The inhibition of the pupillary light reflex by the threat of an electric shock: a potential laboratory model of human anxiety

It has been shown that the eye-blink response evoked by an abrupt loud white noise ('acoustic startle') is potentiated when the subjects anticipate an aversive stimulus, e.g. an electric shock ('fear-potentiated startle'). It has been proposed that this paradigm may be a useful laboratory model of human anxiety. We examined whether the threat of an electric shock, as used in the fear-potentiated startle paradigm, would affect the pupillary light reflex, in 12 healthy volunteers. Light stimuli (0.32 mW/cm(2), 200 msec) were generated by a light-emitting diode, and pupil diameter was monitored by computerized binocular infrared television pupillometry in the dark. The light reflex was recorded during either the anticipation of a shock ('threat' blocks) or periods in which no shocks were anticipated ('safe' blocks). The shock consisted of a single square wave current pulse (1.5 mA, 50 msec) applied to the median nerve. At the end of each 'threat' or 'safe' block, subjects rated their anxiety using visual analogue scales. Two-factor analysis of variance (condition x block) showed that in the 'threat' condition there was a consistent increase in initial pupil diameter, a decrease in light reflex amplitude and an increase in alertness and anxiety ratings. These effects were observable before the subjects received any shock (a single stimulation of the median nerve). These results show that the anticipation of an electric shock can modify not only the startle reflex response but also the pupillary light reflex, suggesting that the inhibition of the light reflex by threat may be another suitable laboratory model of human anxiety.     

Effects of peripheral sympathetic blockade with dapiprazole on the fear-inhibited light reflex

Fear (e.g. associated with the threat of an electric shock) causes an increase in initial pupil diameter (IPD) and a decrease in the amplitude of the light reflex response. There is evidence for dissociation between the two responses to threat: only the reduction in light reflex response amplitude is sensitive to the anxiolytic drug diazepam. We examined the effects of peripheral sympathetic blockade with the alpha(1)-adrenoceptor antagonist dapiprazole on both responses to threat on the basis of the hypothesis that only the response of the IPD will be affected, whereas the response of the light reflex will remain unaffected. Twelve healthy volunteers (Experiment 1) and eight healthy volunteers with smaller pupils (Experiment 2) participated in one experimental session. Dapiprazole 0.5% (two drops of 20 microl, three times) was instilled in the subjects' right or left eye while the contralateral eye was treated with placebo eye drops (artificial tear, two drops of 20 microl, three times) according to a single-blind balanced design. Pupil diameter was monitored by infrared binocular television pupillometry. At the point of maximum dapiprazole-evoked miosis, the light reflex was elicited three times in each of three Safe blocks (no possibility of electric shock), alternating with three Threat blocks (possibility of electric shock). At the end of each Safe and Threat block, subjects rated their mood and feelings on the Visual Analogue Scales. In Experiment 1, dapiprazole caused significant miosis. Threat increased subjectively rated anxiety and inhibited the light reflex. The inhibition of the light reflex was unaffected by dapiprazole. The threat-induced increase in IPD was also unaffected by dapiprazole, probably due to a ceiling effect curtailing the threat-induced increase in IPD. In the smaller pupil group in Experiment 2, where the possible contribution of a ceiling effect was minimized, dapiprazole suppressed the threat-induced increase in IPD. The inhibition of the light reflex by threat is likely to reflect central parasympathetic inhibition and is unlikely to involve the peripheral sympathetic innervation of the iris. The threat-induced increase in IPD is likely to reflect mainly central sympathetic excitation. The different central autonomic mechanisms underlying the two pupillary responses to threat may explain the dissociation between the separate effects of threat on IPD and light reflex amplitude.     

