Abstract

Evidence suggests both opioid mu anddelta receptors may participate in the regulation of respiration at different central nervous system sites. In the past, the overlapping receptor specificity of various opioid drugs has made it difficult to dissect the receptor subtype-specific activities involved in respiratory regulation. The new family of delta receptor selective agents such as cyclic[d-Pen^2,5]enkephalin, deltorphins, (+)-4-((α-R)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide, naltrindole and H-Tyr-Tic(ψ)[CH₂NH]Phe-Phe-OH have now made it feasible to more clearly define the role of deltareceptors in respiratory control. In a series of experiments we observed that systemic infusion of rats with the highly mureceptor-specific opioid alfentanil induced antinociception and hypercapnia, and both of these effects were antagonized by themu antagonistd-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH₂. However, peripheral administration of the delta receptor antagonist naltrindole reverses the hypercapnia but not the antinociceptive activity of alfentanil. This differential effect of naltrindole on antinociception and hypercapnia could also be produced with thedelta agonist (+)-4-((α-R)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. In addition, intracerebroventricular delivery of a number of peptidedelta ligands cyclic[d-Pen^2,5]enkephalin, deltorpnin II and H-Tyr-Tic(ψ)[CH₂NH]Phe-Phe-OH also produced the same differential reversal of hypercapnia without affecting antinociception. Thus, both the traditional delta agonists and antagonists are able to reverse the alfentanil-induced hypercapnia without affecting antinociception. The reversal of alfentanil-induced hypercapnia by these delta ligands was antagonized by a novel synthetic delta antagonistcis-4-(α-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. We propose that in this experimental respiration model, thedelta antagonists naltrindole and H-Tyr-Tic(ψ)[CH₂NH]Phe-Phe-OH behave likedelta agonists with low but sufficient intrinsic activities to reverse alfentanil-induced hypercapnia in rats. The results suggest that a function of the delta receptor is to modulate or counteract the respiratory depression induced by the mureceptor.