Can alpha 2-adrenoceptor agonists reverse or prevent tolerance to the antinociceptive activity of opioids in rats?

The present study was designed to investigate the possible role of some alpha 2-agonists in the phenomenon of tolerance to opioid-induced antinociception. To do so, the alpha 2-agonists were tested alone and in combination with opioids in naive and repeatedly fentanyl-treated rats in the tail withdrawal reaction (TWR) test. Under the treatment schedule used, rats became tolerant to fentanyl and cross-tolerance was observed with other opioids. The alpha 2-agonists alone were inactive in opioid naive and repeatedly fentanyl-treated rats. The potentiating interaction between the alpha 2-agonists and fentanyl in naive animals diminished considerably after the repeated fentanyl treatment. Adding an alpha 2-agonist to high doses of fentanyl during repeated treatment resulted in a complete tolerance to both compounds. Using lower, but equipotent antinociceptive drug combinations of alpha 2-agonists and opioids, resulted in less tolerance. Alpha 2-agonists are thus unable to directly overcome tolerance to the antinociceptive activity of fentanyl in tolerant animals. Nevertheless, by lowering the dose of the opioid for an equipotent antinociceptive activity, alpha 2-agonists are able to delay the onset of tolerance, probably based on the concept of opioid receptor sparing.