Effect of dexmedetomidine, an alpha2-adrenoceptor agonist, on human pupillary reflexes during general anaesthesia

AIMS: To test the hypothesis that the alpha2-adrenergic agonist, dexmedetomidine, dilates the pupil and does not alter the pupillary light reflex of anaesthetized patients. METHODS: Eight volunteers were administered general anaesthesia with propofol, nitrous oxide and alfentanil. One hour and 25 min after induction of anaesthesia, a 45 min infusion of dexmedetomidine was begun, targeting a plasma concentration of 0.6 ng x ml(-1). Pupil size, pupillary light reflex amplitude, light reflex recovery time, and reflex dilation were measured before and during dexmedetomidine infusion. RESULTS: Dexmedetomidine produced no change in pupil size and light reflex recovery time, increased the light reflex from 0.30 +/- 0.14 to 0.37 +/- 0.12 mm and significantly reduced pupillary reflex dilation by 72 +/- 62%. CONCLUSIONS: These pupillary effects of dexmedetomidine in humans are difficult to reconcile with the findings obtained in cats and rats that have demonstrated a direct inhibitory effect of alpha2-adrenergic agonists on the pupilloconstrictor nucleus. The increase in the magnitude of the light reflex in response to dexmedetomidine does not necessarily involve an anxiolytic mechanism.     

Dose-related effects of controlled release dihydrocodeine on oro-cecal transit and pupillary light reflex. A study in human volunteers

It is well accepted that long-term administration of opioids results in a dose-related constipation. No data so far have demonstrated conclusively whether such constipation is also seen after intake of a controlled release formulation. It was therefore of interest to evaluate whether increasing doses of a controlled release formulation of dihydrocodeine (DHC, CAS 125-28-0) after oral administration also induces a dose-related increase in constipation. Additionally, it was of interest to study whether such a peripheral opioid-related side effect is also seen in another, central receptor-mediated effect, the constriction of the pupil, at clinically relevant doses. Twelve volunteers were given controlled release DHC (60 and 120 mg, respectively) or placebo orally within a randomized, double-blind cross-over study. In order to determine the degree of constipation, oro-cecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripherally and centrally mediated effects were compared to placebo. DHC at both dosages induced a significant (p < 0.01) prolongation of oro-cecal transit time when compared to placebo. However, prolongation of oro-cecal transit was not significantly longer when comparing the lower (60 mg) with the higher dose (120 mg). DHC also induced a significant (p < 0.005) depression of the pupillary light reflex from 53.9 mm (control) to 8.3 and 7.4 mm, respectively. Similar to intestinal transit, the pupillary light reflex was not significantly different among the two doses of DHC. Also, both dosages induced a similar amount of side effects. Tiredness and dry mouth were reported in 80% after both doses while vertigo was reported in 5% and 1% complained of headache. None of the volunteers reported nausea or emesis. It is concluded that opioid receptor sites, which are located in the plexus myentericus of the intestinal wall, are responsible for the delay in propulsion. Because of the controlled release of a fixed amount of DHC over time there is constant binding of the ligand followed by a constant conformational change of peripheral and central receptor sites. Thus constant release induces no dose-related increase in oro-cecal transit and inhibition of the pupillary light reflex.     

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers

Rationale Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be “switched off” by the α₂-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects. Objective The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers. Methods Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary “fatigue waves” (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons. Results Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions. Conclusions Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.     

Effect of anesthesia in a patient with pre-existing anisocoria

In this case report, we describe an accentuation of a pre-existing anisocoria shortly after tracheal intubation in a patient undergoing thyroidectomy. A 45-yr-old female patient with unequal pupillary diameter (right 2 mm > than left) and decreased light reflex in the right eye--due to a previous eye trauma--was scheduled for thyroidectomy because of multinodular goiter. Anesthesia was induced with propofol 2,5 mg/kg, fentanyl 3 mcg/kg and cisatracurium 0.15 mcg/kg. Immediately after tracheal intubation, examination of the right eye revealed a markedly dilated pupil (8 mm) which was nonreactive to direct and consensual light reflex. The left pupil was 2 mm, and normally reactive to light. An increase in heart rate was also registered (> 20% of baseline) with spontaneous return to baseline within 2 minutes. The right pupil returned to preoperative size within approximately one hour after awakening. From this case report, it emerges that a preexisting anisocoria may be exacerbated during anesthesia probably due to incomplete abolition of response to painful stimulus, such as tracheal intubation, provided by anesthetic drugs in the affected eye. The main contributing factor for accentuation of anisocoria could be sympathetic dominance in the pupil with pre-existing mechanical interruption in compensatory parasympathetic mechanisms.     

