The Journal of Neuroscience, March 1994, 14(3): 1756-1765 Differential Ability of Human Cutaneous Nociceptors to Signal Mechanical Pain and to Produce Vasodilatation Martin Koltzenburg’ and Hermann 0. HandwerkeP ‘Neurologische Universit%s-Klinik, D-97080 Wijrzburg, Germany and Ynstitut fijr Physiologie und Biokybernetik, Universitzt Erlangen-Ntirnberg, D-91054 Erlangen, Germany We investigated the ability of human nociceptive primary We conclude that human nociceptive C-fibers signal brief afferent neurons to encode mechanical pain and to produce noxious mechanical stimuli by the total number of action vasodilatation. Pain was induced by shooting a light metal potentials evoked during a short period of time. However, cylinder (0.3 g) at different velocities (6-l 6 m/set) perpen- with repetitive stimulation the total number of action poten- dicularly against the hairy skin of the hand. When single tials evoked from nociceptors is less important for evoking impact stimuli were applied, monotonically increasing stim- pain and temporal summation of the nociceptive primary ulus-response functions were obtained in 10 psychophys- afferent discharge becomes the crucial factor for signaling ical experiments using magnitude estimation techniques. In the magnitude of sensation. 35 microneurographic experiments nine unmyelinated~affer- [Key words: microneurography, low-threshold mechano- ents were recorded from the superficial radial nerve. All units receptors, hyperalgesia, central sensitization, windup, flare, responded readily to impact stimulation even at stimulus neurogenic vasodilatation] intensities that were not rated as painful. However, there was a close linear correlation between the number of action A central problem in the study of sensory systemsis how pri- potentials evoked from the nociceptors and the psycho- mary afferent activity and its processingby higher-order neurons physical magnitude estimates of the perceived sensation or relate to perception (Willis and Coggeshall, 1991). In the so- the stimulus intensity. This was also reflected by a corre- matosensorysystem the function of central pathways mediating sponding increase of neurogenic vasodilatation. While two tactile events is thought to conserve the presentation of a stim- thin myelinated afferents displayed qualitatively similar re- ulus dictated by the peripheral sensoryapparatus (Mountcastle, sponses 12 low-threshold mechanosensitive afferents (4 1984; Kandel and Jessell,199 1). This view has alsobeen adopt- rapidly adapting, 5 slowly adapting type I, 3 slowly adapting ed to explain acute stimulus induced pains. It has been found type II) failed to encode the intensity of the applied impact that the dischargeof nociceptive primary afferentsencodes many force and often became desensitized. This indicates that aspectsof the sensory discriminative component of acute stim- the total number of action potentials is the determinant of ulus-inducedpain (Campbell et al., 1989). Such closecorrelation the magnitude of mechanical pain and the associated va- has been repeatedly found when human psychophysical re- sodilatation following single brief stimuli. sponsesto noxious heat stimuli were compared with the recep- By contrast, the close correlation between nociceptor ac- tive properties of nociceptive afferents recorded from anesthe- tivity and sensation changed when trains of mechanical im- tized monkey (Meyer and Campbell, 1981; LaMotte et al., 1983; pact stimuli (five stimuli of constant intensity, intratrain fre- Robinson et al., 1983) or alert humans (Gybels et al., 1979; quency of l/32 to 2 Hz) were applied. Magnitude estimates LaMotte et al., 1982; Torebjork et al., 1984).These studieshave of pain intensity were frequency dependent and stimuli with short interstimulus intervals were perceived as more painful also determined that the increased pain perception following tissue injuries, notably mild burns, can be explained by the than those delivered with long intervals. However, the total number of action potentials evoked from C-fibers was higher correspondingchange of the stimulus-responsefunctions of no- ciceptive afferents (Meyer and Campbell, 198 1; LaMotte et al., at longer interstimulus intervals than shorter intervals, thus 1982, 1992; Torebjijrk et al., 1984). However, it is unclear yielding a negative correlation between the magnitude es- whether the concept that hasbeen developed for brief heat pain timates of the perceived painful sensation and the number stimuli appliesuniversally to all other modalities ofpain stimuli. of action potentials elicited from nociceptive afferents. This Other studies have also noted important discrepanciesbe- suggests that temporal summation of the nociceptive dis- tween the dischargepattern of nociceptors