Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: Effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment

Abstract

SUMMARY Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and cold allodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB1 and CB2) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30 mg/kg), gabapentin (100 mg/kg), morphine (6 mg/kg), URB597 (0.1 or 1 mg/kg), URB937 (0.1 or 1 mg/kg) or JZL184 (1, 3 or 8 mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB1 (AM251 3 mg/kg), CB2 (AM630 3 mg/kg), TRPV1 (AMG9810 3 mg/kg) or TRPA1 (HC030031 8 mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB1, CB2, TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the neuropathy while amitriptyline, administered acutely, was ineffective. CB1 or CB2 antagonist completely blocked the anti-allodynic effects of both FAAH (URB597, URB937) and MGL (JZL184) inhibitors to mechanical and cold stimulation, while TRPV1 antagonist AMG9810 blocked only the anti-allodynic efficacy of both FAAH inhibitors, but not the MGL inhibitor,. By contrast, the TRPA1 antagonist HC30031 did not attenuate anti-allodynic efficacy of any endocannabinoid modulator. When the levels of endocannabinoids were examined, cisplatin increased both anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels in the lumbar spinal cord and decreased 2-AG levels (but not AEA) in dorsal hind paw skin. RT-PCR showed that mRNA for FAAH, but not other markers, was upregulated by cisplatin treatment in dorsal root ganglia. The present studies demonstrate that cisplatin alters endocannabinoid tone and that inhibition of endocannabinoid hydrolysis alleviates chemotherapy-induced mechanical and cold allodynia. The anti-allodynic effects of FAAH and MGL inhibitors are mediated by CB1 and CB2 cannabinoid receptors, whereas TRPV1, but not TRPA1, -dependent mechanisms ...

A Lipid Gate for the Peripheral Control of Pain

“…These agents are produced and degraded through distinct enzymemediated routes (for review, see Guindon and Hohmann, 2009). Anandamide is formed by cleavage of a membrane phospholipid in which the amine group of phosphatidylethanolamine is covalently linked to arachidonic acid.…”

“…Monoacylglycerol lipase (MGL) is the main serine esterase involved in 2-AG deactivation (Dinh et al, 2002;, with ␣-␤ hydrolase domain 6 (ABHD-6) participating in some cases (Marrs et al, 2010). Like anandamide, 2-AG may be also metabolized by cyclooxygenase-2 to produce oxidized proalgesic derivatives (for review, see Guindon and Hohmann, 2008). 2-AG formation can be inhibited using relatively nonselective probes that block either PLC (e.g., U73122) or DGL (e.g., tetrahydrolipstatin) (Gregg et al, 2012).…”

“…Although highly expressed in neurons of the brain and spinal cord (Herkenham, 1991), CB 1 cannabinoid receptors are also present in neural and non-neural cells throughout the body (for review, see Guindon and Hohmann, 2009). They are synthesized in cell bodies of DRG neurons and are transported to peripheral nerve terminals, where they are localized appropriately to control pain initiation in response to agonist stimulation (Hohmann and Herkenham, 1999).…”

Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice

“…There is also recent evidence that CB targets may be efficacious in treating CIN. For example, selective CB1 and CB2 receptor agonists, as well as compounds that increase endocannabinoid tone, attenuate tactile allodynia in rodent models of CIN [12][13][14].Abstract ! Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy.…”

“…For example, Vera et al [12] demonstrated that cisplatin tactile allodynia in rats can be attenuated by administration of the CB selective and nonselective receptor agonists ACEA, JWH133, and WIN 55,212-2. Cisplatin tactile allodynia can also be attenuated through increased levels of the endocannabinoids anandamide and 2-arachidonylglycerol (2AG) via inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively [13]. While targeting the endocannabinoid system with THC and CBD can modulate CIN, there is a literature that reports THC exposure can lead to increased cancer cell proliferation and tumor metastasis by decreasing antitumor immune responses.…”