Repeated treatment with the synthetic cannabinoid WIN 55,212-2 reduces both hyperalgesia and production of pronociceptive mediators in a rat model of neuropathic pain

Abstract

The antinociceptive properties of cannabinoids in persistent pain are not fully elucidated. We investigated the effect of repeated treatment with the synthetic cannabinoid receptor agonist WIN 55,212-2 on the neuropathic pain induced in rats by chronic constriction of the sciatic nerve. WIN 55,212-2 administered daily throughout the development of neuropathy reversed the hyperalgesia, at a dose (0.1 mg x kg(-1), s.c.) that had no effect on the nociceptive responses of either paw contralateral to the sciatic ligation or of animals subjected to sham surgery. At 14 days after injury, the levels of mediators known to be involved in neuropathic pain, such as prostaglandin E2, NO and the neuronal NOS, were increased. Repeated treatment with WIN 55,212-2 abolished these increases. In the light of the current clinical need for neuropathic pain treatments, these findings indicate that cannabinoid agonists, at doses devoid of psychoactive effects, could constitute important compounds for the development of new analgesics.

Figure 1

Effect of WIN 55,212-2 (0.1 mg kg⁻¹, s.c.) daily administered in CCI rats on thermal hyperalgesia. Withdrawal latency is expressed as S. Data represent mean±s.e.m. of 8–10 rats. ^**P<0.01 vs presurgery; °°P<0.01 vs CCI/vehicle animals; ^#P<0.05 vs CCI/WIN 55,212-2 on day 7.

Figure 2

Effect of WIN 55,212-2 (0.1 mg kg⁻¹, s.c.) daily administered in CCI rats on mechanical hypersensitivity. Withdrawal threshold is expressed as g. Data represent mean±s.e.m. of 8–10 rats. ^**P<0.01 vs presurgery; °°P<0.01 vs CCI/vehicle; ^#P<0.05 vs CCI/WIN 55,212-2 on day 7.

Figure 3

Effect of WIN 55,212-2 (0.1 mg kg⁻¹, s.c.) daily administered in CCI rats on PGE2 plasma level. Data represent mean±s.e.m. of 8–10 rats. ^***P<0.001 vs sham/vehicle animals; °°P<0.01 vs CCI/vehicle animals.

Figure 4

Effect of WIN 55,212-2 (0.1 mg kg⁻¹, s.c.) daily administered in CCI rats on nitrite/nitrate content. Data represent mean±s.e.m. of 8–10 rats. ^***P<0.001 vs sham/vehicle animals; °°°P<0.001 vs CCI/vehicle.

Figure 5

Representative immunoreactive bands of nNOS protein in cytosolic fraction of sciatic nerve homogenate. Each lane was loaded with 100 μg of proteins. Lane 1: sham/vehicle; lane 2: sham/WIN 55, 212-2; lane 3; CCI/vehicle; lane 4: CCI/WIN 55, 212-2.