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 tumor-evoked 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 (3.4 mN) applied to the plantar surface of the hindpaw. WIN 55, 212-2 (1.5 to 10 microg) 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 (10 microg) 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 (10 microg) 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.

Figure 1

WIN 55,212-2 dose-dependently attenuates mechanical hyperalgesia in a murine model of cancer pain. Local injection of 2.5, 5, or 10μg of WIN 55,212-2 into the tumor-bearing hindpaw reduced the mean paw withdrawal frequency evoked by a suprathreshold von Frey monofilament (3.4mN). * indicates a significant difference from vehicle (p<0.05).

Figure 2

Antihyperalgesia produced by intraplantar injection of WIN 55,212-2 occurred through peripheral mechanisms. Administration of WIN 55,212-2 (10μg) into the contralateral hindpaw did not decrease paw withdrawal frequencies in the tumor-bearing paw. This indicates that the antihyperalgesia produced by injection of WIN 55,212-2 into the paw did not occur via systemic uptake of the drug

Figure 3

Attenuation of tumor-evoked mechanical hyperalgesia following intraplantar injection of WIN 55,212-2 is not due to catalepsy. Neither vehicle nor 10μg of WIN 55,212-2 increased the amount of time mice spent on the bar. However, intraplantar injection of the 25μg dose of WIN 55,212-2 produced catalepsy. *indicates a significant difference from vehicle (p<0.05).

Figure 4

CB₁ and CB₂ receptors contribute to the antihyperalgesia produced by WIN 55,212-2. Co-administration of 1 μg of either the CB₁ receptor antagonist, AM251 (A), or the CB₂ receptor antagonist, AM630 (B) with 10μg of WIN 55,212-2 attenuated the antihyperalgesia produced by WIN 55,212-2. * indicates a significant difference from vehicle (p<0.05); # indicates a significant difference from WIN 55,212-2 (10μg).