Spinal opioid delta antinociception in the mouse: Mediation by a 5'-NTII- sensitive delta receptor subtype

Previous studies from our laboratory have indicated that i.c.v. pretreatment of mice with the novel, selective opioid δ receptor antagonists, [D-Ala²,Leu⁵,Cys⁶]enkephalin (DALCE) and naltrindole-5'- isothiocyanate (5'-NTII), differentially antagonized the direct antinociceptive effects of [D-Pen²,D-Pen⁵]enkephalin (DPDPE) and [D- Ala²]deltorphin II (DELT). These findings, and others, suggested the existence of subtypes of opioid δ receptors which could be classified as activated by DPDPE and DALCE sensitive (δ₁ receptor), or selectively activated by DELT and 5'-NTII sensitive (δ₂ receptor). The present study has extended these observations to the characterization of δ-mediated antinociception at the spinal level; thus, we studied the direct antinociceptive effects of DPDPE and DELT after i.t. administration in mice using pretreatment with DALCE and 5'-NTII in order to selectively antagonize the δ subtypes. Additionally, the acute antinociceptive actions of DALCE itself were studied to ensure activity of this compound at the spinal level. The respective antinociceptive A₅₀ value (95% CL) for i.t. DPDPE, DELT and DALCE were 19.0 (12.9-28.1), 19.3. (16.1-23.1) and 2.0 (1.4-3.0) nmol. The δ antagonist, N,N-diallyl-Try-Aib-Aib-Phe-Leu-OH (ICI 174,864) (where Aib is α-aminoisobutyric acid) blocked the antinociceptive effects of DPDPE and DELT, but not those of i.t. morphine or [D-Ala²,NMPhe⁴,Gly-ol⁵]enkephalin (DAMGO), indicating that the observed antinociceptive effects of DPDPE and DELT were δ mediated. Pretreatment 24 hr before testing with graded doses of i.t. 5'-NTII blocked the i.t. antinociceptive effects of DPDPE and DELT, although at least a 10-fold higher dose of 5'-NTII was needed to produce equivalent antagonism of DPDPE. Similarly, i.t. pretreatment with 5'-NTII antagonized i.t. DALCE. In contrast, 24 hr of pretreatment with i.t. DALCE failed to block DPDPE, DELT or DALCE-induced antinociception. The antagonism of the spinal antinociceptive effects of DPDPE, DELT and DALCE by 5'-NTII, but not by DALCE, suggests that the spinal opioid δ receptor involved in antinociception is a 5'-NTII sensitive (i.e., δ₂) subtype.