and the correspond- charge at central neurons becomes increasingly more im- ing sensations.Human nociceptive afferentsare often vigorously portant for the sensory discriminative experience of pain activated by mechanical stimuli that are not rated as painful evoked by repetitive stimulation. (Gybels et al., 1979; Van Hees and Gybels, 1981). Moreover. application of a constant level of noxious pressureover several Received Jan. 4, 1993; revised Aug. 9, 1993; accepted Sept. 9, 1993. minutes results in the gradual buildup of the pain rating, and We thank Dr. Lothar KohllGffel for designing the mechanical stimulator, Dr. Clemens Forster for supplying the software for the spike analysis, and Karl Burian although somefibers dischargeat low intensity when such stim- for his artwork. This work was supported by the Sonderforschungsbereich 353 of uli are applied outside the receptive field (Reeh et al., 1987) the Deutsche Forschungsgemeinschaft and the Marohn Stiftung. the discharge rate of most nociceptors actually decreasessig- Correspondence should be addressed to Martin Koltzenburg, Neurologische Universitats-Klinik, Josef-Schneider-Strasse 11, D-97800 Wiirzburg, Germany. nificantly (Adriaensen et al., 1984a; Handwerker et al., 1987). Copyright 0 1994 Society for Neuroscience 0270-6474/94/141756-10$05.00/O This suggeststhat the discharge rate of nociceptors is not The Journal of Neuroscience, March 1994, 14(3) 1757 always a good predictor for the perception of experimentally investigation. Because of the small mass of the cylinder, mainly the induced pain and emphasizes the importance of central nervous superficial layers of the skin are stimulated by this method (Kohlliiffel mechanisms of nociceptive processing for the consciously per- et al., 1991). Depending on the impact velocity of the bullet a short ceived magnitude of sensations. One factor that could account sensation of nonpainful touch or of pain is elicited. In previous studies we have determined that this technique provides a reliable and repro- for the differential relation of nociceptor discharge and pain ducible method for the application of a wide range of nonpainful and sensation is the coactivation of non-nociceptive afferents. While painful mechanical stimuli (Kohllijffel et al., 1991). noxious thermal stimuli would predominantly activate noci- Stimulus protocols. Two stimulation protocols were used. In the first ceptive afferents, noxious mechanical stimuli will also excite series of experiments stimulus-response functions were obtained for sensitive mechanoreceptors that are known to interact with the single impact stimuli. All stimuli were delivered to the dorsum of the hand using an interstimulus interval of 60 sec. In psychophysical ex- central processing of nociceptive inputs (Melzack and Wall, 1965; perimentsthe different stimulusintensities were presented in random Handwerker et al., 1975). Therefore, it remains unclear whether order. In microneurographic experiments the stimuli were given in as- this discrepancy between the nociceptor discharge and pain cendingorder of intensity.This procedurewas used as a precautionto magnitude is due to inherent properties of thermal or mechan- prevent dislodgement of the electrode and loss of the recording caused by small involuntary movements of the hand that occurred in some ical stimulus energies or whether it is the consequence of the subjects after application of stronger stimuli. As judged by the linear different stimulus duration. The knowledge of the relative im- correlation coefficients of the psychophysical stimulus-response func- portance of peripheral and central determinants of mechanical tions obtained in both experimental designs, there was no significant pain in normal tissue will also be important for the understand- difference between the ascending (range of individual coefficients, 0.92- ing of the increased sensitivity to mechanical stimuli that de- 1 .O; mean,0.93) or random(range of individual coefficients,0.90-l .O; mean, 0.92) stimulus presentation. The coefficients obtained in the pres- velops in injured skin (LaMotte et al., 199 1; Koltzenburg et al., ent investigation are also very similar to those of two independent sets 1992). of experiments that have previously found mean coefficients of 0.92 Apart from signaling nociceptive events, unmyelinated and and 0.94 (KohllBffel et al., 199 1). thin myelinated primary afferents have an efferent function. In the second series of experiments the effect of repetitive stimulation Excitation of cutaneous nociceptors produces a vasodilatation was investigated. Trains of five impact stimuli with a constant impact force of 14 m/set were applied at four different interstimulus intervals that spreads around a focal noxious stimulus (Chahl, 1988;