Sensitivity of the fear-inhibited light reflex to diazepam

 We have shown previously that pupil diameter increases and the amplitude of the pupillary light reflex is reduced when subjects are under threat of an aversive event (electric shock), and that light reflex amplitude correlates negatively with subjective anxiety. We have suggested that the “fear-inhibited light reflex” paradigm could be used as a laboratory model of human anxiety. In the present study, we examined whether two doses (5 mg and 10 mg) of the anxiolytic drug diazepam would antagonize the effects of threat on the pupillary light reflex. Twelve healthy male volunteers participated in three weekly sessions, each associated with one of three treatments (diazepam 5 mg or 10 mg or placebo) in a double-blind, balanced, cross-over design. The light reflex was recorded during either the anticipation of a shock (“threat” blocks) or periods in which no shocks were anticipated (“safe” blocks). At the end of each “threat” or “safe” block, subjects rated their anxiety using visual analogue scales. Two-factor ANOVA (treatment × condition) showed that diazepam treatment antagonized the effect of threat on light reflex amplitude in a dose-dependent manner but it did not affect the threat-induced increase in pupil diameter. Diazepam had no effect on the pupillary light reflex in the “safe” condition. Diazepam also reduced subjective anxiety and alertness in the threat condition. These results show the sensitivity of the threat-induced reduction of light reflex amplitude to anxiolytic drugs, and provide further evidence for the utility of the fear-inhibited light reflex paradigm as a laboratory model of human anxiety. Received: 20 March 1997/Final version: 7 July 1997     

Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers

AIMS: To investigate the effects of the D2-receptor agonist pramipexole with and without the co-administration of the peripherally acting D2-receptor antagonist domperidone on measures of alertness, autonomic and endocrine function. METHODS: Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg, domperidone 40 mg, their combination, and placebo administered according to a balanced, double-blind design. Alertness (visual analogue scales (VAS), critical flicker fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine (prolactin, thyroid-stimulating hormone (TSH), growth hormone (GH)) functions were assessed. Data were analyzed with anova with multiple comparisons. RESULTS: The pre-post treatment changes in VAS alertness were reduced by pramipexole with and without domperidone (mean difference from placebo (95% confidence interval), mm): pramipexole -15.75 (-23.38, -8.13), combination -11.84 (-20.77, -2.91). Treatment condition significantly affected pupil diameter measured in different ways (resting pupil diameter (F(3,45) = 8.39, P < 0.001), initial diameter of the light reflex response (F(3,42) = 3.78, P < 0.05), and light (F(3,45) = 5.21, P < 0.005) and dark (F(3,45) = 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole without domperidone consistently increased pupil diameter on all measures (P < 0.05), whereas with domperidone only the increase in resting and dark diameters reached significance. Pramipexole reduced light reflex amplitude and increased latency, whereas the combination affected latency only. Concentrations of prolactin and TSH were increased by domperidone. Pramipexole reduced prolactin and increased GH concentrations. CONCLUSIONS: The attenuation of the central pupillary effects of pramipexole by domperidone indicates that domperidone had access to some central D2-receptors.     

