σ antagonist and k agonist activity of naltriben: Evidence for differential k interaction with the σ1 and σ2 opioid receptor subtypes

The selective σ2 receptor antagonist Naltriben (NTB) has played an important role in the identification of subtypes of the σ opioid receptor, termed σ1 and σ2, 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 σ2 receptor agonist [D-Ala2, Glu4]deltorphin (DELT) or the σ1 receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE), but did not antagonize the k receptor agonist [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO). These data confirm previous reports that NTB is a selective σ opioid receptor antagonist. However, this dose of NTB antagonized DELT and DPDPE to an equivalent extent, suggesting that its selectivity for the σ2 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 k receptor antagonist nor-binaltorphimine (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 k receptor agonist-like activity and support the proposal that k opioid agonists diminish the actions of σ receptor antagonists. They also suggest that nor-BNI-sensitive k opioid receptors interact with σ2, but not σ1 opioid receptors in the spinal cord.