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Does Threat Enlarge Nociceptive Reflex Receptive Fields?

Published:November 06, 2020DOI:https://doi.org/10.1016/j.jpain.2020.10.006

      Highlights

      • Threat engages endogenous top-down nociceptive circuitry.
      • Threat can amplify pain and spinal nociception.
      • Reflex receptive fields measure spinal nociception.
      • Threat enlarges reflex receptive fields.

      Abstract

      Threat-induced pain modulation can increase survival by amplifying physiological and behavioral reactions toward danger. Threat can also modulate spinal nociception, suggesting engagement of endogenous top-down circuitry. A unique method to assess spinal nociception is via reflex receptive fields (RRF) associated with the nociceptive withdrawal reflex (NWR, a protective spinally-mediated reflex). The size of nociceptive RRFs can be modulated by top-down circuitry with the enlargement of RRFs related to increased spinal nociception. Threat has been previously shown to enhance pain and spinal nociception, but the relationship between threat and RRFs has not been investigated. The present study investigated this issue in 25 healthy individuals. RRFs were determined from NWRs measured by electromyography of the tibialis anterior following electrocutaneous stimulations. RRFs and pain were assessed during periods in which participants were under threat of unpredictable painful abdominal stimulations and when they were not under threat. Results indicated that threat periods led to significantly higher pain, larger nociceptive RRFs and NWR magnitudes. These findings imply that threat produces changes in protective reflexes related to spinal nociceptive sensitivity and increased pain perception. This is likely mediated by top-down circuitry that enhances dorsal horn nociceptive neurons by enlarging RRFs and amplifying ascending pain signals.

      Perspective

      This article presents the enlargement of RRF during periods of threat. The results from this study may help clarify the mechanism underlining emotional modulation of spinal nociception.

