Highlights
- •Distress increases tonic sympathetic pupillary drive during cold pressor tests.
- •Pain increases phasic sympathetic pupillary drive during cold pressor tests.
- •Phasic influences persist whereas tonic influences decline during repeated tests.
- •Phasic and tonic effects may reflect different aspects of locus coeruleus function.
- •Both effects should be assessed in patients with suspected locus coeruleus deficits.
Abstract
Nociceptive and affective stimuli increase reflex sympathetic outflow to the pupils.
To investigate effects of stimulus intensity, unpleasantness and distress on these
pupillary reflexes, and to assess their stability, healthy participants immersed their
hand in ice-water three times (for 20, 40 and 60 s; or 60, 40 and 20 s; or three times
for 60 s) (N = 21 in each condition). Each ice-water immersion was preceded by a 90 s warm water
immersion. To evaluate phasic sympathetic influences on pupil diameter, pupillary
re-dilatation after 1 s of bright light was assessed during the last 10 s of each
immersion. By-and-large, pain ratings and pupil diameter were greater during longer
than shorter ice-water immersions, and ice-water immersions facilitated pupillary
re-dilatation after the flash stimulus. However, mean pupil diameter during ice- and
warm water immersions, minor ipsilateral amplification of the pupillary response,
and ratings of pain unpleasantness and distress decreased across the experiment. Together,
these findings suggest that nociceptive input increased sympathetic pupillary tone
and amplified phasic increases in sympathetic activity after exposure to light. However,
tonic sympathetic influences on pupil diameter and lateralization decreased across
repeated immersions, possibly as novel or threatening aspects of the experience declined.
Pupillary nociceptive and affective reflexes involve the locus coeruleus, an integral
component of neural circuits that heighten cortical arousal and regulate pain. As
these reflexes appear to reflect different aspects of sensory and affective processing,
their combined assessment might increase the sensitivity and specificity of tests
of locus coeruleus function in patients with suspected deficits.
Keywords
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References
- Changes in autonomic function with age: a study of pupillary kinetics in healthy young and old people.Age Ageing. 1996; 25: 432-438
- Direct evidence of neurally mediated vasodilatation in hairy skin of the human foot.J. Physiol. 1987; 382: 105-121
- Habituation of the stress response multiplex to repeated cold pressor exposure.Front. Physiol. 2022; 13752900
- Redefining noradrenergic neuromodulation of behavior: impacts of a modular locus coeruleus architecture.J. Neurosci. 2019; 39: 8239-8249
- Effects of cold-pressor and mental arithmetic on pupillary light reflex.Physiol. Meas. 2013; 34: 873-882
- Habituation to pain: a motivational-ethological perspective.Pain. 2019; 160: 1693-1697
- Pain-autonomic interaction is a reliable measure of pain habituation in healthy subjects.Eur. J. Pain. 2022; 26: 1679-1690
- Immersion of the hand in ice water releases adrenergic vasoconstrictor tone in the ipsilateral temple.Auton. Neurosci. 2006; 128: 70-75
- Sensory disturbances in complex regional pain syndrome: clinical observations, autonomic interactions, and possible mechanisms.Pain Med. 2010; 11: 1257-1266
- A possible role of the locus coeruleus in complex regional pain syndrome.Front. Integr. Neurosci. 2012; 6: 104
- Asymmetry of the pupillary light reflex during a cold pressor test.Auton. Neurosci. 2022; 241102989
- Immersing the foot in painfully-cold water evokes ipsilateral extracranial vasodilatation.Auton. Neurosci. 2012; 166: 89-92
- Photophobia in complex regional pain syndrome: visual discomfort is greater on the affected than unaffected side.Pain. 2021; 162: 1233-1240
- Auditory disturbances in patients with complex regional pain syndrome.Pain. 2022; (in press)
- Pupillary reflexes in complex regional pain syndrome: asymmetry to arousal stimuli suggests an ipsilateral locus coeruleus deficit.J. Pain. 2022; 23: 131-140
- Facilitation of extracranial vasodilatation to limb pain in migraine sufferers.Neurology. 2003; 61: 60-63
- Staring at one side of the face increases blood flow on that side of the face.Psychophysiology. 2004; 41: 281-287
- Hemisensory disturbances in patients with complex regional pain syndrome.Pain. 2018; 159: 1824-1832
- Relationship between baroreceptor cardiac reflex sensitivity and pain experience in normotensive individuals.Int. J. Psychophysiol. 2007; 65: 193-200
- Brainstem substructures and cognition in prodromal Alzheimer's disease.Brain Imaging Behav. 2021; 15: 2572-2582
