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Interaction between histamine-induced itch and experimental muscle pain
European Journal of Pain 8 (2004) 179–185 www.EuropeanJournalPain.com
Interaction between histamine-induced itch and experimental muscle pain G. Wasner
a,*
, K. Schwarz a, J. Schattschneider a, A. Binder a, T.S. Jensen b, R. Baron
a
a Klinik f€ur Neurologie, Christian-Albrechts-Universit€at Kiel, Kiel, Germany Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark
b
Received 28 October 2002; accepted 29 July 2003
Abstract Itch sensation can be inhibited by simultaneously applied cutaneous pain at the same skin site via a central mechanism. Deep muscle pain is often associated with sensory changes in the corresponding dermatome. We investigated whether experimentally induced muscle pain has any influence on histamine-induced itch and vice versa in a double blind placebo-controlled study. Experiments were performed in 18 healthy subjects. In nine individuals control iontophoresis of histamine into the forearm produced a distinct itch sensation. Another nine individuals participated in an additional experiment in which histamine and saline were iontophoresed on the forearm in a randomized double-blinded two-way crossover design after intramuscular injection of capsaicin into the ipsilateral brachioradial muscle. Capsaicin-induced muscle pain reduced itch sensation significantly. In contrast, capsaicininduced muscle pain increased significantly after cutaneous histamine application compared to muscle pain after iontophoresis of saline (placebo). These novel data indicate that muscle pain inhibits itch and histamine increases muscle pain. A bi-directional interaction between cutaneous histamine-sensitive afferents and nociceptive muscle afferents via central mechanisms is suggested. Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Capsaicin; Histamine; Itch; Nociceptor; Skeletal muscle pain
1. Introduction Cutaneous application of histamine induces an itch sensation due to activation of histamine-sensitive C-fiber afferents (Schmelz et al., 1997). The evidence for itchspecific central afferent neurons suggested the existence of a seperate neural system mediating itch-sensations (Andrew and Craig, 2001; Schmelz, 2001). Interestingly, cutaneous pain inhibits itch if both sensations are applied to the same skin site (Bickford, 1937; Graham et al., 1951). It has been demonstrated that painful chemical or electrical stimulation of the skin can reduce histamine induced itch locally for hours (Ward et al., 1996; Nilsson et al., 1997; Brull et al., 1999; Baron et al., 2001). This phenomenon is explained by the effect of central inhibitory projections from cutaneous nocicep*
Corresponding author. Tel.: +49-431-597-2633; fax: +49-431-5972712. E-mail address: [email protected] (G. Wasner).
tive neurons on itch mediating pathways and might be utilized for treatment in patients suffering from itch (Nilsson et al., 1997; Schmelz, 2001). It is not clear whether also pain from other tissues like deep muscle pain interferes with cutaneous itch sensation. A classical clinical feature of musculo-skeletal pain disorders is the occurrence of cutaneous sensory changes in the skin overlying the painful muscle and in referred pain areas (Travell and Simons, 1982). Besides the development of referral pain areas, alterations of cutaneous perception were also observed in the area of primary muscle pain. In patients with temporomandibular disorders and cervicobrachialgia an increased mechanical threshold was found (Hollins et al., 1996; Voerman et al., 2000). Laitinen (1982) described cutaneous hypalgesia in a patient with deep musculo-skeletal pain. The disappearance of the sensory deficit in this patient after inhibition of muscle pain by local anesthesia points to a central functional interaction between nociceptive muscle and sensory afferents.
