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-Pen2,5]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-Pen2,5]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.
Footnotes
-
Send reprint requests to: Dr. Y.-F. Su, Department of Medicine, Box 3942, Duke University Medical Center, Durham, NC 27710.
-
↵1 This work was supported in part by United States Public Health Service Grants DA04240 and DA08362 from the National Institute on Drug Abuse.
- Abbreviations:
- BNTX
- 7-benzylidenenaltrexone
- (+)BW373U86
- (+)-4-((α-R)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide
- CTOP
- d-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH2
- Del II
- deltorphin II, Tyr-d-Met-Phe-Glu-Val-Val-Gly
- DPDPE
- cyclic[d-Pen2,5]enkephalin
- DPI2505
- cis-4-(α-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide
- MPE
- maximal percent effect
- NTI
- naltrindole
- NTB
- naltriben
- TIPP(ψ)
- H-Tyr-Tic(ψ)[CH2NH]Phe-Phe-OH
- i.c.v.
- intracerebroventricular
- Received December 26, 1997.
- Accepted May 5, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|