      Key words

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      References

        • Adolphs R
        The biology of fear.
        Curr Biol. 2013; 23: R79-R93
        • Andersen OK
        • Finnerup NB
        • Spaich EG
        • Jensen TS
        • Arendt-Nielsen L
        Expansion of nociceptive withdrawal reflex receptive fields in spinal cord injured humans.
        Clin Neurophysiol. 2004; 115: 2798-2810
        • Andersen OK
        • Sonnenborg FA
        • Arendt-Nielsen L
        Modular organization of human leg withdrawal reflexes elicited by electrical stimulation of the foot sole.
        Muscle Nerve. 1999; 22: 1520-1530
        • Andersen OK
        • Sonnenborg FA
        • Arendt-Nielsen L
        Reflex receptive fields for human withdrawal reflexes elicited by non-painful and painful electrical stimulation of the foot sole.
        Clin Neurophysiol. 2001; 112: 641-649
        • Andersen OK
        • Spaich EG
        • Madeleine P
        • Arendt-Nielsen L
        Gradual enlargement of human withdrawal reflex receptive fields following repetitive painful stimulation.
        Brain Res. 2005; 1042: 194-204
        • Andersen OK
        • Spaich EG
        • Madeleine P
        • Arendt-Nielsen L
        Gradual enlargement of human withdrawal reflex receptive fields following repetitive painful stimulation.
        Brain Res. 2005; 1042: 194-204
        • Apkarian AV
        • Bushnell MC
        • Schweinhardt P
        Representation of pain in brain.
        in: McMahon SB koltzenburg M Tracey I Turk D Wall and Melzack's Textbook of Pain. Elsevier, Philidelphia, PA2013
        • Apkarian AV
        • Bushnell MC
        • Treede R-D
        • Zubieta J-K
        Human brain mechanisms of pain perception and regulation in health and disease.
        Eur J Pain. 2005; 9: 463-484
        • Bjerre L
        • Andersen AT
        • Hagelskjær MT
        • Ge N
        • Mørch CD
        • Andersenl O
        Dynamic tuning of human withdrawal reflex receptive fields during cognitive attention and distraction tasks.
        Eur J Pain. 2011; 15: 816-821
        • Bushnell MC
        • Čeko M
        • Low LA
        Cognitive and emotional control of pain and its disruption in chronic pain.
        Nat Rev Neurosci. 2013; 14: 502-511
        • Carlsson K
        • Petersson KM
        • Lundqvist D
        • Karlsson A
        • Ingvar M
        • Öhman A
        Fear and the amygdala: Manipulation of awareness generates differential cerebral responses to phobic and fear-relevant (but nonfeared) stimuli.
        Emotion. 2004; 4: 340
        • Cervero F
        • Laird JM
        • Pozo MA
        Selective changes of receptive field properties of spinal nociceptive neurones induced by noxious visceral stimulation in the cat.
        Pain. 1992; 51: 335-342
        • Chu KL
        • Faltynek CR
        • Jarvis MF
        • McGaraughty S
        Increased WDR spontaneous activity and receptive field size in rats following a neuropathic or inflammatory injury: Implications for mechanical sensitivity.
        Neurosci Lett. 2004; 372: 123-126
        • Cook AJ
        • Woolf CJ
        • Wall PD
        • McMahon SB
        Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input.
        Nature. 1987; 325: 151-153
        • Cordero-Erausquin M
        • Inquimbert P
        • Schlichter R
        • Hugel S
        Neuronal networks and nociceptive processing in the dorsal horn of the spinal cord.
        Neuroscience. 2016; 338: 230-247
        • Crews JC
        • Cahall MA
        An investigation of the neurophysiologic mechanisms of tourniquet-related pain: Changes in spontaneous activity and receptive field size in spinal dorsal horn neurons.
        Reg Anesth Pain Med. 1999; 24: 102-109
        • Davey HM
        • Barratt AL
        • Butow PN
        • Deeks JJ
        A one-item question with a Likert or Visual Analog Scale adequately measured current anxiety.
        J Clin Epidemiol. 2007; 60: 356-360
        • Davis M
        • Lang PJ
        Emotion.
        in: Gallagher M Nelson RJ Handbook of Psychology: Biological Psychology. 3. John Wiley & Sons, Inc, New York, NY2003: 405-439
        • Davis M
        • Walker DL
        • Miles L
        • Grillon C
        Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety.
        Neuropsychopharmacology. 2010; 35: 105-135
