The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms

Abstract

Several lines of evidence suggest that cannabinoids can attenuate various types of pain and hyperalgesia through peripheral mechanisms. The development of rodent cancer pain models has provided the opportunity to investigate novel approaches to treat this common form of pain. In the present study, we examined the ability of peripherally administered cannabinoids to attenuate tumorevoked mechanical hyperalgesia in a murine model of cancer pain. Unilateral injection of osteolytic fibrosarcoma cells into and around the calcaneus bone resulted in tumor formation and mechanical hyperalgesia in the injected hindpaw. Mechanical hyperalgesia was defined as an increase in the frequency of paw withdrawals to a suprathreshold von Frey filament (3.4mN) applied to the plantar surface of the hindpaw. WIN 55, 212-2 (1.5 to 10μg) injected subcutaneously into the tumor-bearing hindpaw produced a dose-dependent decrease in paw withdrawal frequencies to suprathreshold von Frey filament stimulation. Injection of WIN 55,212-2 (10μg) into the contralateral hindpaw did not decrease paw withdrawal frequencies in the tumor-bearing hindpaw. Injection of the highest antihyperalgesic dose of WIN 55,212-2 (10μg) did not produce catalepsy as determined by the bar test. Co-administration of WIN 55,212-2 with either cannabinoid 1 (AM251) or cannabinoid 2 (AM630) receptor antagonists attenuated the antihyperalgesic effects of WIN 55, 212-2. In conclusion, peripherally administered WIN 55,212-2 attenuated tumor-evoked mechanical hyperalgesia by activation of both peripheral cannabinoid 1 and cannabinoid 2 receptors. These results suggest that peripherally-administered cannabinoids may be effective in attenuating cancer pain.

Cannabinoids as therapeutic agents in cancer: current status and future implications

“…Effects of subcutaneously administered WIN55,212-2 on weight bearing and mechanical hyperalgesia were consistent with cannabinoid receptor mediated anti-nociception [93]. WIN55,212-2 also attenuates tumour-evoked mechanical hyperalgesia following local (intraplantar) administration through activation of CB1 and CB2 receptors [95]. Injection of CP55 940 produced anti-nociceptive properties in the tail flick test and suppressed mechanical hyperalgesia in NCTC-2472 or melanoma B16-F10 xenografted bone tumor model [96].…”

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

“…In addition, results obtained from experiments with mice indicate that R-(þ)-WIN55212 can act through CB 1 and CB 2 receptors to reduce signs of hyperalgesia without also inducing catalepsy when it is injected into tumour-bearing hind paws [19], and that the CB 2 -selective agonist, JWH-015, can induce a CB 2 -receptor-mediated reduction in bone-cancer-related pain caused by implantation of NCTC2472 fibrosarcoma cells into the femur [20]. It has been found too that intraplantar injection of 2-arachidonoyl glycerol can induce CB 2 receptor-mediated relief from hyperalgesia in a murine model of human metastatic bone cancer pain in which fibrosarcoma cells are injected into and around the calcaneus bone of the left hind paw of each animal, and in which CB 2 receptor expression increases in non-neuronal cells in the plantar skin of the tumour-bearing paw [21].…”

Dynamic changes to the endocannabinoid system in models of chronic pain

“…Studies in models of cancer pain have revealed differing effects on the expression of cannabinoid receptors within the CNS, with some groups reporting an upregulation of CB1 receptor in the L5 DRG in mice injected with squamous cell carcinoma into the hindpaw [46], while others studying models of bone cancer report no change in expression [48,60]. Despite these differences, administration of cannabinoid agonists produces robust analgesia in all models of cancer pain via activation of both CB1 [46,50,60] and CB2 receptors [46][47][48][49][50]. Interestingly, antinociceptive effects of both intrathecal and systemic administration of the CB2 receptor selective agonist AM1241 were abolished by intrathecal administration of the CB2 receptor antagonist SR144528, indicating a spinal site of action [48], and the effects of systemic AM1241 were blocked by naloxone [48], indicating a role of endogenous opioids, which warrants further investigation.…”