1090-3801/$30 Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/S1090-3801(03)00099-5
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After experimentally induced muscle pain by intramuscular injection of hypertonic saline cutaneous hypoesthesia to pinprick and touch stimulation developed around the site of applicated saline (Graven-Nielsen et al., 1997; Stohler et al., 2001). It was suggested that muscle nociceptors activated central inhibitory pathways suppressing transmission from cutaneous afferents (Stohler et al., 2001). Interestingly, no significant cutaneous sensory changes to nociceptive C-fiber stimulation by heat were found (Graven-Nielsen et al., 1997). On the other hand cutaneous hyperalgesia has also been observed in both experimental muscle pain and in patients with muskulo-skeletal pain disorders (Travell and Simons, 1982; Svensson et al., 1998). Taken together these findings suggest an interaction between activity in small fibers from deep and superficial tissue. In this study we hypothesize that the sensory perception by activation of cutaneous itch fibers is modulated by activity in deep muscle nociceptive afferents. Furthermore, we investigated whether the muscle pain is affected by the activated itch fibers. Hence, muscle pain and itch sensation were measured during cutaneous histamine application after intramuscular injection of capsaicin in a placebo controlled double-blind study.
rating the intensity on a numeric rating scale (NRS 0–10, with 0 representing ‘‘Õno pain’’ and 10 being ‘‘the maximum pain that can be imagined’’) for 10 min by asking the subjects every minute to rate the pain. Quality of muscle pain was documented by using the following descriptors from the McGill pain questionnaire: burning, cramping, dull, itching, like sore muscle, shooting, stinging, tingling, throbbing, and wrenching. The term ‘‘like sore muscle’’ was added because of the experience in other investigations (Wasner et al., 2002). 2.3. Induction and assessment of itch sensation Itch sensation was induced by iontophoretic intracutaneous application of histamine (histamine hydrochlorid 1%, charge 14 mC: 700 lA for 20 s) about 2–3 cm medial from the site of capsaicin-injection. Iontophoresis of 0.9% saline was performed as placebo control for histamine application during muscle pain (see Section 2.4). Intensity of sensations due to iontophoresis of histamine and placebo were quantified on a numeric rating scale (NRS 0–10) for 7 min by asking the subjects every minute for rating. Furthermore, individuals noted the quality of histamine-evoked sensations by using descriptors from the McGill pain questionnaire (see Section 2.2).
2. Materials and methods 2.4. Experimental protocol 2.1. Individuals Eighteen healthy volunteers participated in the experiments. The individuals were tested in supine position at room temperature (24 °C). In nine individuals (two women, seven men; mean age 30.2 2.6 years) control application of histamine was performed, in another nine sex and aged matched individuals (two women, seven men; mean age 30.9 2.7 years) histamine and saline (placebo) were given during capsaicin-induced muscle pain. The aim of the study and the nature of the tests were explained to the individuals according to the Helsinki Declaration. The study was approved by the local ethical committee. All volunteers gave their informed consent to participate in the study. 2.2. Induction and assessment of experimental muscle pain Muscle pain was induced by intramuscular injection of 50 ll of a solution containing 25 lg capsaicin into the brachioradial muscle 5 cm below the elbow (Witting et al., 2000; Wasner et al., 2002). Capsaicin was prepared by pharmacists (Kieler Hofapotheke, Kiel, Germany) as described previously (LaMotte et al., 1992; Baron et al., 1999). Intramuscular capsaicin injection induced a deep muscle pain at the injection site that was quantified by
Nine individuals rated itch sensation during control histamine application in the forearm. In another nine individuals capsaicin injection was performed twice in each individual in a randomized double-blinded twoway crossover procedure: (1) into one brachioradial muscle followed by cutaneous iontophoresis of histamine after three minutes and (2) into the contralateral brachioradial muscle followed by cutaneous iontophoresis of 0.9% saline (placebo) after 3 min. Neither the individuals nor the investigators were aware whether histamine or saline was iontophoresed first, because substances were encoded by a technical assistent. Areas of iontophoresis were covered in order to avoid detection of flare reaction as a sign for application of histamine. The right and left forearm were alternated for the first injection in each experiment. The intertrial interval between the two capsaicin injections was 30 min. There was no remaining spontaneous pain when the second injection was performed. 2.5. Data acquisation and analysis Intensity (NRS 0–10) and quality (McGill pain questionnaire) of histamine-induced sensations and capsaicin-induced local muscle pain were documented at 1 min intervals. Data are given as mean values SEM.
