Actions of N-arachidonyl-glycine in a rat inflammatory pain model

Abstract

Background: While cannabinoid receptor agonists have analgesic activity in inflammatory pain states they produce a range of side effects. Recently, it has been demonstrated that the arachidonic acid-amino acid conjugate, N-arachidonyl-glycine (NA-glycine) is effective in acute pain models.

Results: In the present study we examined the effect of NA-glycine in a rat model of inflammatory pain. Intrathecal administration of NA-glycine (70 - 700 nmol) and the pan-cannabinoid receptor agonist HU-210 (10 nmol) reduced the mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Freund's complete adjuvant (FCA). The actions of HU-210, but not NA-glycine were reduced by the cannabinoid CB1 receptor antagonist AM251. The cannabinoid CB2 receptor antagonist SR144528 also had no effect on the actions of NA-glycine. In contrast, N-arachidonyl-GABA (NA-GABA, 700 nmol) and N-arachidonyl-alanine (NA-alanine, 700 nmol) had no effect on allodynia and hyperalgesia. HU-210, but not NA-glycine produced a reduction in rotarod latency.

Conclusion: These findings suggest that NA-glycine may provide a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.

Figure 1

NA-glycine reduces mechanical allodynia. (a) Time plots of the effect of NA-glycine (NAGly,700 nmol, filled circles), HU-210 (10 nmol, filled squares), or vehicle (open circles) on mechanical paw withdrawal threshold (Mech PWT). Animals received an intrathecal injection of NA-glycine, HU-210 or a matched vehicle at time 0 h, 24 h after intraplantar injection of FCA. Data is also shown prior to FCA injection (Pre-FCA). (b) Bar charts depicting the effect of intrathecal injection of combinations of NA-glycine (NAGly 70 – 700 nmol), HU-210 (10 nmol), AM251 (30 nmol) and vehicle on mean mechanical paw withdrawal threshold, measured as the area-under-the-curve (AUC). * denotes P < 0.05, ** P < 0.01 and # P < 0.0001 compared to time 0 post-FCA in (a) and to vehicle in (b).

Figure 2

NA-glycine reduces thermal hyperalgesia. (a) Time plots of the effect of NA-glycine (NAGly,700 nmol, filled circles), HU-210 (10 nmol, filled squares), or vehicle (open circles) on thermal paw withdrawal latency (PWL). Animals received an intrathecal injection of NA-glycine, HU-210 or a matched vehicle at time 0 h, 24 h after intraplantar injection of FCA. Data is also shown prior to FCA injection (Pre-FCA). (b) Bar charts depicting the effect of intrathecal injection of combinations of NA-glycine (NAGly 70 – 700 nmol), HU-210 (10 nmol), AM251 (30 nmol) and vehicle on mean thermal paw withdrawal latency, measured as the area-under-the-curve (AUC). * denotes P < 0.05, ** P < 0.01 and # P < 0.0001 compared to time 0 post-FCA in (a) and vehicle in (b).

Figure 3

NA-glycine does not affect motor function. Time plots of the effect of NA-glycine (NAGly,700 nmol, filled circles), HU-210 (10 nmol, filled squares), or vehicle (open circles) on rotarod latency. Animals received an intrathecal injection of NA-glycine, HU-210 or a matched vehicle at time 0 h,24 h after intraplantar injection of FCA. Rotarod latency is shown as the difference to the latency at the time zero point, with negative values indicating a decrease in latency. * denotes P < 0.05, ** P < 0.01 and # P < 0.0001 compared to time 0.