        • Dostrovsky JO
        • Craig AD
        Ascending projection system.
        in: McMahon SB Koltzenburg M Tracey I Turk D Wall and Melzack's Textbook of Pain. Elsevier, Philadelphia, PA2013: 182-210
        • Faul F
        • Erdfelder E
        • Lang A-G
        • Buchner A
        G* Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
        Behav Res Methods. 2007; 39: 175-191
        • Fillingim RB
        Individual differences in pain responses.
        Curr Rheumatol Rep. 2005; 7: 342-347
        • Gatchel RJ
        • Peng YB
        • Peters ML
        • Fuchs PN
        • Turk DC
        The biopsychosocial approach to chronic pain: Scientific advances and future directions.
        Psychol Bull. 2007; 133: 581
        • Grimby L
        Normal plantar response: Integration of flexor and extensor reflex components.
        J Neurol Neurosurg Psychiatry Res. 1963; 26: 39
        • Grubb B
        • Stiller R
        • Schaible H-G
        Dynamic changes in the receptive field properties of spinal cord neurons with ankle input in rats with chronic unilateral inflammation in the ankle region.
        Exp Brain Res. 1993; 92: 441-452
        • Hans J
        Clinical Neuroanatomy: Brain Circuitry and Its Disorders.
        Springer Science & Business Media, 2011
        • Heinricher M
        • Fields H
        Central nervous system mechanisms of pain modulation.
        in: McMahon SB Koltzenburg M Tracey I Turk D Wall and Melzack's Textbook of Pain. Elsevier, Philadelphia, PA2013: 129-219
        • Hermens HJ
        • Freriks B
        • Disselhorst-Klug C
        • Rau G
        Development of recommendations for SEMG sensors and sensor placement procedures.
        J Electromyogr Kinesiol. 2000; 10: 361-374
        • Hoheisel U
        • Mense S
        Long-term changes in discharge behaviour of cat dorsal horn neurones following noxious stimulation of deep tissues.
        Pain. 1989; 36: 239-247
        • Hubbard CS
        • Ornitz EM
        • Gaspar JX
        • Smith S
        • Amin J
        • Labus JS
        • Kilpatrick LA
        • Rhudy JL
        • Mayer EA
        • Naliboff B
        Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women.
        Pain. 2011; 152: 1632-1634
        • Hylden JL
        • Nahin RL
        • Traub RJ
        • Dubner R
        Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: The contribution of dorsal horn mechanisms.
        Pain. 1989; 37: 229
        • Jensen MB
        • Manresa JB
        • Andersen OK
        A new objective method for acquisition and quantification of reflex receptive fields.
        Pain. 2015; 156: 555-564
        • Kawamata M
        • Koshizaki M
        • Shimada SG
        • Narimatsu E
        • Kozuka Y
        • Takahashi T
        • Namiki A
        • Collins JG
        Changes in response properties and receptive fields of spinal dorsal horn neurons in rats after surgical incision in hairy skin.
        Anesthesiology. 2005; 102: 141-151
        • Laird J
        • Cervero F
        A comparative study of the changes in receptive-field properties of multireceptive and nocireceptive rat dorsal horn neurons following noxious mechanical stimulation.
        J Neurophysiol. 1989; 62: 854-863
        • Latremoliere A
        • Woolf CJ
        Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926
        • Ledoux J
        • Phelps E
        Emotional networks in the brain.
        in: Lewis M Haviland-Jones J Barrett L Handbook of Emotions. The Guilford Press, New York2010: 159-179
        • Lundberg A
        Multisensory Control of Spinal Reflex Pathwaysprog Brain Res.
        Elsevier, 1979: 11-28
        • Manresa J
        • Finnerup NSB
        • Johannesen IL
        • Biering-Sørensen F
        • Jensen TS
        • Arendt-Nielsen L
        • Andersen OK
        Central sensitization in spinal cord injured humans assessed by reflex receptive fields.
        Clin Neurophysiol. 2014; 125: 352-362
        • Manresa J
        • Jensen MB
        • Andersen OK
        Introducing the reflex probability maps in the quantification of nociceptive withdrawal reflex receptive fields in humans.
        J Electromyogr Kinesiol. 2011; 21: 67-76
        • Manresa J
        • Mørch CD
        • Andersen OK
        Long‐term facilitation of nociceptive withdrawal reflexes following low‐frequency conditioning electrical stimulation: A new model for central sensitization in humans.