G. Wasner et al. / European Journal of Pain 8 (2004) 179–185
The U test was used to compare the intensity of sensations during control iontophoresis of histamine with the intensity of histamine-induced sensations during capsaicin-evoked deep muscle pain on the one hand and with the intensity of saline-induced sensations during capsaicin-evoked deep muscle pain on the other hand (unpaired data). The Wilcoxon-test was used to compare the intensity of histamine-induced sensations during capsaicin-evoked deep muscle pain with the intensity of saline-induced sensations during capsaicinevoked deep muscle pain and for the comparison between the intensity of capsaicin-evoked deep muscle pain following cutaneous iontophoresis of histamine and the intensity of capsaicin-evoked deep muscle pain following iontophoresis of saline (paired data). p values of <0.05 were regarded as statistically significant.
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iontophoresis of histamine. Five individuals reported a moderate tingling and only one felt a slight itch sensation. Sensations decreased rapidly after application. On average, the intensity of histamine-induced sensations was significantly decreased during deep muscle pain in comparison to control iontophoresis of histamine (p < 0:001). The differences ranged from NRS 3.3 0.4 (control histamine) versus NRS 1.0 0.3 (histamine following capsaicin) to NRS 1.3 0.3 (control histamine) versus NRS 0 (histamine following capsaicin) (Fig. 1). Intensity of histamine-induced sensation during muscle pain was not significantly different from sensory changes due to iontophoresis of saline that served as placebo control (Fig. 1). Furthermore, quality of sensations were almost identical: four individuals had no cutaneous sensation following saline-application during muscle pain, four noticed a moderate tingling and one felt a slight itch.
3. Results 3.2. Effect of histamine on capsaicin-induced muscle pain 3.1. Effect of muscle pain on histamine-induced sensations
NRS (histamine/saline-induced sensations)
Control iontophoresis of histamine in the forearm produced a distinct itch sensation in all individuals that decreased continuously after application (Fig. 1). Additionally, six individuals described an initial short lasting tingling sensation that was probably due to the current of iontophoresis. These results are in good correlation with data in the literature describing the effect of histamine iontophoresis (Heyer et al., 1989; Schmelz et al., 1997; Baron et al., 2001). Histamine-induced sensations changed during capsaicin-evoked deep muscle pain: Three of the nine individuals had no cutaneous sensation at all following
Immediately after capsaicin-injection into the brachioradial muscle individuals felt a deep pain described as dull, stinging and sore at the site of capsaicin injection. Additionally, three individuals felt an initial short lasting burning sensation, probably due to cutaneous stimulation by a small amount of capsaicin during syringe penetration through the skin. Deep muscle pain decreased continuously after capsaicin injection. However, cutaneous iontophoresis of histamine three minute after intramuscular capsaicin had an enhancing effect on deep muscle pain (Figs. 2 and 3): pain intensity increased significantly by a value of about NRS 1.5 in
* **
4
2
0 0
1
min
7
Histamine/Saline
Fig. 1. Histamine-induced sensations in controls and during deep muscle pain. In controls (rhombuses, n ¼ 9) iontophoresis of histamine (arrow) induced a distinct itch sensation that decreased continuously after application. Intensity of histamine-evoked sensations decreased significantly during capsaicin-induced muscle pain (squares, n ¼ 9), but were not significant different from saline-induced sensations (triangles, n ¼ 9) during deep muscle pain. NRS, numeric rating scale. Mean SEM. ***p < 0:001.
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multiple comparison procedure, because the findings are due to a post hoc analysis (Saville, 1990). Changes in pain quality were not observed neither after cutaneous histamine nor after saline.