Comparison of the effects of clonidine and yohimbine on pupillary diameter at different illumination levels

AIMS: To evaluate the pupillary effects of single doses of the alpha2-adrenoceptor agonist clonidine and the alpha2-adrenoceptor antagonist yohimbine under several illumination conditions. METHODS: Sixteen healthy male volunteers received clonidine 0.2 mg, yohimbine 22 mg, clonidine 0.2 mg + yohimbine 22 mg in a double-blind placebo-controlled, cross-over study. 2 h post drug ingestion pupil diameter was recorded in darkness, and at luminance levels of 6 Cd m-2, 91 Cd m-2 and 360 Cd m-2. The effects of the active treatments on pupil diameter were also expressed as the differences from the placebo condition ('placebo-corrected' data; mean [95% CI]). RESULTS: Clonidine had little effect on pupil diameter in darkness; however, it caused a significant, light-dependent, miosis when the eye was illuminated. On the other hand yohimbine increased pupil size; this increase was significant at 91 and 360 Cd m-2. There were no significant differences between the effects of the combined treatment (clonidine 0.2 mg + yohimbine 22 mg) and the effect of placebo. CONCLUSIONS: The pupillary effects of clonidine and yohimbine are likely to reflect the interaction of these drugs with inhibitory alpha2-adrenoceptors located on central noradrenergic neurones, which in turn would lead to a decrease and an increase, respectively, in sympathetic outflow to the iris. The light dependence of the pupillary effects of these drugs, however, suggests that the parasympathetic light reflex pathway is also involved, which is known to be under inhibitory control from the central noradrenergic neurones. Modulation of parasympathetic outflow seems to play an important role since both drugs had relatively little effect on pupil diameter in darkness when sympathetic activity predominates.     

The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man.     

Comparison of the effects of venlafaxine, paroxetine and desipramine on the pupillary light reflex in man

Rationale: The time-course of the pupillary light reflex response is determined by the successive activation of the parasympathetic and sympathetic innervations of the iris, the latency and the amplitude reflecting parasympathetic and the recovery time mainly sympathetic activity. Objective: To compare the effects of single doses of three antidepressants (venlafaxine: serotonin/noradrenaline reuptake inhibitor, paroxetine: selective serotonin reuptake inhibitor, and desipramine: tricyclic antidepressant) on resting pupil diameter and the pupillary light reflex response. Methods: Fifteen healthy male volunteers participated in five weekly sessions, each of which was associated with one treatment (venlafaxine 75 mg or 150 mg, paroxetine 20 mg, desipramine 100 mg, or placebo) according to a double-blind, double-dummy, balanced, cross-over design. An infrared binocular television pupillometer was used for the recording of the resting pupil diameter and the pupillary light reflex in darkness, in previously dark-adapted eyes. Resting pupil diameter in darkness was recorded before and after treatment. The pupillary light reflex was elicited after treatment, with six light flashes (green, 565 nm peak wavelength) of 200 ms duration and of incremental illuminance (measured in the plane of the cornea): 3.0 × 10^–3, 8.5 × 10^–3, 2.5 × 10^–2, 7.0 × 10^–2, 0.18, 0.43 mW cm⁻². The parameters studied were: latency, amplitude and 75% recovery time. Results: Analyses of variance followed by post hoc tests (least significant difference test or Dunnett’s test; P < 0.05) revealed that both doses of venlafaxine produced a significant increase in resting pupil diameter, decrease in amplitude and shortening of the 75% recovery time of the light reflex response; venlafaxine 150 mg prolonged the latency, while the other treatments had no significant effects. Conclusions: The increase in resting pupil diameter could be indicative of parasympathetic inhibition and/or sympathetic activation. The shortening of the recovery time of the light reflex response is consistent with sympathetic potentiation resulting from noradrenaline uptake blockade in the iris. The prolongation of the latency and decrease of the amplitude of the light reflex response are indicative of a parasympatholytic effect of venlafaxine. However, as venlafaxine has negligible affinity for muscarinic cholinoceptors, this effect cannot be attributed to the blockade of cholinoceptors in the iris. A possible explanation for this finding is that it reflects a central rather than a peripheral effect of the drug: the blockade of noradrenaline uptake in the brain could lead to the potentiation of the noradrenergic inhibition of central parasympathetic (Edinger-Westphal) neurones. These results demonstrate the ability of therapeutically relevant single doses of venlafaxine to potentiate noradrenergic responses in man, consistent with the blockade of noradrenaline uptake. Received: 29 July 1998/Final version: 17 November 1998     

Muscarinic receptor dysfunction induced by exposure to low levels of soman vapor.

