The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain

Abstract

Pain from cancer can be severe, difficult to treat, and greatly diminishes patients’ quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. In this model, implantation of fibrosarcoma cells into and around the calcaneous bone produces mechanical and thermal hyperalgesia in mice. C-fiber nociceptors in tumor-bearing mice develop spontaneous ongoing activity and sensitization to thermal stimuli. However, it is unclear whether sensitization of nociceptors to mechanical stimuli underlies the mechanical hyperalgesia seen in tumor-bearing mice. We therefore examined responses of C-fiber nociceptors to suprathreshold mechanical stimuli in tumor-bearing mice and found they did not differ from those of C-nociceptors in control mice. Thus, sensitization of C-fiber nociceptors to mechanical stimulation does not appear to underlie tumor-evoked mechanical hyperalgesia in this murine model of bone cancer pain. We also examined the effect of the non-selective cannabinoid receptor agonist, WIN 55, 212-2, on spontaneous activity and responses evoked by mechanical stimuli of C-fiber nociceptors innervating the tumor-bearing paw. Selective CB1 and CB2 antagonists were administered to determine the contribution of each receptor subtype to the effects of WIN 55,212-2. Intraplantar administration of WIN 55,212-2 attenuated spontaneous discharge and responses evoked by mechanical stimulation of C-fiber nociceptors. These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C-fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide further evidence that activation of peripheral cannabinoid receptors may be a useful target for the treatment of cancer pain.

Peripherally Restricted Cannabinoids for the Treatment of Pain

“…A similar effect has been shown with drugs that inhibit 2‐AG hydrolysis, JZL 184, URB602, or by 2‐AG administered locally (intraplantar) in the formalin model in rats . The activation of both CB 1 and CB 2 receptors with nonselective agonists (WIN 55,212‐2) also reduces peripheral nociceptor (C fibers) sensitivity in mice in a model of cancer pain, a chronic pain condition …”

Evidence for the involvement of descending pain-inhibitory mechanisms in the attenuation of cancer pain by carvacrol aided through a docking study

“…Spontaneous nociception has been associated with the sensitization of C-fiber nociceptors in several nociception models (Uhelski et al, 2013). The palpation evoked nociception in animals with cancer mimics the allodynia, defined as pain in response to a non-nociceptive stimulus induced by low-threshold fibers, as A-β fibers (Sandkühler, 2009).…”

Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis

“…There is growing evidence that increasing local levels of endocannabinoids can decrease hyperalgesia in models of chronic pain (for reviews, see [23,28,47,63,64]) including bone cancer pain [32,33,54,57] and chemotherapy-induced neuropathic pain [35,59]. Importantly, targeting cannabinoid receptors in the periphery can limit the incidence of unwanted side effects associated with the activation of CB1 receptors in the CNS.…”