NRS (muscle pain)
8
*
* 4
4. Discussion
0
5
0
Capsaicin
min
10
Histamine/Saline
Fig. 2. Effect of histamine on capsaicin-induced muscle pain. Intramuscular injection of capsaicin (arrow-capsaicin) induced a deep muscle pain that decreased continuously after application. Three minutes after capsaicin histamine (squares) or saline (triangles) were iontophoresed (arrow-histamine/saline) in a randomized double-blinded two-way crossover design. Histamine led to a moderate, but significant increase in muscle pain for a few minutes whereas pain was not effected by saline. NRS, numeric rating scale. Mean SEM. *p < 0:05.
*
NRS-changes in % (muscle pain)
250
200
100
0
5
0
Capsaicin
min
10
Histamine/Saline
Fig. 3. Effect of histamine on capsaicin-induced muscle pain expressed by percentual changes of numeric rating scale (NRS) values. The individual pain ratings in the ‘‘capsaicin + histamine series’’ (squares) were expressed as percentage compared to the ratings in the ‘‘capsaicin + saline’’ series that were set 100% as baseline (dotted line). Intramuscular injection of capsaicin (arrow-capsaicin) induced a deep muscle pain that was not significant different during both series until histamine/saline was iontophorized (arrow). Histamine iontophoresis was followed by a significant increase in muscle pain for a few minutes compared to muscle pain following saline application. Mean SEM. *p < 0:05.
the first minutes after histamine application compared to muscle pain after iontophoresis of saline (p < 0:05) (Fig. 2). This corresponded to an averaged percentual increase of NRS values of about 100%, when the individual pain ratings in the ‘‘capsaicin + saline’’ series was set 100% as baseline (Fig. 3). These results are based on the Wilcoxon-test without performing an additional
The experiments resulted in two different findings: First, histamine-induced cutaneous itch sensation was abolished by capsaicin-evoked deep muscle pain. Secondly, intensity of deep muscle pain increased after cutaneous histamine application. This indicates a bi-directional interaction between cutaneous histaminesensitive afferents and nociceptive muscle afferents. 4.1. Inhibition of itch sensation by muscle pain Iontophoresis of histamine into the skin of the forearm in healthy volunteers evoked a distinct itch sensation that was nearly completely absent during capsaicin-induced muscle pain in the brachioradial muscle. Until now the phenomenon of an inhibited itch sensation was described exclusively when cutaneous pain was applied to the same skin site (Bickford, 1937; Graham et al., 1951). Histamine-induced itch was significantly reduced during chemical activation of cutaneous nociceptors by topical application of mustard oil and capsaicin also when histamine was applied in the area of primary and secondary hyperalgesia (Ward et al., 1996; Brull et al., 1999; Wasner et al., 1999; Baron et al., 2001). Ward et al. (1996) found a decreased itch sensation due to noxious heat stimuli. Furthermore, stimulation of nociceptive C-fibers by cutaneous field stimulation abolished ipsilateral itch significantly for many hours (Nilsson et al., 1997). There is strong evidence from recent research that itch and pain are conducted in seperate peripheral and central pathways (Schmelz et al., 1997; Andrew and Craig, 2001; Schmelz, 2001). It is suggested that a specialized subset of itch-mediating C-units (mechanoinsensitive and heat-sensitive fibers) are the primary afferents that exclusively respond to histamine (Schmelz et al., 1997). Therefore, a peripheral mechanism that might cause an inhibition of itch by pain can be ruled out and an interaction within the central nervous system, probably at spinal cord level, has been suggested, though a supraspinal coupling might be also possible (Ward et al., 1996; Brull et al., 1999; Baron et al., 2001). It is postulated that inhibitory projections from nociceptive neurons in the dorsal horn project on itch mediating pathways (Fig. 4). The present data demonstrated that such an interaction seems to exist not only between afferents originating from the same tissue, but also between muscle pain and cutaneous itch. Therefore, it is hypothesized that nociceptive input from different
G. Wasner et al. / European Journal of Pain 8 (2004) 179–185 Itch
Muscle pain Central afferents
Dorsal horn
Peripheral afferents
Histamine Capsaicin
Fig. 4. Schematic drawing illustrating the interaction between activated cutaneous itch fibers and muscle nociceptors. Itch conducting specific primary afferents were activated by histamine (left side) and primary muscle nociceptors were activated by capsaicin (right side). Both project to their spinal secondary order afferents in the dorsal horn. Level of neuronal activity is illustrated by different flash sizes. Activity in central nociceptive muscle afferents inhibits the discharge of central itch conducting fibers in the dorsal horn (dark arrow). Activity in primary itch fibers facilitates activity in spinal nociceptors (bright arrow).