        Eur J Pain. 2010; 14: 822-831
        • Manresa J
        • Neziri AY
        • Curatolo M
        • Arendt-Nielsen L
        • Andersen OK
        Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain.
        Pain. 2013; 154: 1318-1324
        • Manresa J
        • Nguyen GP
        • Curatolo M
        • Moeslund TB
        • Andersen OK
        Probabilistic model for individual assessment of central hyperexcitability using the nociceptive withdrawal reflex: A biomarker for chronic low back and neck pain.
        BMC Neurosci. 2013; 14: 110
        • McMahon S
        • Wall P
        Receptive fields of rat lamina 1 projection cells move to incorporate a nearby region of injury.
        Pain. 1984; 19: 235-247
        • Morris JS
        • Öhman A
        • Dolan RJ
        A subcortical pathway to the right amygdala mediating “unseen” fear.
        Proc Natl Acad Sci U S A. 1999; 96: 1680-1685
        • Naliboff B
        • Rhudy JL
        Anxiety and functional pain disorders.
        in: Mayer EA Bushnell MC Functional Pain Syndromes: Presentation and Pathophysiology. IASP Press, Seattle2009
        • Neugebauer V
        • Li W
        • Bird GC
        • Han JS
        The amygdala and persistent pain.
        Neuroscientist. 2004; 10: 221-234
        • Neziri AY
        • Haesler S
        • Petersen-Felix S
        • Müller M
        • Arendt-Nielsen L
        • Manresa J
        • Andersen OK
        • Curatolo M
        Generalized expansion of nociceptive reflex receptive fields in chronic pain patients.
        Pain. 2010; 151: 798-805
        • Ploghaus A
        • Narain C
        • Beckmann CF
        • Clare S
        • Bantick S
        • Wise R
        • Matthews PM
        • Rawlins JNP
        • Tracey I
        Exacerbation of pain by anxiety is associated with activity in a hippocampal network.
        J Neurosci. 2001; 21: 9896-9903
        • Pogatzki EM
        • Vandermeulen EP
        • Brennan TJ
        Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision.
        Pain. 2002; 97: 151-161
        • Price D
        • Bush FM
        • Long S
        • Harkins SW
        A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales.
        Pain. 1994; 56: 217-226
        • Pud D
        • Granovsky Y
        • Yarnitsky D
        The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.
        Pain. 2009; 144: 16-19
      1. (al')
        • Rhudy JL
        Emotional modulation of pain.
        in: Absi M Flaten MA The Neuroscience of Pain, Stress, and Emotion. 3. Academic Press, San Diego, CA2016: 51-75 (al')
        • Rhudy JL
        • France CR
        Defining the nociceptive flexion reflex (NFR) threshold in human participants: A comparison of different scoring criteria.
        Pain. 2007; 128: 244-253
        • Rhudy JL
        • Grimes JS
        • Meagher MW
        Fear-induced hypoalgesia in humans: Effects on low intensity thermal stimulation and finger temperature.
        J Pain. 2004; 5: 458-468
        • Rhudy JL
        • Meagher MW
        Fear and anxiety: Divergent effects on human pain thresholds.
        Pain. 2000; 84: 65-75
        • Rhudy JL
        • Meagher MW
        The role of emotion in pain modulation.
        Curr Opin Psychiatry. 2001; 14: 241-245
        • Rhudy JL
        • Meagher MW
        Individual differences in the emotional reaction to shock determine whether hypoalgesia is observed.
        Pain Med. 2003; 4: 244-256
        • Rhudy JL
        • Williams AE
        • Dubbert PM
        • Parker JD
        • Burke RS
        Affective Modulation of Pain in Substance Dependent Veterans.
        Society for Neuroscience, Washington, DC2004 (Progr No. 63.5. 2004 Itiner PlanOnline., 2004)
        • Rhudy JL
        • Williams AE
        • McCabe K
        • Nguyen MA
        • Rambo P
        Affective modulation of nociception at spinal and supraspinal levels.
        Psychophysiology. 2005; 42: 579-587
        • Rhudy JL
        • Williams AE
        • McCabe KM
        • Maynard LJ
        • Russell JL
        Affective modulation of spinal nociception and pain: Valence and arousal contribute.
        Psychophysiology. 2006; 43: S80
        • Rhudy JL
        • Williams AE
        • McCabe KM
        • Rambo PL
        • Nguyen MV
        • Russell JL
