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
Graphical abstract
Introduction
Chemotherapeutic agents used in the treatment of cancer are associated with major toxicities including painful neuropathy, renal toxicity and bone marrow suppression [1], [2]. Of these toxicities, chemotherapy-evoked neuropathic pain is dose limiting and represents a leading cause of discontinuation of chemotherapy, resulting in suboptimal effects on cancer cell destruction [3], [4], [5]. Cisplatin, a platinum-derived chemotherapeutic agent, is widely used to treat breast, ovarian, lung, kidney, liver, thyroid, lymphoma and other cancers [6], [7]. Cisplatin produces painful neuropathy through mechanisms that remain poorly understood [8], [9], [10], [11].
The development of animal models of chemotherapy-induced toxicities has advanced our understanding about the mechanisms underlying peripheral neuropathy [12]. In preclinical studies, morphine, gabapentin and antidepressants alleviate signs attributed to the development of the neuropathy [13], [14], [15], [16], [17], [18]. These observations are consistent with the results of clinical studies suggesting that chemotherapy-evoked neuropathies can be alleviated by the use of morphine, gabapentin and tricyclic antidepressants [4], [19], [20], [21], [22]. Pharmacodynamic and pharmacokinetic properties of these compounds vary and may affect their time course of action and therapeutic efficacy in vivo [23], [24], [25].
In the last decade, the endocannabinoid system has emerged as a target for novel pharmacotherapies aimed at ameliorating neuropathic pain [26], [27]. Endocannabinoids are endogenous lipid-signaling molecules that mimic the pharmacological actions of the principal psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC) [28]. Anandamide (AEA) [29] and 2-arachidonoylglycerol (2-AG) [30], [31] are the two best-studied endocannabinoids identified to date. Endocannabinoids possess cannabimimetic properties because they bind and activate cannabinoid CB1 [32], [33] and/or CB2 [34] receptor subtypes. AEA is mainly hydrolyzed by the enzyme fatty-acid amide hydrolase (FAAH) [35] whereas 2-AG is mainly, although not exclusively, hydrolyzed by the enzyme monoacylglycerol lipase (MGL) [36], [37], [38], [39].
A small number of preclinical studies have recently demonstrated that cannabinoids attenuate chemotherapy-induced neuropathic pain. Indeed, direct agonists such as WIN55,212-2, a mixed CB1 and CB2 agonist, attenuates mechanical allodynia in models of paclitaxel [40], vincristine [41] and cisplatin [42]-induced neuropathy. Moreover, CB2 agonists ((R,S)-AM1241, (R)-AM1241, AM1714, MDA7 and MDA19) also alleviate mechanical allodynia in paclitaxel [43], [44], [45] and vincristine-induced neuropathy [41].
An alternative approach to the use of direct cannabinoid agonists is to increase endocannabinoid accumulation indirectly by inhibiting endocannabinoid hydrolysis. This approach aims to harness the therapeutic potential of the endocannabinoid signaling system [46], [47], [48], [49], [50], while producing a more limited spectrum of unwanted side-effects compared to direct cannabinoid agonists (for review see [26]). This strategy also offers the potential to improve our current knowledge of the functional roles of endogenous AEA and 2-AG in modulating pathological pain. The beneficial impact of modulating the endocannabinoid system in different neuropathic pain models has recently been reviewed [26]. Indeed, FAAH (URB937, URB597, OL-135, N-arachidonoyl 5-HT (AA-5-HT)) and MGL (JZL184, URB602) inhibitors alleviate surgically-induced neuropathic pain in animal models [46], [47], [48], [51], [52], [53]. However, efficacy of blocking endocannabinoid hydrolysis through inhibition of FAAH and MGL in models of chemotherapy-induced neuropathy remains relatively uncharacterized [see 54].
