H M Himmel1, T M Eriksson Faelker2. 1. Bayer AG, Safety Pharmacology, Aprather Weg 18a, 42096 Wuppertal, Germany. Electronic address: herbert.himmel@bayer.com. 2. Bayer AG, Safety Pharmacology, Aprather Weg 18a, 42096 Wuppertal, Germany. Electronic address: therese.erikssonfaelker@bayer.com.
Abstract
INTRODUCTION: Pupillary function is a sensitive pharmacological readout in humans, but drug effects are not well characterized in rodents. Hence improved methods are needed for quantifying pupillary responses in conscious albino rodents. METHODS: A novel camera-based pupillary imaging method was developed for conscious rats under red-light settings to investigate the effect of various reference compounds on pupil and iris diameter and light reflex. The chosen compounds (pilocarpine, tropicamide, phenylephrine, clonidine, cocaine, morphine) possess well characterized effects in humans. In rats, the compounds were administered topically as eye drops and/or systemically by intraperitoneal injection. RESULTS: Red-light was utilized in order to induce intermediate pupillary width at baseline conditions in conscious albino and pigmented rats, thereby enabling detection of light-induced constriction (miosis) and dilation (mydriasis) of the pupil. Pupil diameter and light reflex were affected by both topical and systemic administration of pilocarpine, tropicamide, phenylephrine, clonidine, cocaine, morphine. However only pharmacologically induced mydriasis was found in albino rats, whereas pigmented rats displayed both mydriasis and miosis albeit with differential responses. The pupillary imaging system is suitable for stand-alone studies as well as for pupil function assessment within the frame of a typical CNS study evaluating behavior (modified Irwin test), locomotor activity and body temperature. DISCUSSION: Strain-specific pharmacological responses were detected for pupillary function, with slightly more human-like responses in pigmented rats than albino rats, illustrating that effects on the rat pupil/iris cannot be directly translated to humans. Nevertheless, changes in pupillary diameter and/or pupillary light reflex in rats is a functional endpoint that can be quantified during early testing, and may trigger more detailed mechanistic characterization beyond the safety pharmacology core CNS battery.
INTRODUCTION: Pupillary function is a sensitive pharmacological readout in humans, but drug effects are not well characterized in rodents. Hence improved methods are needed for quantifying pupillary responses in conscious albino rodents. METHODS: A novel camera-based pupillary imaging method was developed for conscious rats under red-light settings to investigate the effect of various reference compounds on pupil and iris diameter and light reflex. The chosen compounds (pilocarpine, tropicamide, phenylephrine, clonidine, cocaine, morphine) possess well characterized effects in humans. In rats, the compounds were administered topically as eye drops and/or systemically by intraperitoneal injection. RESULTS: Red-light was utilized in order to induce intermediate pupillary width at baseline conditions in conscious albino and pigmented rats, thereby enabling detection of light-induced constriction (miosis) and dilation (mydriasis) of the pupil. Pupil diameter and light reflex were affected by both topical and systemic administration of pilocarpine, tropicamide, phenylephrine, clonidine, cocaine, morphine. However only pharmacologically induced mydriasis was found in albino rats, whereas pigmented rats displayed both mydriasis and miosis albeit with differential responses. The pupillary imaging system is suitable for stand-alone studies as well as for pupil function assessment within the frame of a typical CNS study evaluating behavior (modified Irwin test), locomotor activity and body temperature. DISCUSSION: Strain-specific pharmacological responses were detected for pupillary function, with slightly more human-like responses in pigmented rats than albino rats, illustrating that effects on the rat pupil/iris cannot be directly translated to humans. Nevertheless, changes in pupillary diameter and/or pupillary light reflex in rats is a functional endpoint that can be quantified during early testing, and may trigger more detailed mechanistic characterization beyond the safety pharmacology core CNS battery.