Abstract

In this study, we examined the presence of ς₁ and ς₂ sites in the rabbit iris-ciliary body by receptor binding and investigated their effects on intraocular pressure (IOP) in albino rabbits. The iris-ciliary body has binding sites for the ς₁-site agonist [³H](+)-pentazocine (K_d = 4.6 nM;B_max = 212 fmol/mg protein) and ς₂ sites labeled with [³H]1,3-di-o-tolylguanidine (DTG) (K_d = 8.2 nM;B_max = 1120 fmol/mg protein). In competition binding studies, (+)-pentazocine and the ς antagonist NE-100 displayed high affinity for ς₁ sites (K_i = 2.1 and 2.4 nM, respectively), whereas (+)-N-allylnormetazocine (NANM) was less potent (K_i = 178 nM). Unilateral topical (+)-pentazocine (0.01–0.1%) caused a significant dose-related reduction of IOP in ocular normotensive rabbits and in the α-chymotrypsin model of ocular hypertension. (+)-NANM was less potent than (+)-pentazocine. Neither compound altered the IOP of the contralateral eye, and their hypotensive activity was blocked by NE-100 that, by itself, had no effect on IOP. (−)-Pentazocine, (−)-NANM, and DTG had no effect on IOP. DTG prevented the hypotensive effect of (+)-pentazocine, suggesting that it acts as a ς₁-site antagonist. ς-Site ligands did not affect pupil diameter or cause ocular inflammation. Topical [³H](+)-pentazocine reaches the intraocular tissues within 30 min, and its uptake in the iris-ciliary body and retina was significantly reduced by topical pretreatment with NE-100, as expected for a receptor-specific agent. Reverse-phase HPLC confirmed the presence of intact (+)-pentazocine in iris-ciliary body homogenates. ς₁-Site agonists may offer a novel class of agents potentially effective in the control of ocular hypertension.