Multiple receptors involved in peripheral alpha sub(2), mu , and A sub(1) antinociception, tolerance, and withdrawal

• Published in: The Journal of neuroscience 1997-01, Vol.17 (2), p.735-744
• Main Authors: Aley, KO, Levine, Jon D
• Format: Article
• Language: English
• ISSN: 0270-6474

We examined the interactions among three classes of peripherally-acting antinociceptive agents ( mu -opioid, alpha sub(2)-adrenergic, and A sub(1)-adenosine) in the development of tolerance and dependence to their antinociceptive effects. Antinociception was determined by assessing the degree of inhibition of prostaglandin E sub(2) (PGE sub(2))-induced mechanical hyperalgesia, using the Randall-Selitto paw-withdrawal test. Tolerance developed within 4 hr to the antinociceptive effect of the alpha sub(2)-adrenergic agonist clonidine; dependence also occurred at that time, demonstrated as a withdrawal hyperalgesia that was precipitated by the alpha sub(2)-receptor antagonist yohimbine. These findings are similar to those reported previously for tolerance and dependence to mu and A sub(1) peripheral antinociception O. The studies demonstrated that mu -opioid ODN administration decreased not only mu -opioid but also alpha sub(2)-adrenergic antinociception; A sub(1) antinociception was unaffected. In contrast, alpha sub(2C)-adrenergic ODN decreased antinociception induced by all three classes of antinociceptive agents. In conclusion, these data suggest that peripheral antinociception induced by mu , alpha sub(2), and A sub(1) agonists requires the physical presence of multiple receptors. We propose that there is a mu , A sub(1), alpha sub(2) receptor complex mediating antinociception in the periphery. In addition, there is cross-tolerance and cross-dependence between mu , A sub(1), and alpha sub(2) antinociception, suggesting that their underlying mechanisms are related.