Antinociceptive effects of isoleucine derivatives of deltorphin I and deltorphin II in rat spinal cord: a search for selectivity of delta receptor subtypes

Deltorphins show a high affinity and selectivity for delta opioid receptors , Analogs of deltorphins with substitution of Val(5,6) residues with more h ydrophobic Ile(5,6) appear to have a higher in vitro activity and selectivi ty than parent deltorphins. In our study, changes in the nociceptive thresh old after intrathecally injected deltorphin I (DELT I), deltorphin II (DELT II) and their Ile(5,6) - derivatives (ILE-DELT I and ILE-DELT II, respecti vely) were investigated in a tail-flick (TF) and a paw pressure (PP) tests. Male Wistars rats (260-350 g) with a chronically implanted catheter in the lumbar enlargement of the spinal cord were used. DELT I and DELT II, injec ted i.th. in doses of 0.15, 1.5 and 15 mu g, increased the TF latency in a dose-dependent manner. The effect of their derivatives was similar, but the action of ILE-DELT II was shorter than that of the parent peptide. In the PP test, the antinociceptive effects of DELT I and their derivative ILE-DEL T I were similar, but the effect of a higher dose of ILE-DELT I lasted long er in comparison with the parent peptide. Both DELT II and ILE-DELT II exhi bited a low and short-lasting antinociceptive potency in the PP test. The e ffect of DELT 1 (1.5 mu g) was antagonized by pretreatment with NTI (30 IJ- g), a non-selective delta opioid receptor antagonist, as well as by the del ta 2 receptor antagonist NTB (3 mu g) and the delta 1 antagonist BNTX (1 mu g) in both those tests used. The antinociceptive effect of DELT II (1.5 mu g) was antagonized by pretreatment with NTI (30 mu g) and NTB (3 mu g) in the TF test, but not in the PP test. In the latter test, the antinociceptiv e effect of DELT II was potentiated by pretreatment with BNTX (1 mu g). The effects of both the derivatives ILE-DELT I and ILE-DELT II were antagonize d by NTI (30 mu g) in the TF test, and by NTI (30 mu g) and NTB (3 mu g) in the PP test. Like in the case of the parent peptide, the effect of ILE-DEL T II was potentiated by pretreatment with the delta 1 antagonist BNTX (1 mu g). Summing up, modification of the DELT I and II by substituting Ile(5,6) for Val(5,6) residues appears to influence the delta selectivity rather th en the potency of the peptides at spinal delta receptors.