The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain

Abstract

The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed. The effect of WIN55,212-2 (0.1 - 5.0 mg kg(-1), i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co-administration of the CB(1) receptor antagonist SR141716a, but not by co-administration of the CB(2) receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB(1) receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone. These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB(1) receptor.

Figures

Figure 1

Bilateral hind limb withdrawal responses to cold stimulation (acetone drop) in rats rendered neuropathic by L5 spinal nerve ligation administered WIN55,212-2 (0.1–2.5 mg kg−1, i.p., n=6 per dose). Attenuation of cold allodynia was observed at a dose of 2.5 mg kg−1 WIN55,212-2. +P<0.05, paired t-test, *P<0.05, one-way ANOVA (Dunnett's).

Figure 2

Bilateral hind limb withdrawal responses to thermal stimulation (Hargreaves' device) in rats rendered neuropathic by L5 spinal nerve ligation administered WIN55,212-2 (0.1–2.5 mg kg−1, i.p., n=6 per dose). Attenuation of thermal hyperalgesia was observed at doses of 0.5 and 2.5 mg kg−1 WIN55,212-2. +P<0.05, paired t-test, *P<0.05, one-way ANOVA (Dunnett's).

Figure 3

Bilateral hind limb withdrawal responses to mechanical stimulation (electronic Von Frey) in rats rendered neuropathic by L5 spinal nerve ligation administered WIN55,212-2 (0.5–5.0 mg kg−1, i.p., n=6 per dose). Attenuation of mechanical allodynia was observed at a dose of 5.0 mg kg−1 WIN55,212-2. +P<0.05, paired t-test, *P<0.05, one-way ANOVA (Dunnett's).

Figure 4

Bilateral hind limb withdrawal responses to (a) cold (acetone drop), (b) thermal (Hargreaves' device) and (c) mechanical (electronic Von Frey) stimulation in rats rendered neuropathic by L5 spinal nerve ligation (n=6 per group) co-administered SR141716a (0.5 mg kg−1, i.p.) and an effective dose of WIN55,212-2. SR141716a reversed the anti-allodynic and anti-hyperalgesic effects of WIN55,212-2. +P<0.05, paired t-test, *P<0.05, one way ANOVA (Dunnett's).

Figure 5

Bilateral hind limb withdrawal responses to (a) cold (acetone drop), (b) thermal (Hargreaves' device) and (c) mechanical (electronic Von Frey) stimulation in rats rendered neuropathic by L5 spinal nerve ligation (n=6 per group) administered SR141716a (0.5 mg kg−1, i.p.) alone. SR141716a administered alone was associated with no change in sensory thresholds. +P<0.05, paired t-test.

Figure 6

Bilateral hind limb withdrawal responses to cold (acetone drop) stimulation in rats rendered neuropathic by L5 spinal nerve ligation (n=6) co-administered SR144528 (1.0 mg kg−1, i.p.) and WIN55,212-2 (2.5 mg kg−1, i.p.). SR144528 did not attenuate the anti-allodynic effect of WIN55,212-2. +P<0.05, paired t-test), *P<0.05, one way ANOVA (Dunnett's).