In the eye, it has been previously reported that exposure to a cholinesterase inhibitor results in a reduced miotic response following prolonged exposure and a decreased miotic response to the cholinergic agonists. However, no studies exist that characterize the effect of a single low-level vapor exposure to a nerve agent on parasympathetic function in the eye or determine the threshold dose for such an effect. The present study investigated the hypotheses that a single low-level exposure to soman vapor would result in dysfunction of the parasympathetic pathway mediating the pupillary light reflex resulting from a loss of muscarinic receptor function on the pupillary sphincter muscle. Adult male rats were exposed to soman vapor in a whole-body dynamic airflow exposure chamber. Rats exposed to low levels of soman vapor dose-dependently developed miosis (threshold dose between 4.1 and 6.1 mg-min/m3). Pupil size returned to preexposure levels within 48 h due to desensitization of pupillary muscarinic receptors, as assessed by the pupillary response to the muscarinic agonist oxotremorine. An attenuated pupillary light reflex was also present in miotic animals (threshold dose near 6.1 mg-min/m3). While pupil size recovers within 48 h, other measures of pupillary function, including the light reflex, acetylcholinesterase activity, and muscarinic receptor responsiveness, did not return to normal for up to 10 days postexposure. Recovery of the light reflex coincided with the recovery of pupillary muscarinic receptor function, suggesting that the attenuation of the light reflex was due to receptor desensitization.     

Why patients with Alzheimer’s disease may show increased sensitivity to tropicamide eye drops: role of locus coeruleus

Rationale Patients suffering from Alzheimer’s disease (AD) may show increased sensitivity to tropicamide, a muscarinic cholinoceptor antagonist. AD is associated with a severe loss of noradrenergic neurones in the locus coeruleus (LC), which can be “switched off” experimentally by the α₂-adrenoceptor agonist clonidine. The possibility arises that increased pupillary sensitivity to tropicamide in AD may be due to diminished LC activity. Objective To examine the hypothesis that clonidine may potentiate tropicamide-evoked mydriasis. Materials and methods Sixteen healthy male volunteers participated in two experimental sessions (0.2 mg clonidine or placebo) conducted 1 week apart. In each session tropicamide (0.01% 10 μl×2) was applied to the left eye and artificial tear (10 μl×2) was applied to the right eye. Pupillary functions (resting pupil diameter and light and darkness reflexes), alertness and non-pupillary autonomic functions (blood pressure, heart rate, core temperature and salivary output) were measured. Data were analysed by ANOVA, with multiple comparisons. Results Tropicamide increased resting pupil diameter, velocity and amplitude of the darkness reflex response, and decreased recovery time of the light reflex response. Clonidine affected all these pupillary measures in the opposite direction with the exception of the recovery time. The mydriatic response to tropicamide was potentiated by pre-treatment with clonidine. Clonidine reduced critical flicker fusion frequency, subjective alertness, blood pressure, salivation and temperature. Conclusions The potentiation of tropicamide-evoked pupil dilatation by clonidine may be due to the abolition of the increase in parasympathetically mediated pupil constriction due to reduced LC activity.     

Comparison of the effects of clonidine on tyramine- and methoxamine-evoked mydriasis in man

