Evidence suggests both
opioid mu and
delta 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-Pen2, 5]
enkephalin, deltorphins, (+)-4-((alpha-R)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N,N-diethylbenzamide,
naltrindole and H-
Tyr-Tic(psi)[CH2NH]
Phe-Phe-
OH have now made it feasible to more clearly define the role of
delta receptors in respiratory control. In a series of experiments we observed that systemic infusion of rats with the highly
mu receptor-specific
opioid alfentanil induced antinociception and
hypercapnia, and both of these effects were antagonized by the mu antagonist D-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 the delta agonist (+)-4-((alpha-R)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N,N-diethylbenzamide. In addition, intracerebroventricular delivery of a number of
peptide delta
ligands cyclic[D-Pen2,5]
enkephalin, deltorpnin II and H-
Tyr-Tic(psi)[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 antagonist cis-4-(alpha-(4-((Z)-2-butenyl)-3, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. We propose that in this experimental respiration model, the delta antagonists
naltrindole and H-
Tyr-Tic(psi)[CH2NH]
Phe-Phe-
OH behave like delta 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
mu receptor.