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, 67 (1), 94-109

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

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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

Josée Guindon et al. Pharmacol Res.

Abstract

Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and coldallodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid signaling system consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB(1) and CB(2)) 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 CB(1) (AM251 3 mg/kg), CB(2) (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 (CB(1), CB(2), 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 observed allodynia while amitriptyline, administered acutely, was ineffective. CB(1) or CB(2) antagonists completely blocked the anti-allodynic effects of both FAAH (URB597, URB937) and MGL (JZL184) inhibitors to mechanical and cold stimulation. By contrast, the TRPV1 antagonist AMG9810 blocked 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 lumbar spinal cord. 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 CB(1) and CB(2) cannabinoid receptors, whereas TRPV1, but not TRPA1, -dependent mechanisms contribute to the anti-allodynic efficacy of FAAH (but not MGL) inhibitors. Strikingly, endocannabinoid modulators potently suppressed cisplatin-evoked allodynia with a rapid onset and showed efficacy that equaled or exceeded that of major classes of anti-neuropathic pain medications used clinically. Thus, inhibition of endocannabinoid hydrolysis, via FAAH or MGL inhibitors, represents an efficacious pharmacological approach for suppressing chemotherapy-induced neuropathic pain.

Conflict of interest statement

Conflict of interest

The authors state no conflict of interest.

