σ1 recognition sites in rabbit iris-ciliary body:: Topical σ1-site agonists lower intraocular pressure

In this study, we examined the presence of sigma(1) and sigma(2) 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 sigma(1)-site agonist [H-3](+)pentazocine (K-d = 4.6 nM; B-max = 212 fmol/mg protein) and sigma(2) sites labeled with [H-3]1,3-di-o-tolylguanidine (DTG) (K-d = 8.2 nM; B-max = 1120 fmol/mg protein). In competition binding studies, (+)-pentazocine and the sigma antagonist NE-100 displayed high affinity for sigma(1) 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 alpha-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 sigma(1)-site antagonist. sigma-Site ligands did not affect pupil diameter or cause ocular inflammation. Topical [H-3](+)-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. sigma(1)-Site agonists may offer a novel class of agents potentially effective in the control of ocular hypertension.