Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms

Abstract

Previous studies in our laboratory have demonstrated that cannabinoids administered intravenously attenuate the duration of nocifensive behavior and block the development of hyperalgesia produced by intraplantar injection of capsaicin. In the present study, we extended these observations and determined whether cannabinoids attenuate capsaicin-evoked pain and hyperalgesia through spinal and peripheral mechanisms, and whether the antihyperalgesia was receptor mediated. Separate groups of rats were pretreated 7 min before capsaicin with an intrathecal injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 0.1, 1.0 or 10 microg in 10 microl. Although the intrathecal application of WIN 55,212-2 did not alter nocifensive behavior following capsaicin, it produced a dose-dependent decrease in hyperalgesia to heat and mechanical stimuli. Intrathecal pretreatment with the CB1 receptor antagonist SR141716A (10 microg) blocked the antihyperalgesia produced by WIN 55,212-2. The ability of intrathecal administration of WIN 55,212-2 to attenuate hyperalgesia was not due to motor deficits since the highest dose of WIN 55,212-2 did not alter performance on the rota-rod test. To investigate whether cannabinoids attenuated capsaicin-evoked hyperalgesia through peripheral mechanisms, separate groups of rats were pretreated with an intraplantar injection of WIN 55,212-2 at doses of 0.1, 1.0, 10 or 30 microg in 100 microl 5 min before capsaicin. Intraplantar pretreatment with WIN 55,212-2 produced a dose-dependent attenuation of hyperalgesia to heat, but did not attenuate mechanical hyperalgesia or the duration of nocifensive behavior. The inactive enantiomer WIN 55,212-3 did not alter the development of hyperalgesia. SR141716A (100 microg) co-injected with WIN 55,212-2 (30 microg) partially attenuated the effects of WIN 55,212-2 on hyperalgesia to heat. Intraplantar injection of the highest dose of WIN 55,212-2 did not interfere with the development of hyperalgesia following capsaicin injection into the contralateral paw. These data show that cannabinoids possess antihyperalgesic properties at doses that alone do not produce antinociception, and are capable of acting at both spinal and peripheral sites.

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

“…Taken together with previous reports 9, [19][20][21][22]30,[42][43][44] , this study presents a strong basis for the design of novel synthetic cannabinoids that do not cross the blood-brain barrier as a new class of peripherally acting analgesics without the psychotropic liability of centrally acting CB 1 agonists.…”

The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat

“…Thus, the endocannabinoid anandamide inhibits capsaicin-evoked CGRP release from rat hind paw skin in vitro (Richardson et al, 1998), and the nonselective cannabinoid receptor agonist WIN 55,212-2, injected directly into the hind paw, inhibits mechanical allodynia and thermal hyperalgesia induced by capsaicin injection in vivo (Johanek et al, 2001). Similarly, utilizing the partial sciatic ligation model of neuropathic pain, Fox et al (2001) showed that intraplantar injection of WIN 55,212-2 decreased mechanical allodynia.…”

“…While peripheral effects of cannabinoid agonists on nociceptive responses have not been explored in sensory neurons of CB1 −/− mice, the data shown here, when considered in the context of cannabinoid effects on nociceptors that are sensitive to SR141716A, raise the possibility of a novel cannabinoidresponsive receptor with similar pharmacology to CB1 that is expressed by nociceptive primary sensory neurons. Interestingly, while some studies found that the peripheral antihyperalgesic effects of can-nabinoids were blocked by the CB1 selective antagonist SR141716A (Richardson et al, 1998), another found only partial (60%) inhibition (Johanek et al, 2001), consistent with a non-CB1 receptor mechanism for peripheral cannabinoid effects on nociception.…”

“…While peripheral effects of cannabinoid agonists on nociceptive responses have not been explored in sensory neurons of CB1 −/− mice, the data shown here, when considered in the context of cannabinoid effects on nociceptors that are sensitive to SR141716A, raise the possibility of a novel cannabinoidresponsive receptor with similar pharmacology to CB1 that is expressed by nociceptive primary sensory neurons. Interestingly, while some studies found that the peripheral antihyperalgesic effects of can-nabinoids were blocked by the CB1 selective antagonist SR141716A (Richardson et al, 1998), another found only partial (60%) inhibition (Johanek et al, 2001), consistent with a non-CB1 receptor mechanism for peripheral cannabinoid effects on nociception.In conclusion, we have demonstrated that CB1 mRNA is expressed in a subset of primary sensory afferents in TG. Somewhat surprisingly, based on cell size distributions and colocalization analysis, CB1 receptors in TG likely are restricted almost entirely to neurons that give rise to Aβ fibers that are not involved in nociception in the normal animal and that are generally not in the ophthalmic division of the trigeminal nerve.…”

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

“…[18,20] Cannabinoid's analgesic action in cancer pain is less clear. [2,10,19] In a murine bone sarcoma pain model, systemic cannabinoids act through CBr1. [15,21] However, the role of peripheral CBr1 and CBr2 receptors in soft tissue carcinoma pain is not known.…”