Effects of Alterations in Cannabinoid Signaling, Alone and in Combination with Morphine, on Pain-Elicited and Pain-Suppressed Behavior in Mice

Abstract

Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain-elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (Ϫ)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and painsuppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedulecontrolled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus.

Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications

“…In addition to inhibiting the cellular uptake of anandamide, AM404 can activate and desensitise TRPV1 receptors, and inhibit COX-1, COX-2 and PG synthesis (49,91) . Even so, this compound has been found to reduce signs of visceral pain in mice in a manner that seems to be CB 1 receptor-mediated (23) . Importantly, LY2183240 is an inhibitor not only of endocannabinoid cellular uptake but also of FAAH and MAG lipase, and VDM11, UCM707 and AM404, which is a FAAH substrate, also have the ability to reduce the metabolism of anandamide and other acylethanolamides by FAAH (10,90) .…”

“…Evidence has already emerged from animal experiments that FAAH inhibitors are effective at ameliorating signs of acute, inflammatory, visceral and neuropathic pain (2,4,13,(17)(18)(19)(20)(21)(22)(23)(24) , and that URB597 can ameliorate the signs of both osteoarthritic pain (25) , and referred hyperalgesia induced by bladder inflammation (26) . Animal experiments have also yielded data suggesting that FAAH inhibitors might have a number of other therapeutic applications (Table 1).…”

“…been several investigations in which a selective CB 1 or CB 2 receptor antagonist (17,23,24,50,51) , or genetic deletion of the CB 1 receptor (52) , has been found to attenuate signs of antinociception induced by URB597, PF3845 or ST4070 in rodent models of visceral, inflammatory or neuropathic pain. In two of these investigations, however, the TRPV1 antagonist, 5…”

“…These include AM404, VDM11 and UCM707 (Fig. 1d), as well as OMDM1, OMDM2 and LY2183240 (2,10) , one or more of which has been found to decrease cancer cell proliferation and tumour growth and to be effective in animal models against signs of pain, multiple sclerosis, excitotoxicity, Parkinson's disease, Huntington's disease, anxiety, cholera toxin-induced diarrhoea and colitis (2,10,23) . In addition, evidence has recently emerged that reinstatement of nicotine-seeking behaviour can be inhibited by both VDM11 and AM404 in rats, and that the latter compound can prevent the development of nicotine dependence in rats as well (89,90) .…”

“…It is noteworthy, too, first that the peripherally restricted FAAH inhibitor, URB937, has been found in mice both to interact synergistically with the NSAID, indomethacin, to reduce signs of inflammatory and neuropathic pain and to lower the number and severity of indomethacin-induced gastric lesions (34) , and second, that the MAG lipase inhibitor, JZL184, has also been found to protect against NSAID-induced gastric damage in mice (62) . Other potential adjunctive therapeutic strategies include the combined administration of a FAAH inhibitor, with a COX-2 inhibitor and a low dose of a glucocorticoid for rheumatoid arthritis (84) , with palmitoylethanoamide for the treatment of melanoma (85) , with morphine for relieving visceral pain (23) , and with an inhibitor of the metabolism of endogenous opioids (enkephalins) for the alleviation of inflammatory and neuropathic pain (86) . Finally, there has been one recent published report about a clinical trial performed with the FAAH inhibitor, PF04457845 (87) .…”