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.