Recently, a series of endogenous ligands related to inhibition of sensory transduction of noxious stimuli at the spinal level has been described, including endomorphins, agmatine, and adenosine, which act on different receptors; however, little data exist concerning their effect during continuous administration or their interactions. In this study, we investigated the antinociceptive properties of continuously administered (for 60 min) adenosine and agmatine on carrageenan-induced thermal hyperalgesia by means of a thermal paw withdrawal test in awake rats. The possible interaction between endomorphin-1 and adenosine or agmatine was also determined. Continuous administration of adenosine (0.3-3 microg/min) did not influence the paw withdrawal latencies of the normal or inflamed paws during the infusion but in larger doses it resulted in a significant increase in latencies after the cessation of the infusion. Agmatine (0.3-3 microg/min) dose-dependently decreased the hyperalgesia, but the largest dose caused a temporary excitation in 50% of animals. The continuous administration of adenosine or agmatine (3 micro g/min) potentiated and prolonged the antinociceptive effect of endomorphin-1 (1 microg/min). Our results revealed that adenosine and agmatine have a small antinociceptive efficacy during continuous intrathecal administration but that both potentiate the effect of endomorphin-1. These data suggest that the combination of these endogenous ligands might represent novel targets for the therapeutic modulation of pain; however, the systematic examination of side effects is essential.
Implications: Adenosine and agmatine have little antinociceptive efficacy during continuous intrathecal administration, as shown by the inflammatory pain test in rats, but both potentiate the effect of endomorphin-1. These data suggest that the combination of these endogenous ligands might represent novel targets for the therapeutic modulation of pain; however, the systematic examination of side effects is essential.