Advertisement

The Dynamics of Pain: Evidence for Simultaneous Site-Specific Habituation and Site-Nonspecific Sensitization in Thermal Pain

      Abstract

      Repeated exposure to noxious stimuli changes their painfulness, due to multiple adaptive processes in the peripheral and central nervous systems. Somewhat paradoxically, repeated stimulation can produce an increase (sensitization) or a decrease (habituation) in pain. Adaptation processes may also be body-site-specific or operate across body sites, and considering this distinction may help explain the conditions under which habituation versus sensitization occurs. To dissociate the effects of site-specific and site-nonspecific adaptation processes, we examined reported pain in 100 participants during counterbalanced sequences of noxious thermal stimulation on multiple skin sites. Analysis of pain ratings revealed 2 opposing sequential effects: repeated stimulations of the same skin site produced temperature-dependent habituation, whereas repeated stimulations across different sites produced sensitization. Stimulation trials were separated by ∼20 seconds, and sensitization was unrelated to the distance between successively stimulated sites, suggesting that neither temporal nor spatial summation occurred. To explain these effects, we propose a dynamic model with 2 adaptation processes, one site-specific and the other site-nonspecific. The model explains 93% of the variance in the group-mean pain ratings after controlling for current stimulation temperature, with its estimated parameters showing evidence for habituation for the site-specific process and sensitization for the site-nonspecific process. The 2 pain adaptation processes revealed in this study, and the ability to disentangle them, may hold keys to understanding multiple pain-regulatory mechanisms and their disturbance in chronic pain syndromes.

      Perspective

      This article presents novel evidence for simultaneous site-specific habituation and site-nonspecific sensitization in thermal pain, which can be disentangled (and the direction and strength of each process estimated) by a dynamic model. The dissociation of site-specific and site-nonspecific adaptation processes may hold keys to understanding multiple pain-regulatory mechanisms in both healthy and patient populations.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Atlas L.Y.
        • Bolger N.
        • Lindquist M.A.
        • Wager T.D.
        Brain mediators of predictive cue effects on perceived pain.
        J Neurosci. 2010; 30: 12964-12977
        • Becerra L.R.
        • Breiter H.C.
        • Stojanovic M.
        • Fishman S.
        • Edwards A.
        • Comite A.R.
        • Gonzalez R.G.
        • Borsook D.
        Human brain activation under controlled thermal stimulation and habituation to noxious heat: An fMRI study.
        Magn Reson Med. 1999; 41: 1044-1057
        • Becker S.
        • Kleinbohl D.
        • Baus D.
        • Holzl R.
        Operant learning of perceptual sensitization and habituation is impaired in fibromyalgia patients with and without irritable bowel syndrome.
        Pain. 2011; 152: 1408-1417
        • Bingel U.
        • Lorenz J.
        • Schoell E.
        • Weiller C.
        • Buchel C.
        Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.
        Pain. 2006; 120: 8-15
        • Casey K.L.
        • Morrow T.J.
        • Lorenz J.
        • Minoshima S.
        Temporal and spatial dynamics of human forebrain activity during heat pain: Analysis by positron emission tomography.
        J Neurophysiol. 2001; 85: 951-959
        • Cecchi G.A.
        • Huang L.
        • Hashmi J.A.
        • Baliki M.
        • Centeno M.V.
        • Rish I.
        • Apkarian A.V.
        Predictive dynamics of human pain perception.
        PLoS Comput Biol. 2012; 8: e1002719
        • Coleman T.F.
        • Li Y.Y.
        An interior trust region approach for nonlinear minimization subject to bounds.
        Siam J Optimiz. 1996; 6: 418-445
        • Condes-Lara M.
        • Calvo J.M.
        • Fernandez-Guardiola A.
        Habituation to bearable experimental pain elicited by tooth pulp electrical stimulation.
        Pain. 1981; 11: 185-200
        • Coppola G.
        • Pierelli F.
        • Schoenen J.
        Is the cerebral cortex hyperexcitable or hyperresponsive in migraine?.
        Cephalalgia. 2007; 27: 1427-1439
        • Coppola G.
