An ultrafast system for signaling mechanical pain in human skin
Saad S Nagi, Andrew G Marshall, Adarsh Makdani, Ewa Jarocka, Jaquette Liljencrantz, Mikael Ridderström, Sumaiya Shaikh, Francis O'Neill, Dimah Saade, Sandra Donkervoort, A Reghan Foley, Jan Minde, Mats Trulsson, Jonathan Cole, Carsten G Bönnemann, Alexander T Chesler, M Catherine Bushnell, Francis McGlone, Håkan Olausson, Saad S Nagi, Andrew G Marshall, Adarsh Makdani, Ewa Jarocka, Jaquette Liljencrantz, Mikael Ridderström, Sumaiya Shaikh, Francis O'Neill, Dimah Saade, Sandra Donkervoort, A Reghan Foley, Jan Minde, Mats Trulsson, Jonathan Cole, Carsten G Bönnemann, Alexander T Chesler, M Catherine Bushnell, Francis McGlone, Håkan Olausson
Abstract
The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.
Figures
References
- Lloyd D. P. C., Neuron patterns controlling transmission of ipsilateral hind limb reflexes in cat. J. Neurophysiol. 6, 293–315 (1943).
- Adrian E. D., Zotterman Y., The impulses produced by sensory nerve endings: Part 3. Impulses set up by touch and pressure. J. Physiol. 61, 465–483 (1926).
- Adrian E. D., The impulses produced by sensory nerve-endings: Part 4. Impulses from pain receptors. J. Physiol. 62, 33–51 (1926).
- Torebjörk H. E., Hallin R. G., Perceptual changes accompanying controlled preferential blocking of A and C fibre responses in intact human skin nerves. Exp. Brain Res. 16, 321–332 (1973).
- Mackenzie R. A., Burke D., Skuse N. F., Lethlean A. K., Fibre function and perception during cutaneous nerve block. J. Neurol. Neurosurg. Psychiatry 38, 865–873 (1975).
- Ochoa J., Torebjörk E., Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves. J. Physiol. 415, 583–599 (1989).
- Bromm B., Treede R. D., Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation. Hum. Neurobiol. 3, 33–40 (1984).
- Löken L. S., Wessberg J., Morrison I., McGlone F., Olausson H., Coding of pleasant touch by unmyelinated afferents in humans. Nat. Neurosci. 12, 547–548 (2009).
- Rolke R., Baron R., Maier C., Tölle T. R., Treede R. D., Beyer A., Binder A., Birbaumer N., Birklein F., Bötefür I. C., Braune S., Flor H., Huge V., Klug R., Landwehrmeyer G. B., Magerl W., Maihöfner C., Rolko C., Schaub C., Scherens A., Sprenger T., Valet M., Wasserka B., Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain 123, 231–243 (2006).
- Djouhri L., Lawson S. N., Aβ-fiber nociceptive primary afferent neurons: A review of incidence and properties in relation to other afferent A-fiber neurons in mammals. Brain Res. Rev. 46, 131–145 (2004).
- Koltzenburg M., Stucky C. L., Lewin G. R., Receptive properties of mouse sensory neurons innervating hairy skin. J. Neurophysiol. 78, 1841–1850 (1997).
- Treede R.-D., Meyer R. A., Campbell J. N., Myelinated mechanically insensitive afferents from monkey hairy skin: Heat-response properties. J. Neurophysiol. 80, 1082–1093 (1998).
- Burgess P. R., Perl E. R., Myelinated afferent fibres responding specifically to noxious stimulation of the skin. J. Physiol. 190, 541–562 (1967).
- Willer J. C., Boureau F., Albe-Fessard D., Role of large diameter cutaneous afferents in transmission of nociceptive messages: Electrophysiological study in man. Brain Res. 152, 358–364 (1978).
- Willer J.-C., Albe-Fessard D., Further studies on the role of afferent input from relatively large diameter fibers in transmission of nociceptive messages in humans. Brain Res. 278, 318–321 (1983).
- Bai L., Lehnert B. P., Liu J., Neubarth N. L., Dickendesher T. L., Nwe P. H., Cassidy C., Woodbury C. J., Ginty D. D., Genetic identification of an expansive mechanoreceptor sensitive to skin stroking. Cell 163, 1783–1795 (2015).
- H. Merskey, N. Bogduk, Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms (IASP Press, 1994).
- Ranade S. S., Woo S.-H., Dubin A. E., Moshourab R. A., Wetzel C., Petrus M., Mathur J., Begay V., Coste B., Mainquist J., Wilson A. J., Francisco A. G., Reddy K., Qiu Z., Wood J. N., Lewin G. R., Patapoutian A., Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014).
