Multiple Receptors Involved in Peripheral α2, μ, and A1Antinociception, Tolerance, and Withdrawal

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Abstract
We examined the interactions among three classes of peripherally-acting antinociceptive agents (μ-opioid, α2-adrenergic, and A1-adenosine) in the development of tolerance and dependence to their antinociceptive effects. Antinociception was determined by assessing the degree of inhibition of prostaglandin E2 (PGE2)-induced mechanical hyperalgesia, using the Randall-Selitto paw-withdrawal test. Tolerance developed within 4 hr to the antinociceptive effect of the α2-adrenergic agonist clonidine; dependence also occurred at that time, demonstrated as a withdrawal hyperalgesia that was precipitated by the α2-receptor antagonist yohimbine. These findings are similar to those reported previously for tolerance and dependence to μ and A1 peripheral antinociception (Aley et al., 1995). Furthermore, cross-tolerance and cross-withdrawal between μ, A1, and α2 agonists occurred. The observations of cross-tolerance and cross-withdrawal suggest that all three receptors are located on the same primary afferent nociceptors. In addition, the observations suggest that the mechanisms of tolerance and dependence to the antinociceptive effects of μ, A1, and α2 are mediated by a common mechanism. Although any of the agonists administered alone produce antinociception, we found that μ, A1, and α2 receptors may not act independently to produce antinociception, but rather may require the physical presence of the other receptors to produce antinociception by any one agonist. This was suggested by the finding that clonidine (α2-agonist) antinociception was blocked not only by yohimbine (α2-antagonist) but also by PACPX (A1-antagonist) and by naloxone (μ-antagonist), and that DAMGO (μ-agonist) antinociception and CPA (A1-agonist) antinociception were blocked not only by naloxone (μ-antagonist) and PACPX (A1-antagonist), respectively, but also by yohimbine (α2-antagonist). This cross-antagonism of antinociception occurred at the ID80 dose for each antagonist at its homologous receptor. To test the hypothesis that the physical presence of μ-opioid receptor is required not only for μ antinociception but also for α2 antinociception, antisense oligodeoxynucleotides (ODNs) for the μ-opioid and α2C-adrenergic receptors were administered intrathecally to reduce the expression of these receptors on primary afferent neurons. These studies demonstrated that μ-opioid ODN administration decreased not only μ-opioid but also α2-adrenergic antinociception; A1 antinociception was unaffected. In contrast, α2C-adrenergic ODN decreased antinociception induced by all three classes of antinociceptive agents. In conclusion, these data suggest that peripheral antinociception induced by μ, α2, and A1 agonists requires the physical presence of multiple receptors. We propose that there is a μ, A1, α2 receptor complex mediating antinociception in the periphery. In addition, there is cross-tolerance and cross-dependence between μ, A1, and α2antinociception, suggesting that their underlying mechanisms are related.