1 It has been reported previously that clonidine can potentiate tyramine-evoked mydriasis on the pain-free side of cluster headache patients. We examined whether a single oral dose of clonidine (200 μg) can also potentiate tyramine-evoked mydriasis in healthy subjects, using mydriasis to methoxamine, a directly acting sympathomimetic amine, as a control. 2 Eight healthy male volunteers participated in four weekly sessions. In the first two sessions (Experiment 1) the effect of clonidine or placebo on the mydriasis to tyramine hydrochloride eyedrops (75 mm; 2×10 μl), and in the last two sessions (Experiment 2) the effect of clonidine or placebo on the mydriasis to methoxamine hydrochloride eyedrops (20 mm; 2×10 μl) was examined. In both experiments subjects were allocated to drugs and sessions according to a double-blind balanced design. In both experiments, pupil diameter of both the treated and the untreated eyes was recorded in standard ambient light and in the dark, before, and 2 h after clonidine/placebo, via binocular infrared television pupillometry. Salivation (dental roll technique), systolic and diastolic blood pressure (sitting), heart rate, and self-ratings of mood and feelings (visual analogue scales), were also measured before, and 2 h after the ingestion of clonidine or placebo. 3 Both tyramine and methoxamine produced a significant mydriasis, which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: tyramine/light 1.05±0.28; tyramine/dark: 0.73±0.15; methoxamine/light: 1.65±0.28; methoxamine/dark: 0.85±0.15). Clonidine produced a significant miosis in the untreated eye which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: Experiment 1, light: −1.34±0.19; Experiment 1, dark: −0.46±0.1; Experiment 2, light −0.97±0.18; Experiment 2, dark: −0.29±0.17). Clonidine had no significant effect on either tyramine- or methoxamine-evoked mydriasis. 4 In agreement with previous reports, clonidine significantly reduced salivation (g, mean±s.e.mean; Experiment 1: −0.84±0.22; Experiment 2: −0.55±0.11), systolic blood pressure (mm Hg; Experiment 1: −17.5±3.76; Experiment 2: −23.38±4.67), diastolic blood pressure (mm Hg; Experiment 2: −12.38±2.05), alertness (mm; Experiment 2: −24.19±5.40), and anxiety (mm; Experiment 1: −13.82±4.60), indicating the presence of pharmacodynamically effective tissue levels of the drug. 5 These results show that a single oral dose (200 μg) of clonidine causes significant miosis in human subjects, and fails to potentiate tyramine-evoked mydriasis. This indicates that the pupil on the asymptomatic side of cluster headache patients is affected differently from the pupils of healthy volunteers by tyramine and/or clonidine.     

Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers

Rationale In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D₂/D₃ autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger–Westphal nucleus (via a putative meso-pupillomotor pathway).Objectives We investigated the hypothesis that amisulpride, a D₂/D₃ receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions.Materials and methods Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA.Results Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels.Conclusions The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D₂/D₃ receptors on VTA neurones and in the tuberoinfundibular system.     

Effect of locally applied prazosin on the kinetics of the pupillary light reflex

The effect of locally applied prazosin on pupillometric measures was studied in healthy volunteers, in an attempt to identify the role of α₁-adrenoceptors in the recovery time of the light reflex. Prazosin antagonized the mydriatic effect of phenylephrine, but did not alter that of tropicamide. Miotic responses to a range of light stimuli were measured under ambient temperature conditions of 22°  C and 40°  C. The 40°  C condition was associated with shorter recovery times of the light reflex; prazosin increased the recovery time under both temperature conditions. Response amplitude was not affected by the temperature condition or prazosin. The results are consistent with the hypothesis that sympathetic neuromuscular transmission is involved in the redilatation of the pupil following a miotic response to light stimulation.     

Comparative studies of the effects of some antimuscarinic agents on gastric damage and pupillary reflex in the rat.

The effects of some antimuscarinic compounds on oxotremorine-induced gastric damage, the pupil size and the pupillary light reflex have been studied in the rat. Unlike atropine, propantheline and methylscopolamine, pirenzepine is effective in preventing gastric erosions at doses much lower than those that affect pupillary reflex.     

Effects of tramadol and tilidine/naloxone on oral-caecal transit and pupillary light reflex