Figures

Fig. 1
Fig. 1
Cisplatin produces time-dependent sensitization to mechanical and cold stimulation without altering sensitivity to heat. Time course of development of (a) mechanical and (b) cold allodynia in cisplatin-treated animals (n = 168) relative to saline-treated animals (n = 24). (c) The same cisplatin dosing paradigm did not produce either hypersensitivity or hyposensitivity to heat (n = 6 per group). Data are expressed as mean ± s.e.m. * P < 0.0001 vs. saline (NaCl 0.9 %) group (one way ANOVA).
Fig. 2
Fig. 2
FAAH (URB597 and URB937) and MGL (JZL184) inhibitors produce dose-related suppressions of cisplatin-induced mechanical allodynia. (a) Acute treatment with URB597 (0.1 and 1 mg/kg i.p.), (b) URB937 (0.1 and 1 mg/kg i.p.) and (c) JZL184 (1, 3 and 8 mg/kg i.p.) suppressed mechanical allodynia in cisplatin-treated animals. Data are expressed as mean ± s.e.m. (n = 6 per group). * P < 0.001 vs. vehicle group (ANOVA, Bonferroni post hoc); + P < 0.001 vs. high dose of endocannabinoid modulator (i.e. URB597 (1 mg/kg i.p.), URB937 (1 mg/kg) or JZL184 (8 mg/kg i.p.); x P < 0.04 vs. JZL184 (1 mg/kg) (ANOVA, Bonferroni post hoc).
Fig. 3
Fig. 3
Comparison of suppressions of cisplatin-evoked mechanical allodynia produced by acute treatment with FAAH (URB597, URB937) and MGL (JZL184) inhibitors and reference compounds morphine, gabapentin and amitriptyline. (a) URB597 (1 mg/kg i.p.), URB937 (1 mg/kg i.p.) or JZL184 (8 mg/kg i.p.) suppressed cisplatin-induced mechanical allodynia throughout the 150 min post-injection observation interval. The anti-allodynic effects of endocannabinoid modulators outlasted that of morphine (6 mg/kg i.p.). Amitriptyline (30 mg/kg i.p.) failed to attenuate cisplatin-evoked mechanical allodynia, whereas gabapentin (100 mg/kg i.p.) was only partially effective in elevating mechanical withdrawal thresholds. (b) FAAH (URB597, URB937) and MGL (JZL184) inhibitors did not alter mechanical withdrawal thresholds in saline-treated rats. Data are expressed as mean ± s.e.m. (n = 6 per group). * P < 0.001 vs. vehicle (DMSO) group (ANOVA, Bonferroni post hoc); + P < 0.05 vs. endocannabinoid modulators and morphine(ANOVA, Bonferroni post hoc).
Fig. 4
Fig. 4
FAAH (URB597, URB937) and MGL (JZL184) inhibitors suppress cisplatin-induced mechanical allodynia through CB1 and CB2 but not TRPA1 receptor mechanisms whereas FAAH inhibitors additionally engage TRPV1 dependent mechanisms. (a) The CB1 (AM251; 3 mg/kg i.p.), CB2 (AM630; 3 mg/kg i.p.), TRPV1 (AMG9810; 3 mg/kg) and TRPA1 (HC030031; 8 mg/kg) antagonists did not alter cisplatin-induced mechanical allodynia relative to vehicle treatment (i.p.). (b) JZL184 (8 mg/kg i.p.), (c) URB597 (1 mg/kg i.p.) and (d) URB937 (1 mg/kg i.p.) suppressed cisplatin-induced mechanical allodynia through mechanisms blocked by either the CB1 (AM251; 3 mg/kg i.p.) or the CB2 (AM630; 3 mg/kg i.p.) antagonists, but not the TRPA1 (HC030031; 8 mg/kg i.p) antagonist. Anti-allodynic effects of FAAH (URB597, URB937), but not MGL (JZL184), inhibitors were also blocked by the TRPV1 (AMG9810; 3 mg/kg i.p.) antagonist. Data are expressed as mean ± s.e.m. (n = 6 per group). * P < 0.001 vs. DMSO, AM251 + MGL/FAAH inhibitors, AM630 + MGL/FAAH inhibitors and AMG9810 + FAAH inhibitors (ANOVA, Bonferroni post hoc).
Fig. 5
Fig. 5
FAAH (URB597 and URB937) and MGL (JZL184) inhibitors produce dose-related suppressions of cisplatin-induced cold allodynia. (a) Acute treatment with URB597 (0.1 and 1 mg/kg), (b) URB937 (0.1 and 1 mg/kg) and (c) JZL184 (1, 3 and 8 mg/kg) suppressed cold allodynia in cisplatin-treated animals. Data are expressed as mean ± s.e.m. (n = 6 per group). * P < 0.024 vs. vehicle group (ANOVA, Bonferroni post hoc); + P < 0.048 vs. URB597 (1 mg/kg) or URB937 (1 mg/kg) or JZL184 (1 or 3 mg/kg) (ANOVA, Bonferroni post hoc).
Fig. 6
Fig. 6
Comparison of suppressions of cisplatin-evoked cold allodynia produced by acute treatment with FAAH (URB597, URB937) and MGL (JZL184) inhibitors and reference compounds morphine, gabapentin and amitriptyline. (a) URB597 (1 mg/kg i.p.), URB937 (1 mg/kg i.p.) and JZL184 (8 mg/kg i.p.) suppressed cisplatin-induced cold allodynia throughout the 150 min observation interval. The anti-allodynic effects of endocannabinoid modulators outlasted that of morphine (6 mg/kg i.p.). Amitriptyline (30 mg/kg i.p.) failed to attenuate cisplatin-evoked cold allodynia whereas gabapentin (100 mg/kg i.p.) was only partially effective in reducing frequency of withdrawal to acetone stimulation. (b) FAAH (URB597, URB937) and MGL (JZL184) inhibitors did not alter frequency of withdrawal to cold in saline-treated rats. Data are expressed as mean ± s.e.m. (n = 6 per group). * P < 0.005 vs. vehicle (DMSO) group (ANOVA, Bonferroni post hoc); + P < 0.037 vs. endocannabinoid modulators or morphine (ANOVA, Bonferroni post hoc).
Fig. 7
Fig. 7
FAAH (URB597, URB937) and MGL (JZL184) inhibitors suppress cisplatin-induced cold allodynia through CB1 and CB2 but not TRPA1 receptor mechanisms whereas FAAH inhibitors additionally engage TRPV1 dependent mechanisms. (a) The CB1 (AM251; 3 mg/kg i.p.), CB2 (AM630; 3 mg/kg i.p.), TRPV1 (AMG9810; 3 mg/kg i.p.) and TRPA1 (HC030031; 8 mg/kg i.p.) antagonists did not alter cisplatin-induced cold allodynia relative to vehicle treatment (i.p.). (b) JZL184 (8 mg/kg i.p.), (c) URB597 (1 mg/kg i.p.) and (d) URB937 (1 mg/kg i.p.) suppressed cisplatin-induced cold allodynia in a manner blocked by either the CB1 (AM251; 3 mg/kg i.p.) or the CB2 (AM630; 3 mg/kg i.p.) antagonists, but not the TRPA1 (HC030031; 8 mg/kg i.p.) antagonist. Anti-allodynic effects of FAAH (URB597, URB937), but not MGL (JZL184), inhibitors were also blocked by the TRPV1 (AMG9810; 3 mg/kg i.p.) antagonist. Data are expressed as mean ± s.e.m. (n = 6 per group). * P < 0.001 vs. DMSO, AM251 + MGL/FAAH inhibitors, AM630 + MGL/FAAH inhibitors and AMG9810 + FAAH inhibitors (ANOVA, Bonferroni post hoc).
Fig. 8
Fig. 8
Cisplatin increases levels of (a, b) endocannabinoids (2-AG, AEA) but not (c, d) fatty-acid amides (OEA, PEA) or (e,f) other inflammatory mediators (PGE2, PGF) levels in the lumbar spinal cord relative to saline treatment. Data are expressed as mean ± s.e.m. (n = 5–8 per group). * P < 0.049 vs. Saline (t-test, two-tailed).
Fig. 9
Fig. 9
Cisplatin decreases levels of (a) the endocannabinoid 2-AG in rat hind paw skin without altering levels of (b) AEA relative to saline treatment. Levels of (c, d) fatty-acid amides (OEA, PEA) and (e,f) other inflammatory mediators (PGE2,PGF) were not altered in rat hind paw skin relative to saline treatment. Data are expressed as mean ± s.e.m. (n = 6–8 per group). * P < 0.029 vs. Saline (t-test, two-tailed).
Fig. 10
Fig. 10
(a) Cisplatin increases levels of FAAH, but not MGL, mRNA in the lumbar spinal cord without altering levels of CB1, CB2, TRPV1 or TRPA1 mRNAs. (b) Cisplatin did not reliably alter mRNAs for either endocannabinoid hydrolyzing enzymes (MGL, FAAH) or receptors (CB1, CB2, TRPV1, TRPA1) in DRG. Data are expressed as mean ± s.e.m. (n = 7–8 for spinal cord and n = 3–7 per group for DRG). * P < 0.0071 vs. Saline (t-test, two-tailed).

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