PF-04457845 did not reduce pain in a clinical trial of osteo- arthritis (Huggins et al., 2012), raising questions about the Neuropathic pain is characterized by altered nerve function translation of preclinical to clinical application of this en- stemming from peripheral nerve injury, autoimmune and zyme. Similarly, the MAGL inhibitors, JZL184 and KML29, other disease states, or toxic insult. Treating neuropathic pain attenuate pain in models of neuropathic pain (Kinsey et al., is difficult, because it is often refractory to traditional analge- 2010; 2013; Ignatowska-Jankowska et al., 2014) and inflam- sics (Attal et al., 2006; Rahn and Hohmann, 2009). As com- matory pain (Guindon et al., 2011; Ghosh et al., 2013). MAGL pared with the well-documented side effects and abuse inhibitors attenuate allodynia (i.e. the painful perception of potential of traditional analgesics, such as opioids, anticon- non-noxious stimuli) and hyperalgesia (i.e. increased sensi- fi vulsants have a relatively strong safety pro le with minimal tivity to noxious stimuli) after nerve injury through a CB1 adverse drug interactions and are the recommended first-line receptor-mediated mechanism of action (Kinsey et al., 2009; treatment for neuropathic pain (Kukkar et al., 2013). How- 2010; Ignatowska-Jankowska et al., 2014). ever, anticonvulsants are associated with negative side ef- Despite the benefits of MAGL inhibition, chronic admin- fects, including drowsiness, dizziness and ataxia (Beal et al., istration of high-dose JZL184 or KML29 induces physical de- 2012; Stahl et al., 2013). Gabapentin is the most commonly pendence and cross-tolerance to cannabinoid receptor prescribed anticonvulsant for neuropathy and, unlike opi- agonists and down-regulates and desensitizes CB1 receptors oids, repeated administration of gabapentin does not un- (Ignatowska-Jankowska et al., 2014; Schlosburg et al., 2014). dergo tolerance (Hao et al., 2000; Gottrup et al., 2004), To circumvent the effects of high doses and maximize which reduces abuse potential. Gabapentin is a structural an- analgesia, research has focused on using lower doses of alogue of GABA but binds to α2δ subtype 1 of voltage-gated endocannabinoid modulators in combination with other an- calcium channels (Sills, 2006; Kukkar et al., 2013). The algesics (Gunduz et al., 2011; Grim et al., 2014; Kazantzis specific mechanisms through which gabapentin produces et al., 2016). For example, the combined pharmacological in- analgesia are not completely clear. However, gabapentin is hibition of MAGL and COX1 and 2 synergistically attenuated thought to suppress central sensitization by blocking α2δ mechanical allodynia and additively attenuated cold channels, which are densely expressed on presynaptic dor- allodynia (Crowe et al., 2015), indicating that MAGL might sal horn neurons (Tuchman et al., 2010; Stahl et al., 2013), be a good candidate for combination therapy. However, re- thus reducing hyperexcitability of spinal nociceptive peated administration of MAGL combined therapy has not neurons. been studied. In addition, commonly prescribed anticonvul- Despite being routinely prescribed, gabapentin is effective sants have not been evaluated in conjunction with drugs af- in only half of chronic pain patients (Moore et al., 2014). fecting the endocannabinoid system. Therefore, the Using an alternative approach targeting multiple systems objective of the present study was to determine the anti- with combination therapies could increase the efficacy of allodynic effects of acute and chronic administration of the treating neuropathic pain (Chaparro et al., 1996; Gilron preclinical MAGL inhibitor, KML29, in combination with et al., 2005; Grim et al., 2014; Crowe et al., 2015). Combina- the clinically available anticonvulsant, gabapentin. tion therapy combines two or more drugs with different mechanisms of action, thereby increasing potential efficacy as compared with administration of either drug alone (Raffa, 2001; Perez et al., 2013). Using this approach offers multiple Methods advantages, such as allowing for lower doses of each drug, thereby potentially reducing negative side effects of each Animals drug, while maintaining pain relief (Raffa, 2001). For exam- All animal care and experimental procedures were in accor- ple, gabapentin has been characterized alone (Moore et al., dance with ARRIVE guidelines (Kilkenny et al., 2010; 2014) and in combination with other analgesics, including McGrath and Lilley, 2015) and were approved by the Insti- opioids and antidepressants (Chaparro
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