σ Recognition sites in rabbit iris-ciliary body: Topical σ-1-site agonists lower intraocular pressure

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(j) = 178 nM). Unilateral topical (+)-pentazocine (0.010.1%) 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.