Efectos espinales y supraespinales de la N-ciclopentil adenosina (CPA) en ratas adultas con inflamación de tejidos blandos|binteracción con sistemas opioides

Abstract

The adenosine derivative N6-cyclopentyladenosine (CPA) is a selective agonist for the Al receptor type. It is a very potent antinociceptive drug whose actions have been located within the spinal cord and at peripheral sites. However, although high concentrations of the adenosine Al receptor are located at supraspinal areas of the central nervous system, little is known about the involvernent of supraspinal adenosine in the nociceptive system. In addition, sorne studies suggest an interaction between adenosine and opioid systerns but it is not known how and where this interaction occurs. We have, therefore, studied the antinociceptive effect of CPA and its interactions with j.i and K opioid receptors using the technique of electrophysiological recording of single motor units (SMUs) in intact, spinalized and sham-spinalized male rats. SMUs were activated by noxious mechanical stimulation and by repetitive electrical stimulation that generates the wind-up phenomenon. In a first series of experiments, we observed that CPA dose dependently reduced the responses to noxious mechanical and electrical stirnulation in ¡ntact and sham-spinalized animals, but not in spinalized rats. This clearly suggests that, in the present experimental conditions, CPA effect was mainly localized at supraspinal sites. We also observed that surgery of sham-spinalization induced an enhancement of CPA effect, indicating that spine-related surgery triggers an endogenous antinociceptive system that involves the adenosine systems, similar to that previously observed with endogenous opioids. In a second series of experiments, we observed that CPA effect in intact and sham-spinalized animais was only partially reversed by the selective adenosine Al receptor antagonist 8-cyclopentyl-l ,3- dimethylxanthine (CPT). However, the pretreatment with CPT inhibited any effect of CPA. The non-selective opioid receptor antagonist naloxone induced full reversal of CPA activity but pretreatment with naloxone did not inhibit the effect. These results suggest that although the antinociceptive activity of CPA is initiated by its interaction with the adenosine Al receptor, a secondary activation of opioid receptors is also present in the maintenance of ttie analgesia, in adult rats with inflammation. Finaily, we observed an important increase of wind-up when CPA and CPT were injected together in spinalized animais, in such a way that the level of wind-up was similar to that observed in animais with an intact spinal cord. These results suggest that the depression of wind-up in spinalized animals, observed in previous studies,¡5 dependent on the activity of the adenosine Al receptor and can be prevented by the combined administration of CPA and CPT. The mechanism involved in this effect is not known. In a third series of experiments, we studied the reversal of CPA effect by Iow doses of naloxone (selective for the t opioid receptor) and by the K oploid receptor antagonist nor-binaltorphimine (nor-BNI). We observed that 10w doses of naloxone did not induce any reversal of CPA effect. However, the administration of nor-BNI induced fuli reversal of CPA antinociception. This indicates that the interaction suggested by adenosine and oploid systems is mainly related to K opioid receptor.