The selective delta 2 receptor antagonist Naltriben (NTB) has played an important role in the identification of subtypes of the delta opioid receptor, termed delta 1 and delta 2, and their role in antinociception. However, the majority of these studies have been conducted in the mouse. The present study determined the opioid receptor selectivity of subcutaneously (s.c.) administered NTB in the rat. Five minute pretreatment with 1 mg/kg s.c. NTB antagonized the increase in TFL produced by i.t. administration of equieffective doses of the delta 2 receptor agonist [D-Ala2,Glu4]deltorphin (DELT) or the delta 1 receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE), but did not antagonize the mu receptor agonist [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO). These data confirm previous reports that NTB is a selective delta opioid receptor antagonist. However, this dose of NTB antagonized DELT and DPDPE to an equivalent extent, suggesting that its selectivity for the delta 2 receptor is not maintained after s.c. administration in the rat. A lower dose of NTB (0.56 mg/kg s.c.) was ineffective. When the dose of NTB was increased to 3 mg/kg s.c. the antagonism of DELT and of DPDPE was unexpectedly lost. Pretreatment with the kappa receptor antagonist norbinaltorphimine (nor-BNI) partially restored the antagonism of DELT, but not DPDPE by this dose of NTB and did not modify the antagonism of DAMGO by NTB. These data suggest that high doses of NTB have kappa receptor agonist-like activity and support the proposal that kappa opioid agonists diminish the actions of delta receptor antagonists. They also suggest that nor-BNI-sensitive kappa opioid receptors interact with delta 2, but not delta 1 opioid receptors in the spinal cord.