        • Pierelli F.
        • Schoenen J.
        Reply to the topical review entitled “The phenomenon of changes in cortical excitability in migraine is not migraine-specific–A unifying thesis” by Anne Stankewitz and Arne May published in Pain 2009;145:14–7.
        Pain. 2010; 149 (author reply 408-409): 407-408
        • de Tommaso M.
        • Libro G.
        • Guido M.
        • Losito L.
        • Lamberti P.
        • Livrea P.
        Habituation of single CO2 laser-evoked responses during interictal phase of migraine.
        J Headache Pain. 2005; 6: 195-198
        • Defrin R.
        • Pope G.
        • Davis K.D.
        Interactions between spatial summation, 2-point discrimination and habituation of heat pain.
        Eur J Pain. 2008; 12: 900-909
        • Dickenson A.H.
        • Sullivan A.F.
        Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation.
        Neuropharmacology. 1987; 26: 1235-1238
        • Ernst M.
        • Lee M.H.
        • Dworkin B.
        • Zaretsky H.H.
        Pain perception decrement produced through repeated stimulation.
        Pain. 1986; 26: 221-231
        • Flor H.
        • Diers M.
        • Birbaumer N.
        Peripheral and electrocortical responses to painful and non-painful stimulation in chronic pain patients, tension headache patients and healthy controls.
        Neurosci Lett. 2004; 361: 147-150
        • Gold M.S.
        • Gebhart G.F.
        Nociceptor sensitization in pain pathogenesis.
        Nat Med. 2010; 16: 1248-1257
        • Granot M.
        • Granovsky Y.
        • Sprecher E.
        • Nir R.R.
        • Yarnitsky D.
        Contact heat-evoked temporal summation: Tonic versus repetitive-phasic stimulation.
        Pain. 2006; 122: 295-305
        • Greffrath W.
        • Baumgartner U.
        • Treede R.D.
        Peripheral and central components of habituation of heat pain perception and evoked potentials in humans.
        Pain. 2007; 132: 301-311
        • Grill J.D.
        • Coghill R.C.
        Transient analgesia evoked by noxious stimulus offset.
        J Neurophysiol. 2002; 87: 2205-2208
        • Groves P.M.
        • Thompson R.F.
        Habituation: A dual-process theory.
        Psychol Rev. 1970; 77: 419-450
        • Hardy J.D.
        • Stolwijk J.A.
        • Hammel H.T.
        • Murgatroyd D.
        Skin temperature and cutaneous pain during warm water immersion.
        J Appl Physiol. 1965; 20: 1014-1021
        • Hashmi J.A.
        • Davis K.D.
        Women experience greater heat pain adaptation and habituation than men.
        Pain. 2009; 145: 350-357
        • Hashmi J.A.
        • Davis K.D.
        Effects of temperature on heat pain adaptation and habituation in men and women.
        Pain. 2010; 151: 737-743
        • Herrero J.F.
        • Laird J.M.
        • Lopez-Garcia J.A.
        Wind-up of spinal cord neurones and pain sensation: Much ado about something?.
        Prog Neurobiol. 2000; 61: 169-203
        • Hollins M.
        • Harper D.
        • Maixner W.
        Changes in pain from a repetitive thermal stimulus: The roles of adaptation and sensitization.
        Pain. 2011; 152: 1583-1590
        • Janicki P.
        • Libich J.
        • Gumulka W.
        Lack of habituation of pain evoked potentials after naloxone.
        Pol J Pharmacol Pharm. 1979; 31: 201-205
        • Johnstone T.
        • Salomons T.V.
        • Backonja M.M.
        • Davidson R.J.
        Turning on the alarm: The neural mechanisms of the transition from innocuous to painful sensation.
        Neuroimage. 2012; 59: 1594-1601
        • LaMotte R.H.
        • Campbell J.N.
        Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain.
        J Neurophysiol. 1978; 41: 509-528
        • Li J.
        • Simone D.A.
        • Larson A.A.
        Windup leads to characteristics of central sensitization.
        Pain. 1999; 79: 75-82
        • Lindquist M.A.
        • Spicer J.