- Woo S.-H., Lukacs V., de Nooij J. C., Zaytseva D., Criddle C. R., Francisco A., Jessell T. M., Wilkinson K. A., Patapoutian A., Piezo2 is the principal mechanotransduction channel for proprioception. Nat. Neurosci. 18, 1756–1762 (2015).
- Chesler A. T., Szczot M., Bharucha-Goebel D., Čeko M., Donkervoort S., Laubacher C., Hayes L. H., Alter K., Zampieri C., Stanley C., Innes A. M., Mah J. K., Grosmann C. M., Bradley N., Nguyen D., Foley A. R., Le Pichon C. E., Bönnemann C. G., The role of PIEZO2 in human mechanosensation. N. Engl. J. Med. 375, 1355–1364 (2016).
- Murthy S. E., Loud M. C., Daou I., Marshall K. L., Schwaller F., Kühnemund J., Francisco A. G., Keenan W. T., Dubin A. E., Lewin G. R., Patapoutian A., The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci. Transl. Med. 10, eaat9897 (2018).
- Vallbo Å. B., Hagbarth K.-E., Activity from skin mechanoreceptors recorded percutaneously in awake human subjects. Exp. Neurol. 21, 270–289 (1968).
- Vallbo Å. B., Olausson H., Wessberg J., Kakuda N., Receptive field characteristics of tactile units with myelinated afferents in hairy skin of human subjects. J. Physiol. 483, 783–795 (1995).
- Serra J., Campero M., Ochoa J., Bostock H., Activity-dependent slowing of conduction differentiates functional subtypes of C fibres innervating human skin. J. Physiol. 515, 799–811 (1999).
- Watkins R. H., Wessberg J., Wasling H. B., Dunham J. P., Olausson H., Johnson R. D., Ackerley R., Optimal delineation of single C-tactile and C-nociceptive afferents in humans using latency slowing. J. Neurophysiol. 117, 1608–1614 (2017).
- Ackerley R., Wiklund Fernstrom K., Backlund Wasling H., Watkins R. H., Johnson R. D., Vallbo Å. B., Wessberg J., Differential effects of radiant and mechanically applied thermal stimuli on human C-tactile afferent firing patterns. J. Neurophysiol. 120, 1885–1892 (2018).
- Ochoa J., Torebjörk H., Sensation evoked by intraneural microstimulation of single mechanoreceptor units innervating the human hand. J. Physiol. 342, 633–654 (1983).
- Vallbo Å. B., Olsson K. A., Westberg K. G., Clark F. J., Microstimulation of single tactile afferents from the human hand. Sensory attributes related to unit type and properties of receptive fields. Brain 107, 727–749 (1984).
- Olausson H., Cole J., Rylander K., McGlone F., Lamarre Y., Wallin B. G., Krämer H., Wessberg J., Elam M., Bushnell M. C., Vallbo Å., Functional role of unmyelinated tactile afferents in human hairy skin: Sympathetic response and perceptual localization. Exp. Brain Res. 184, 135–140 (2008).
- Cole J. D., Merton W. L., Barrett G., Katifi H. A., Treede R. D., Evoked potentials in a subject with a large-fibre sensory neuropathy below the neck. Can. J. Physiol. Pharmacol. 73, 234–245 (1995).
- Cole J., Bushnell M. C., McGlone F., Elam M., Lamarre Y., Vallbo Å., Olausson H., Unmyelinated tactile afferents underpin detection of low-force monofilaments. Muscle Nerve 34, 105–107 (2006).
- Minde J., Svensson O., Holmberg M., Solders G., Toolanen G., Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation. Acta Orthop. 77, 198–202 (2006).
- Minde J., Andersson T., Fulford M., Aguirre M., Nennesmo I., Remahl I. N., Svensson O., Holmberg M., Toolanen G., Solders G., A novel NGFB point mutation: A phenotype study of heterozygous patients. J. Neurol. Neurosurg. Psychiatry 80, 188–195 (2009).
- Morrison I., Löken L. S., Minde J., Wessberg J., Perini I., Nennesmo I., Olausson H., Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch. Brain 134, 1116–1126 (2011).
- Szczot M., Liljencrantz J., Ghitani N., Barik A., Lam R., Thompson J. H., Bharucha-Goebel D., Saade D., Necaise A., Donkervoort S., Foley A. R., Gordon T., Case L., Bushnell M. C., Bönnemann C. G., Chesler A. T., PIEZO2 mediates injury-induced tactile pain in mice and humans. Sci. Transl. Med. 10, eaat9892 (2018).
- Perl E. R., Myelinated afferent fibres innervating the primate skin and their response to noxious stimuli. J. Physiol. 197, 593–615 (1968).
- Vallbo Å. B., Olausson H., Wessberg J., Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J. Neurophysiol. 81, 2753–2763 (1999).
