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Volume 17, Number 2, Issue of January 15, 1997 pp. 735-744
Copyright ©1997 Society for Neuroscience

Multiple Receptors Involved in Peripheral ₂, µ, and A₁ Antinociception, Tolerance, and Withdrawal

Received Sept. 3, 1996; revised Oct. 22, 1996; accepted Oct. 25, 1996.

K. O. Aley and Jon D. Levine

Departments of Anatomy, Medicine, and Oral and Maxillofacial Surgery, Division of Neuroscience and Biomedical Sciences Program, University of California at San Francisco, San Francisco, California 94143-0452

We examined the interactions among three classes of peripherally-acting antinociceptive agents (µ-opioid, ₂-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 ₂-adrenergic agonist clonidine; dependence also occurred at that time, demonstrated as a withdrawal hyperalgesia that was precipitated by the ₂-receptor antagonist yohimbine. These findings are similar to those reported previously for tolerance and dependence to µ and A₁ peripheral antinociception ().

Furthermore, cross-tolerance and cross-withdrawal between µ, A₁, and ₂ 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 ₂ are mediated by a common mechanism.

Although any of the agonists administered alone produce antinociception, we found that µ, A₁, and ₂ 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 (₂-agonist) antinociception was blocked not only by yohimbine (₂-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 (₂-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 ₂ antinociception, antisense oligodeoxynucleotides (ODNs) for the µ-opioid and _2C-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 ₂-adrenergic antinociception; A₁ antinociception was unaffected. In contrast, _2C-adrenergic ODN decreased antinociception induced by all three classes of antinociceptive agents.

In conclusion, these data suggest that peripheral antinociception induced by µ, ₂, and A₁ agonists requires the physical presence of multiple receptors. We propose that there is a µ, A₁, ₂ receptor complex mediating antinociception in the periphery. In addition, there is cross-tolerance and cross-dependence between µ, A₁, and ₂ antinociception, suggesting that their underlying mechanisms are related.

Key words: pain; analgesia; dorsal root ganglion; opioid; antisense oligodeoxynucleotide; receptor cross-talk

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