        • Asllani I.
        • Wager T.D.
        Estimating and testing variance components in a multi-level GLM.
        Neuroimage. 2012; 59: 490-501
        • Loftus G.R.
        • Masson M.E.
        Using confidence intervals in within-subject designs.
        Psychon Bull Rev. 1994; 1: 476-490
        • May A.
        Chronic pain may change the structure of the brain.
        Pain. 2008; 137: 7-15
        • May A.
        • Rodriguez-Raecke R.
        • Schulte A.
        • Ihle K.
        • Breimhorst M.
        • Birklein F.
        • Jurgens T.P.
        Within-session sensitization and between-session habituation: A robust physiological response to repetitive painful heat stimulation.
        Eur J Pain. 2012; 16: 401-409
        • Mendell L.M.
        Physiological properties of unmyelinated fiber projection to the spinal cord.
        Exp Neurol. 1966; 16: 316-332
        • Milne R.J.
        • Kay N.E.
        • Irwin R.J.
        Habituation to repeated painful and non-painful cutaneous stimuli: A quantitative psychophysical study.
        Exp Brain Res. 1991; 87: 438-444
        • Mobascher A.
        • Brinkmeyer J.
        • Warbrick T.
        • Musso F.
        • Schlemper V.
        • Wittsack H.J.
        • Saleh A.
        • Schnitzler A.
        • Winterer G.
        Brain activation patterns underlying fast habituation to painful laser stimuli.
        Int J Psychophysiol. 2010; 75: 16-24
        • Montgomery G.
        • Kirsch I.
        Mechanisms of placebo pain reduction: An empirical investigation.
        Psychol Sci. 1996; 7: 174-176
        • Peng Y.B.
        • Ringkamp M.
        • Meyer R.A.
        • Campbell J.N.
        Fatigue and paradoxical enhancement of heat response in C-fiber nociceptors from cross-modal excitation.
        J Neurosci. 2003; 23: 4766-4774
        • Peters M.L.
        • Schmidt A.J.M.
        • Vandenhout M.A.
        Chronic low-back pain and the reaction to repeated acute pain stimulation.
        Pain. 1989; 39: 69-76
        • Price D.D.
        • Craggs J.G.
        • Zhou Q.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.E.
        Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: Evidence from human psychophysics, animal models, and neuroimaging.
        Neuroimage. 2009; 47: 995-1001
        • Price D.D.
        • Hu J.W.
        • Dubner R.
        • Gracely R.H.
        Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses.
        Pain. 1977; 3: 57-68
        • Price D.D.
        • Mao J.
        • Frenk H.
        • Mayer D.J.
        The N-methyl-d-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man.
        Pain. 1994; 59: 165-174
        • Price D.D.
        • McGrath P.A.
        • Rafii A.
        • Buckingham B.
        The validation of visual analogue scales as ratio scale measures for chronic and experimental pain.
        Pain. 1983; 17: 45-56
        • Price D.D.
        • McHaffie J.G.
        • Larson M.A.
        Spatial summation of heat-induced pain: Influence of stimulus area and spatial separation of stimuli on perceived pain sensation intensity and unpleasantness.
        J Neurophysiol. 1989; 62: 1270-1279
        • Price D.D.
        • Zhou Q.
        • Moshiree B.
        • Robinson M.E.
        • Verne G.N.
        Peripheral and central contributions to hyperalgesia in irritable bowel syndrome.
        J Pain. 2006; 7: 529-535
        • Rankin C.H.
        • Abrams T.
        • Barry R.J.
        • Bhatnagar S.
        • Clayton D.F.
        • Colombo J.
        • Coppola G.
        • Geyer M.A.
        • Glanzman D.L.
        • Marsland S.
        • McSweeney F.K.
        • Wilson D.A.
        • Wu C.F.
        • Thompson R.F.
        Habituation revisited: An updated and revised description of the behavioral characteristics of habituation.
        Neurobiol Learn Mem. 2009; 92: 135-138
        • Rennefeld C.
        • Wiech K.
        • Schoell E.D.
        • Lorenz J.
        • Bingel U.
        Habituation to pain: Further support for a central component.