As has been demonstrated in binding studies the two opioids tilidine (CAS 27107-79-7)/naloxone (CAS 357-08-4) and tramadol (CAS 36282-47-0) differ in regard to their affinities to the opioid receptor site. Therefore it is of interest to evaluate whether such a difference in opioid affinity is also seen in the pharmacological effects of clinically relevant doses in man. Following institutional approval by the local ethical committee and informed consent, 12 volunteers received oral doses of tramadol (100 mg), tilidine/naloxone (100 mg) and placebo, respectively, in a randomized, double-blind cross-over design. In order to determine the degree of constipation, oral-caecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripheral and central mediated effects were compared to placebo. Tramadol as well as tilidine/naloxone induced a significant (p < 0.05) prolongation of oral-caecal transit when compared to placebo. However, prolongation of oral-caecal transit was significantly longer in the tilidine/naloxone (p < 0.05) than in the tramadol group. Compared to tramadol, the pronounced constipating effect of tilidine/naloxone is likely to be due to the 10 fold higher affinity of that drug to the peripheral opioid receptor sites in the intestinal tract, which are responsible for normal propulsion. Such difference in binding is underlined by a central effect, the pupillary light reflex response. The amount of constriction of the iris to light was reduced after both opioids. Again, tilidine/naloxone significantly reduced (p < 0.001) the pupillary light reflex when compared to tramadol. Other side effects such as tiredness, nausea, emesis and dry mouth were more often reported after tilidine/naloxone than after tramadol (40% versus 15%; p < 0.05). Vertigo and perspiration were more often reported after tramadol than after after tilidine/naloxone (58% and 78% versus 8%; p < 0.01). All these data support the findings that while tramadol is considered an opioid, it does not mediate its main clinical relevant properties via binding at the opioid receptor. More likely, due to its monoaminergic reuptake mechanism, to a lesser extent opioid-like effects are induced.     

Relationship between sedation and pupillary function: comparison of diazepam and diphenhydramine

AIMS: To examine the relationship between sedation and pupillary function by comparing the effects of diazepam and diphenhydramine on arousal and pupillary activity. METHODS: Fifteen male volunteers participated in three weekly sessions in which they received (i) diazepam 10 mg, (ii) diphenhydramine 75 mg and (iii) placebo, according to a balanced, double-blind protocol. Pupil diameter was measured with infrared pupillometry under four luminance levels. Alertness was assessed by visual analogue scales (VAS) and by critical flicker fusion frequency (CFFF). Blood pressure, heart rate and skin conductance were recorded by conventional methods. Data were analysed with analysis of variance (anova) with multiple comparisons. RESULTS: There were significant effects of ambient luminance (F3,42 = 305.7, P < 0.001) and treatment condition (F2,28 = 9.0, P < 0.01) on pupil diameter; diphenhydramine caused miosis at all luminance levels (P < 0.05). The light reflex response was not affected. Both active drugs reduced the pre-post treatment changes compared with placebo [mean difference from placebo (95% confidence interval)]: in CFFF (Hz), diazepam -0.73 (-1.63, 0.17), diphenhydramine -1.46 (-2.40, -0.52); and VAS alertness (mm), diazepam -11.49 (-19.19, -3.79), diphenhydramine -19.83 (-27.46, -12.20). There were significant effects of both session (F2,26 = 145.1, P < 0.001) and treatment (F2,26 = 5.5, P < 0.01) on skin conductance; skin conductance was reduced by both drugs (P < 0.05). CONCLUSIONS: The miosis by diphenhydramine and the reduction in skin conductance by both drugs may indicate central sympatholytic effects. A lack of a sympatholytic effect of diazepam on the pupil may be due to the masking of the miosis by mydriasis resulting from the inhibition of the parasympathetic output to the iris.     

Attenuation of the pupillary light reflex in anxious patients.

1. The miotic responses evoked by brief light stimuli were compared between a group of 10 patients suffering from generalized anxiety disorder and 10 age- and sex-matched healthy control subjects. 2. Resting pupil diameter in the dark did not differ significantly between the two groups. 3. In both groups, the amplitude of the light reflex was linearly related to the logarithm of the intensity of the light stimulus; responses in the anxious patient group had consistently lower amplitudes than those in the control group. 4. In both groups, the time taken for 75% recovery of the baseline pupil diameter following a light stimulus was linearly related to the logarithm of the light intensity; the 75% recovery times did not differ significantly between the two groups. 5. It is suggested that these results are consistent with a greater supranuclear inhibition of the parasympathetic oculomotor reflex arc in the anxious patients.