Lack of antinociceptive cross-tolerance between [D-Pen², D-Pen⁵]enkephalin and [D-Ala²]deltorphin ii in mice: Evidence for delta receptor subtypes

This study has investigated the development of antinociceptive tolerance to, and cross-tolerance between, two highly selective delta agonists, [D-Pen²,D-Pen⁵]enkephalin (DPDPE) and [D-Ala²] deltorphin II as well as to [D-Ala²,NMePhe⁴,Gly-ol⁵]enkephalin (DAMGO), a highly selective mu agonist, in mice. Intracerebroventricular administration of DPDPE, [D-Ala²]deltorphin II and DAMGO each produced an antinociceptive effect. Pretreatment with i.c.v. DPDPE twice daily for 3 days resulted in tolerance to DPDPE as shown by a 4.8-fold rightward shift in the dose-response curve. In contrast, in DPDPE pretreated mice, the dose-response lines for [D-Ala²]deltorphin II and DAMGO were not altered when compared to those obtained in naive animals. The development of tolerance was also shown by pretreating mice with i.c.v. [D-Ala²]deltorphin II; following this pretreatment, the [D-Ala²Ideltorphin II dose-response line was displaced to the right by more than 37-fold. In contrast, in [D-Ala²]deltorphin II-pretreated mice, the dose-response lines for DPDPE and DAMGO were not altered compared to those obtained in naive animals. Finally, pretreatment with i.c.v. DAMGO produced a rightward displacement of the DAMGO dose-response line of 47-fold, indicating the development of antinociceptive tolerance. In DAMGO-pretreated mice, however, the dose-response lines for DPDPE and [D-Ala²]deltorphin II were not altered compared to those obtained in naive mice. Thus, the data indicate that antinociceptive tolerance develops to DPDPE, [D-Ala²]deltorphin II and DAMGO but that there is no cross-tolerance between these compounds. Although the lack of cross-tolerance between DAMGO and the two delta agonists is not surprising, the additional lack of cross-tolerance between DPDPE and [D-Ala²]deltorphin II suggests possible differences in their mechanism of action. As both DPDPE and [D-Ala²]deltorphin II are highly selective delta agonists which have been shown to elicit antinociception via interactions with a delta receptor, this lack of cross-tolerance suggests that these compounds produce antinociception via interaction with subtypes of delta receptors.