        Pain. 2010; 148: 503-508
        • Robinson D.L.
        Functional contributions of the primate pulvinar.
        Prog Brain Res. 1993; 95: 371-380
        • Saalmann Y.B.
        • Kastner S.
        Gain control in the visual thalamus during perception and cognition.
        Curr Opin Neurobiol. 2009; 19: 408-414
        • Smith B.W.
        • Tooley E.M.
        • Montague E.Q.
        • Robinson A.E.
        • Cosper C.J.
        • Mullins P.G.
        Habituation and sensitization to heat and cold pain in women with fibromyalgia and healthy controls.
        Pain. 2008; 140: 420-428
        • Stankewitz A.
        • May A.
        The phenomenon of changes in cortical excitability in migraine is not migraine-specific—A unifying thesis.
        Pain. 2009; 145: 14-17
        • Stankewitz A.
        • Schulz E.
        • May A.
        Neuronal correlates of impaired habituation in response to repeated trigemino-nociceptive but not to olfactory input in migraineurs: An fMRI study.
        Cephalalgia. 2013; 33: 256-265
        • Stankewitz A.
        • Valet M.
        • Schulz E.
        • Woller A.
        • Sprenger T.
        • Vogel D.
        • Zimmer C.
        • Muhlau M.
        • Tolle T.R.
        Pain sensitisers exhibit grey matter changes after repetitive pain exposure: A longitudinal voxel-based morphometry study.
        Pain. 2013; 154: 1732-1737
        • Staud R.
        • Craggs J.G.
        • Robinson M.E.
        • Perlstein W.M.
        • Price D.D.
        Brain activity related to temporal summation of C-fiber evoked pain.
        Pain. 2007; 129: 130-142
        • Staud R.
        • Nagel S.
        • Robinson M.E.
        • Price D.D.
        Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study.
        Pain. 2009; 145: 96-104
        • Thompson R.F.
        • Spencer W.A.
        Habituation: A model phenomenon for the study of neuronal substrates of behavior.
        Psychol Rev. 1966; 73: 16-43
        • Timmermann L.
        • Ploner M.
        • Haucke K.
        • Schmitz F.
        • Baltissen R.
        • Schnitzler A.
        Differential coding of pain intensity in the human primary and secondary somatosensory cortex.
        J Neurophysiol. 2001; 86: 1499-1503
        • Treede R.D.
        • Meyer R.A.
        • Raja S.N.
        • Campbell J.N.
        Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin.
        J Physiol. 1995; 483: 747-758
        • Valeriani M.
        • de Tommaso M.
        • Restuccia D.
        • Le Pera D.
        • Guido M.
        • Iannetti G.D.
        • Libro G.
        • Truini A.
        • Di Trapani G.
        • Puca F.
        • Tonali P.
        • Cruccu G.
        Reduced habituation to experimental pain in migraine patients: A CO2 laser evoked potential study.
        Pain. 2003; 105: 57-64
        • Verne G.N.
        • Robinson M.E.
        • Vase L.
        • Price D.D.
        Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients.
        Pain. 2003; 105: 223-230
        • Wager T.D.
        • Waugh C.E.
        • Lindquist M.
        • Noll D.C.
        • Fredrickson B.L.
        • Taylor S.F.
        Brain mediators of cardiovascular responses to social threat, Part I: Reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity.
        Neuroimage. 2009; 47: 821-835
        • Woolf C.J.
        Evidence for a central component of post-injury pain hypersensitivity.
        Nature. 1983; 306: 686-688
        • Woolf C.J.
        Central sensitization: Implications for the diagnosis and treatment of pain.
        Pain. 2011; 152: S2-15
        • Yelle M.D.
        • Oshiro Y.
        • Kraft R.A.
        • Coghill R.C.
        Temporal filtering of nociceptive information by dynamic activation of endogenous pain modulatory systems.
        J Neurosci. 2009; 29: 10264-10271
        • Yelle M.D.
        • Rogers J.M.
        • Coghill R.C.
        Offset analgesia: A temporal contrast mechanism for nociceptive information.
        Pain. 2008; 134: 174-186