- Effect of age on pupillary light reflex: evaluation of pupil mobility for clinical practice and research.Electromyogr. Clin. Neurophysiol. 2007; 47: 11-22
- Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats.J. Neurosci. 2014; 34: 4148-4160
- The effects of carbon dioxide on pulmonary mechanics in hyperventilating, normal volunteers.J. Thorac. Cardiovasc. Surg. 1976; 71: 268-273
- Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats.elife. 2017; 6
- The efficacy of hypnosis- and relaxation-induced analgesia on two dimensions of pain for cold pressor and electrical tooth pulp stimulation.Pain. 1988; 33: 241-251
- A psychosomatic study of contagious dermatitis.Kyushu J.Med.Sci. 1962; 13: 335-352
- Relationships between pupil diameter and neuronal activity in the locus coeruleus, colliculi, and cingulate cortex.Neuron. 2016; 89: 221-234
- Regional differences in facial skin blood flow responses to the cold pressor and static handgrip tests.Eur. J. Appl. Physiol. 2013; 113: 1035-1041
- Dynamic lateralization of pupil dilation evoked by locus coeruleus activation results from sympathetic, not parasympathetic, contributions.Cell Rep. 2017; 20: 3099-3112
- Noradrenergic locus coeruleus pathways in pain modulation.Neuroscience. 2016; 338: 93-113
- Asymmetry and time-course of cutaneous sympathetic reflex responses following sustained excitation of chemosensitive nociceptors in humans.J. Auton. Nerv. Syst. 1996; 57: 63-72
- Pupillometry: psychology, physiology, and function.J. Cogn. 2018; 1: 16
- Pupil diameter covaries with BOLD activity in human locus coeruleus.Hum. Brain Mapp. 2014; 35: 4140-4154
- The noradrenergic pain regulation system: a potential target for pain therapy.Eur. J. Pharmacol. 2013; 716: 2-7
- Pupillometric evaluation and analysis of light reflex in healthy subjects as a tool to study autonomic nervous system changes with aging.Aging. 1996; 8 (Milan, Italy): 55-60
- Individual differences and autonomic control: absorption, hypnotic susceptibility, and the unilateral control of skin temperature.J. Abnorm. Psychol. 1975; 84: 272-279
- A human sensory pathway connecting the foot to ipsilateral face that partially bypasses the spinal cord.Front. Neurosci. 2019; 13: 519
- The role of the locus coeruleus in pain and associated stress-related disorders.Biol. Psychiatry. 2022; 91: 786-797
- Modulation of physiological reflexes by pain: role of the locus coeruleus.Front. Integr. Neurosci. 2012; 6: 94
- Functional organization of the sympathetic pathways controlling the pupil: light-inhibited and light-stimulated pathways.Front. Neurol. 2018; 9: 1069
- Using Multivariate Statistics.Sixth ed. Pearson Education Limited, Harlow, Essex2014
- Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer's disease: high-resolution fast spin-echo T1-weighted imaging.Geriatr. Gerontol. Int. 2015; 15: 334-340
- The sensory and affective components of pain: are they differentially modifiable dimensions or inseparable aspects of a unitary experience? A systematic review.Br. J. Anaesth. 2019; 123: e263-e272
- Pupillary and cardiovascular responses to the cold-pressor test.J. Auton. Nerv. Syst. 1995; 55: 45-49
- Effects of pentagastrin and the cold pressor test on the acoustic startle response and pupillary function in man.J. Psychopharmacol. 2000; 14: 387-394
- The cortical representation of pain.Pain. 1999; 79: 105-111
- Persistent hindpaw inflammation produces coeruleospinal antinociception in the non-inflamed forepaw of rats.Neurosci. Lett. 2004; 367: 66-70
- Biological implications of coeruleospinal inhibition of nociceptive processing in the spinal cord.Front. Integr. Neurosci. 2012; 6: 87
- Effects of PCO2, pH and extracellular calcium on contraction of airway smooth muscle from rats.Respir. Physiol. 1986; 66: 259-267
- Cerebrovascular response to the cold pressor test - the critical role of carbon dioxide.Exp. Physiol. 2017; 102: 1647-1660
- Divergent influences of the locus coeruleus on migraine pathophysiology.Pain. 2019; 160: 385-394
- Studies on pain. Observations on pain due to local cooling and on factors involved in the "cold pressor" effect.J. Clin. Invest. 1941; 20: 521-533
- Locus coeruleus modulates thalamic nociceptive responses via adrenoceptors.Brain Res. 1998; 784: 116-122
- Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: an fMRI study.Neuroimage Clin. 2019; 24101971
Article info
Publication history
Published online: March 15, 2023
Accepted:
March 10,
2023
Received in revised form:
February 28,
2023
Received:
December 14,
2022
Identification
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© 2023 Elsevier B.V. All rights reserved.