The present study was designed to evaluate the impact of inhibition of FAAH and MGL on chemotherapy-induced neuropathy in cisplatin-treated rats. First, we characterized the development of behavioral sensitization to mechanical, cold and heat stimulation following once weekly treatments with cisplatin for three weeks. Second, we used pharmacological inhibitors of FAAH (URB597 (0.1 and 1 mg/kg), URB937 (0.1 and 1 mg/kg)) and MGL (JZL184 (1, 3 and 8 mg/kg)) to evaluate their efficacy in suppressing distinct modalities of cisplatin-induced neuropathic pain in rats. We compared the efficacy of brain permeant (URB597) and impermeant (URB937) inhibitors of the anandamide hydrolyzing enzyme FAAH in suppressing cisplatin-induced mechanical and cold allodynia under identical conditions. Third, we examined the receptor mechanism by which FAAH (URB597, URB937) and MGL (JZL184) inhibitors suppress mechanical and cold allodynia using selective antagonists for CB1 (AM251), CB2 (AM630), TRPV1 (AMG9810) and TRPA1 (HC030031) receptors. Fourth, we evaluated the impact of cisplatin (versus saline) treatment on endocannabinoid levels in both the lumbar spinal cord and hind paw skin. Fifth, we evaluated the impact of cisplatin treatment on transcription of enzymes catalyzing endocannabinoid hydrolysis (FAAH, MGL) and receptors (CB1, CB2, TRPV1, TRPA1). These studies further validate FAAH (URB597, URB937) and MGL (JZL184) inhibitors as important pharmacological tools with high therapeutic potential as anti-allodynic agents. Our studies suggest that pharmacological inhibition of AEA and 2-AG hydrolysis suppresses established mechanical and cold allodynia in cisplatin-treated rats following acute administration with efficacy equaling or exceeding that of anti-neuropathic pain medications employed clinically. Moreover, cisplatin treatment directly modulates the endocannabinoid system. These studies further validate the therapeutic potential of modulating the endocannabinoid system to suppress chemotherapy-induced neuropathy. Our studies also suggest that endocannabinoid modulators exhibit high potency, rapid onset and strong efficacy in suppressing chemotherapy-induced neuropathy in comparison to reference analgesics employed clinically including an opioid (morphine), anti-convulsant (gabapentin) and tricyclic anti-depressant (amitriptyline).
Section snippets
Subjects
Two hundred and forty-eight adult male Sprague-Dawley rats (Harlan, Indianapolis, IN, USA) weighing 260–325 g, at the beginning of the testing, were used in these experiments. Animals were single housed in standard plastic cages with sawdust bedding in a climate-controlled room, under a 12 h light/dark cycle. The rats received free access to standard rodent chow and water. All experimental research was carried out in accordance with the National Institute of Health Guidelines for the Care and Use
Mechanical allodynia
Cisplatin decreased mechanical withdrawal thresholds relative to saline treatment (F1,190 = 1736.98, P < 0.0001), consistent with the development of mechanical allodynia (Fig. 1a). Mechanical allodynia was present from day 4 to day 16 (P < 0.0001) (Fig. 1a).
Cold allodynia
Cisplatin increased the frequency of paw withdrawal to acetone relative to saline treatment (F1,190 = 1456.46, P < 0.0001), consistent with the development of cold allodynia (Fig. 1b). Cold allodynia was similarly present from day 4 to day 16 (P <
Discussion
Our study demonstrates that pharmacological inhibitors of endocannabinoid degradation, targeting either FAAH (URB597, URB937) or MGL (JZL184), suppress chemotherapy-induced neuropathic pain. We found that cisplatin-induced mechanical and cold allodynia was exquisitely sensitive to endocannabinoid modulators; all endocannabinoid modulators reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels following acute administration. In each case, the anti-allodynic effects of
Conclusions
The present study provides evidence that inhibition of FAAH (URB937, URB597) and MGL (JZL184) suppresses cisplatin-evoked mechanical and cold allodynia. A brain impermeant inhibitor of FAAH was as efficacious as a brain permeant inhibitor of either FAAH or MGL. Moreover, endocannabinoid modulators were effective following acute administration, exhibiting efficacy comparable to morphine and superior to that of gabapentin, administered via the same route. In all cases, the anti-allodynic effects
Conflict of interest
The authors state no conflict of interest.
Acknowledgment
Supported by DA021644 and DA028200 (to AGH).
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