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 μg) 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 μg) 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 μg) 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.

Introduction

Pain resulting from cancer still presents a major therapeutic challenge. Current estimates indicate that over half of patients with cancer experience pain, and nearly two-thirds in advanced disease stages experience pain (van den Beuken-van Everdingen et al., 2007). Of those reporting cancer pain, it is estimated that one-third of all cancer patients rate their pain as moderate to severe (van den Beuken-van Everdingen et al., 2007). Although the prevalence of cancer pain differs among the various types of cancer, it is often reported by individuals with both primary and metastatic bone cancer, with greater than 60% of individuals with metastatic bone cancer suffering from severe pain (Coleman, 2006).

Cancer pain is most often treated with opioid drugs; however, these drugs produce dose-limiting side effects and sometimes provide inadequate analgesia (Hanks and Forbes, 1997, Cherny, 2004). Current estimates suggest that adequate analgesia is not achieved in all cancer patients using the World Health Organization's (WHO's) analgesic ladder (Azevedo et al., 2006). Understanding the mechanisms related to the generation and maintenance of cancer pain is needed for the development of novel and more efficacious therapies to treat this condition.

The use of cannabinoids to treat cancer pain may provide a novel therapeutic approach. Two endogenous receptors for cannabinoids have been isolated and cloned so far, cannabinoid 1 (CB₁) and cannabinoid 2 (CB₂) receptors (Matsuda et al., 1990, Murro et al., 1993), and both have been localized to various neuronal and non-neuronal tissues. Previous studies have shown that systemic administration of cannabinoids produces antinociception and attenuates hyperalgesia and allodynia in animal models of acute and chronic pain (for reviews see Walker et al., 1999, Hohmann, 2002, Walker and Huang, 2002, Mbvudula et al., 2004). The efficacy of systemically delivered cannabinoids is limited by adverse cannabimimetic effects (catalepsy, hypolocomotion, and disruptions in memory) which are mediated through CB₁ receptor activation in the central nervous system (for review see Iversen, 2003). One way to avoid these centrally-mediated cannabimimetic effects, while still providing analgesia, is through the selective targeting of peripheral CB₁ receptors expressed on nociceptive primary afferent dorsal root ganglion (DRG) neurons (Hohman and Hekenham, 1999; Ahluwalia et al., 2000) and cutaneous nerve terminals (Ständer et al., 2005, Amaya et al., 2006, Agarwal et al., 2007).

A recent study from our lab demonstrated that systemic administration of the non-selective cannabinoid receptor agonist CP 55,940 attenuated tumor-evoked mechanical hyperalgesia in an established murine model of cancer pain through activation of CB₁ receptors (Hamamoto et al., 2007). In this cancer pain model, osteolytic fibrosarcoma cells were injected into and around the calcaneus bone which produces a tumor mass and eventually leads to hyperalgesia and sensitization of C nociceptors overlying the tumor on the plantar surface of the hindpaw (Cain et al., 2001, Wacnik et al., 2001). Since systemically administered cannabinoids can produce adverse cannabimimetic effects, the present study was designed to determine if local injection of the non-selective cannabinoid receptor agonist WIN 55,212-2 can attenuate tumor-evoked mechanical hyperalgesia and whether this effect occurred through activation of CB₁ or CB₂ receptors.