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 kg À1 , 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.

The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3′-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice

“…One plausible explanation for this result is that short-term dosing with URB597 might induce neuroplastic changes that are responsible for the enhanced efficacy of the drug. Similar enhancements in efficacy after repeated administrations have been observed with the ability of URB597 to increase serotonergic neuron firing in the dorsal raphe nucleus (Gobbi et al, 2005), as well as with the analgesic effects of cannabinoid agonists (Costa et al, 2004) and gabapentin (Fox et al, 2003). The alternate possibility that repeated dosing with URB597 causes incremental elevations in anandamide levels, for example, through alterations in cellular uptake (Kaczocha et al, 2006), is rendered less likely by our finding that single or repeated administration of URB597 elicits similar changes in spinal cord FAE levels (unpublished data).…”

Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain

“…Our findings provide an explanation for the persistent effectiveness of peripherally administered CB 1 R agonists in alleviating the painful symptoms of peripheral neuropathy (Bridges et al, 2001;Fox et al, 2001;Costa et al, 2004). Increased CB 1 R expression in L4 DRG should increase net transport and incorporation of CB 1 R at peripheral sensory terminals (Hohmann and Herkenham, 1999a).…”

“…Furthermore, cannabinoids effectively alleviate neuropathic pain symptoms after repeated treatment (Bridges et al, 2001;Costa et al, 2004), unlike opioids, which have only limited effectiveness (Mao et al, 1995;Ossipov et al, 1995;Rashid et al, 2004).…”

Effect of Cannabinoid Receptor Agonists on Streptozotocin-Induced Hyperalgesia in Diabetic Neuropathy

“…also by activation of CB-2 receptors [15][16][17][18] . In the literature only limited data exist concerning participation of cannabinoid receptors in modification of hyperalgesiaevoked STZ administration.…”