Effects of spinal UCM707 on evoked responses of dorsal horn neurones in neuropathic and sham-operated rats

1D.R Sagar, 2E.deLago, 2J.Fernandez-Ruiz, 1D.A. Kendall, 1V.Chapman; 1Institute of Neuroscience, University of Nottingham, U.K. 2Facultad de Medicina, Universidad Complutense, Madrid, Spain.

Recent work in this group has demonstrated the inhibitory effects of spinal cannabinoids on innocuous and noxious mechanically-evoked responses of dorsal horn neurones in rats with spinal nerve ligation in vivo (Sagar et al., 2005). Levels of endocannabinboids have been reported to be increased in the spinal cord following peripheral nerve injury in vivo (Petrosino et al., 2006). UCM707 is a potent inhibitor of endocannabinoid uptake (L ópez-Rodríguez et al., 2001) . Here, effects of spinal administration of UCM707 on mechanically-(10-100g) evoked responses of dorsal horn neurones of the spinal cord were studied in neuropathic and sham-operated rats in vivo.

Tight ligation of spinal nerves L5 and L6 or sham surgery was performed on male Sprague Dawley rats (110-140g). Extracellular recordings of wide dynamic range dorsal horn neurones were made in isoflurane-anaesthetised neuropathic (spinal nerve-ligated) and sham-operated rats 14-17 days post-surgery. Effects of spinal application of UCM707 (10-100μg/ 50μl) on mechanically-evoked responses were studied. UCM707 (10-100μg/ 50μl) significantly inhibited both low (10g) and high weight (15-100g) mechanically-evoked responses of dorsal horn neurones in neuropathic rats (Figure 1; n=6 neurones in 6 rats) compared to pre-drug values. Effects of the highest dose of UCM707 (100μg/ 50μl) on high weight-evoked responses (26-100g) were significantly different in neuropathic rats compared to vehicle treatment (p<0.05, n=6 neurones in 6 rats and n=7 neurones in 7 rats respectively). In sham-operated rats, UCM707 (10-100μg/ 50μl) significantly facilitated low-weight (10g) responses compared to pre-drug values (Figure 1; n=6 neurones in 6 rats), but was not significant compared to vehicle treated rats (n=7 neurones in 7 rats). Spinal administration of UCM707 in sham-operated rats (10-100μg/ 50μl) did not significantly alter 26g-evoked responses of dorsal horn neurones.

Figure 1. Effects of spinal administration of UCM707 (10-100μg/ 50μl) or vehicle (3% Tween 80 in saline) on mechanically-evoked responses of dorsal horn neurones in neuropathic and sham-operated rats in vivo. Data are presented as mean maximal percentages of control responses (± SEM). No significant difference was observed between vehicle treated sham-operated and neuropathic rats therefore data was pooled. Statistical comparison between effects of UCM707 (10-100μg/ 50μl) or vehicle and pre-drug control responses in neuropathic and sham-operated rats were performed using a one way ANOVA with a Dunnett’s post-hoc test **p<0.01 in neuropathic rats, +p<0.05, ++p<0.01 in sham-operated rats. Statistical comparison between effects of UCM707 (10-100μg/ 50μl) and vehicle was carried out using a two-way ANOVA with a Bonferroni post-hoc test #p<0.05, ##p<0.01.

These data suggest the presence of an endogenous cannabinoid tone in both neuropathic and sham-operated rats. The contrasting effects of UCM707 in neuropathic and sham-operated rats indicate functional changes following spinal nerve injury. The exact mechanisms by which UCM707 exerts its effects are yet to be identified, however, these data indicate an analgesic potential of UCM707 in the treatment of neuropathic pain states.

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