        Modulation of spinal nociception and pain by emotion: Does predictability of the noxious stimulus disengage modulation at spinal levels?.
        in: American Pain Society National Conference, San Antonio, TX2006
        • Rhudy JL
        • Williams AE
        • McCabe KM
        • Rambo PL
        • Russell JL
        Emotional modulation of spinal nociception and pain: The impact of predictable noxious stimulation.
        Pain. 2006; 126: 221-233
        • Rhudy JL
        • Williams AE
        • McCabe KM
        • Russell JL
        Emotional control of nociceptive reactions (ECON): Affective valence and arousal have independent effects across multiple response systems.
        in: American Pain Society National Conference, Washington, DC2007
        • Rhudy JL
        • Williams AE
        • McCabe KM
        • Russell JL
        • Maynard LJ
        Emotional control of nociceptive reactions (ECON): Do affective valence and arousal play a role?.
        Pain. 2008; 136: 250-261
        • Sandrini G
        • Serrao M
        • Rossi P
        • Romaniello A
        • Cruccu G
        • Willer JC
        The lower limb flexion reflex in humans.
        Prog Neurobiol. 2005; 77: 353-395
        • Schouenborg J
        Modular organisation and spinal somatosensory imprinting.
        Brain Res Rev. 2002; 40: 80-91
        • Schouenborg J
        • Holmberg H
        • Weng H
        Functional organization of the nociceptive withdrawal reflexes. II. Changes of excitability and receptive fields after spinalization in the rat.
        Exp Brain Res. 1991; 90: 469-478
        • Schouenborg J
        • Weng H-R
        Sensorimotor transformation in a spinal motor system.
        Exp Brain Res. 1994; 100: 170-174
        • Schouenborg J
        • Weng H-R
        • Holmberg H
        Modular organization of spinal nociceptive reflexes: A new hypothesis.
        Physiology. 1994; 9: 261-265
        • Schouenborg J
        • Weng H-R
        • Kalliomäki J
        • Holmberg H
        A survey of spinal dorsal horn neurones encoding the spatial organization of withdrawal reflexes in the rat.
        Exp Brain Res. 1995; 106: 19-27
        • Schumacher R
        • Velden M
        Anxiety, pain experience, and pain report: A signal-detection study.
        Percept Mot Skills. 1984; 58: 339-349
        • Sherrington CS
        Flexion-reflex of the limb, crossed extension-reflex, and reflex stepping and standing.
        J Physiol. 1910; 40: 28-121
        • Spaich EG
        • Arendt-Nielsen L
        • Andersen OK
        Repetitive painful stimulation produces an expansion of withdrawal reflex receptive fields in humans.
        Artif Organs. 2005; 29: 224-228
        • Suzuki R
        • Kontinen V
        • Matthews E
        • Williams E
        • Dickenson A
        Enlargement of the receptive field size to low intensity mechanical stimulation in the rat spinal nerve ligation model of neuropathy.
        J Peripher Nerv. 2000; 5 (248-248)
        • Terry EL
        • Thompson K
        • Rhudy JL
        Threat-evoked pain facilitation is not influenced by experimental reductions in pain catastrophizing.
        J Pain. 2015; 16: S51
        • Terry EL
        • Thompson K
        • Rhudy JL
        Does pain catastrophizing contribute to threat-evoked amplification of pain and spinal nociception?.
        Pain. 2016; 157: 456-465
        • Urch C
        • Donovan-Rodriguez T
        • Dickenson A
        Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain.
        Pain. 2003; 106: 347-356
        • Wilcox R
        Numerical and Graphical Summaries of DataModern Statistics for the Social and Behavioral Sciences: A Practical Introduction.
        CRC Press, Boca Raton, FL2012
        • Willer JC
        • Boureau F
        • Albe-Fessard D
        Supraspinal influences on nociceptive flexion reflex and pain sensation in man.
        Brain Res. 1979; 179: 61-68
        • Winter KA
        • Kuiper NA
        Individual differences in the experience of emotions.
        Clin Psychol Rev. 1997; 17: 791-821
        • Woolf CJ
        • King AE
        Subthreshold components of the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat lumbar spinal cord.
        J Neurophysiol. 1989; 62: 907-916
        • Woolf CJ
        • King AE
        Dynamic alterations in the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat spinal cord.
        J Neurosci. 1990; 10: 2717-2726