- Lawson S. N., Phenotype and function of somatic primary afferent nociceptive neurones with C-, Aδ- or Aα/β-fibres. Exp. Physiol. 87, 239–244 (2002).
- Adriaensen H., Gybels J., Handwerker H. O., Van Hees J., Response properties of thin myelinated (A-delta) fibers in human skin nerves. J. Neurophysiol. 49, 111–122 (1983).
- Ghitani N., Barik A., Szczot M., Thompson J. H., Li C., Le Pichon C. E., Krashes M. J., Chesler A. T., Specialized mechanosensory nociceptors mediating rapid responses to hair pull. Neuron 95, 944–954.e4 (2017).
- Arcourt A., Gorham L., Dhandapani R., Prato V., Taberner F. J., Wende H., Gangadharan V., Birchmeier C., Heppenstall P. A., Lechner S. G., Touch receptor-derived sensory information alleviates acute pain signaling and fine-tunes nociceptive reflex coordination. Neuron 93, 179–193 (2017).
- Garell P. C., McGillis S. L., Greenspan J. D., Mechanical response properties of nociceptors innervating feline hairy skin. J. Neurophysiol. 75, 1177–1189 (1996).
- Slugg R. M., Meyer R. A., Campbell J. N., Response of cutaneous A- and C-fiber nociceptors in the monkey to controlled-force stimuli. J. Neurophysiol. 83, 2179–2191 (2000).
- Krarup C., Trojaborg W., Compound sensory action potentials evoked by tactile and by electrical stimulation in normal median and sural nerves. Muscle Nerve 17, 733–740 (1994).
- Kakuda N., Conduction velocity of low-threshold mechanoreceptive afferent fibers in the glabrous and hairy skin of human hands measured with microneurography and spike-triggered averaging. Neurosci. Res. 15, 179–188 (1992).
- Macefield G., Gandevia S. C., Burke D., Conduction velocities of muscle and cutaneous afferents in the upper and lower limbs of human subjects. Brain 112, 1519–1532 (1989).
- Simone D. A., Marchettini P., Caputi G., Ochoa J. L., Identification of muscle afferents subserving sensation of deep pain in humans. J. Neurophysiol. 72, 883–889 (1994).
- Inui K., Tran T. D., Hoshiyama M., Kakigi R., Preferential stimulation of Aδ fibers by intra-epidermal needle electrode in humans. Pain 96, 247–252 (2002).
- Tran T. D., Lam K., Hoshiyama M., Kakigi R., A new method for measuring the conduction velocities of Aβ-, Aδ- and C-fibers following electric and CO2 laser stimulation in humans. Neurosci. Lett. 301, 187–190 (2001).
- Iannetti G. D., Baumgärtner U., Tracey I., Treede R. D., Magerl W., Pinprick-evoked brain potentials: A novel tool to assess central sensitization of nociceptive pathways in humans. J. Neurophysiol. 110, 1107–1116 (2013).
- Melzack R., Wall P. D., Pain mechanisms: A new theory. Science 150, 971–978 (1965).
- Richardson R., Arbit J., Siqueira E., Zagar R., Transcutaneous electrical neurostimulation in functional pain. Spine 6, 185–188 (1981).
- Woodbury C. J., Kullmann F. A., McIlwrath S. L., Koerber H. R., Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice. J. Comp. Neurol. 508, 500–509 (2008).
- Edin B. B., Quantitative analysis of static strain sensitivity in human mechanoreceptors from hairy skin. J. Neurophysiol. 67, 1105–1113 (1992).
- Trulsson M., Francis S. T., Kelly E. F., Westling G., Bowtell R., McGlone F., Cortical responses to single mechanoreceptive afferent microstimulation revealed with fMRI. Neuroimage 13, 613–622 (2001).
- Panchuelo R. M. S., Ackerley R., Glover P. M., Bowtell R. W., Wessberg J., Francis S. T., McGlone F., Mapping quantal touch using 7 Tesla functional magnetic resonance imaging and single-unit intraneural microstimulation. eLife 5, e12812 (2016).
- Sterman A. B., Schaumburg H. H., Asbury A. K., The acute sensory neuronopathy syndrome: A distinct clinical entity. Ann. Neurol. 7, 354–358 (1980).
- Herman W. H., Pop-Busui R., Braffett B. H., Martin C. L., Cleary P. A., Albers J. W., Feldman E. L.; DCCT/EDIC Research Group , Use of the Michigan neuropathy screening instrument as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: Results from the diabetes control and complications trial/epidemiology of diabetes interventions and complications. Diabet. Med. 29, 937–944 (2012).
- Edin B. B., Bäckström P. A., Bäckström L. O., Single unit retrieval in microneurography: A microprocessor-based device controlled by an operator. J. Neurosci. Methods 24, 137–144 (1988).
Source: PubMed