tissues might project on the same central inhibitory pathway that suppresses activity in itch-mediating fibers. A spinal inhibition seems to be also the origin for the reduced perception of other sensory qualities induced by muscle pain in patients and experimental pain models (Laitinen, 1982; Travell and Simons, 1982; Hollins et al., 1996; Graven-Nielsen et al., 1997; Voerman et al., 2000; Stohler et al., 2001). However, it is not clear, whether the same spinal neuronal pathways are responsible for decreasing itch sensation and the other sensory deficits. The observation from Graven-Nielsen et al. (1997) that heat perception by activation of heat sensitive C-fibers is not changed during muscle pain argues against such a common pathway and favors a special interaction between itch-mediating C-units and nociceptors from deep tisssue. 4.2. Histamine-induced increase in muscle pain Cutaneous iontophoresis of histamine in the forearm three minutes after intramuscular injection of capsaicin into the brachioradial muscle led to a significant increase in deep muscle pain compared to pain after iontophoresis of saline. This is the first evidence that activity in cutaneous sensory afferents enhances local muscle pain. However, because the effect was moderate and lasted for only a few minutes, several methodological issues need to be discussed before this notion is accepted:
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(1) Rating of intensity of sensations is a psychophysiological approach. Therefore, distraction is an important factor influencing perception, especially when two different sensations were rated simultaneously (deep muscle pain and histamine/saline-induced sensations). However, distraction by iontophoresis of histamine/saline would rather have led to a decreased intensity of deep muscle pain than to an increased perception (Ward et al., 1996). Furthermore, both histamine and saline were iontophoresed in a randomized double-blinded procedure and had therefore probably the same effect of distraction. (2) Another aspect is the difficulty to distinguish between two different sensations presented at the same time so that the supposed increase in muscle pain might be an added histamine-evoked direct cutaneous sensation. The affirmation of all individuals of the present study that they rated a pure deep muscle pain that was not altered in quality after histamine application and that could have been clearly distinguished from additional superficial sensations after histamine argues against this suggestion. Likewise, itch and pain sensations were clearly distinguishable also in other studies when they were presented simultaneously (Ward et al., 1996; Nilsson et al., 1997; Brull et al., 1999; Wasner et al., 1999). (3) Finally, blinding concerning iontophoresis of histamine and saline that served as placebo might be insufficient. However, by encoding substances for iontophoresis by a technical assistent and by covering the areas of iontophoresis in order to avoid detection of histamine-induced flare reaction neither the individuals nor the investigators were aware whether histamine or saline was iontophoresed. Even estimation of cutaneous sensations after iontophoresis gave no evidence which substance was given, because intensity and quality of histamine- and saline-evoked sensations were not significantly different during deep muscle pain. In summary, it is unlikely that methodological issues are responsible for the increased muscle pain after histamine. However, an additional multiple comparison procedure was not performed in the statistical analysis, because the findings are the result of a post hoc analysis (Saville, 1990). Therefore, the design of further studies to investigate the present findings in more detail have to include the use of a multiple comparison procedure. Atanassoff et al. (1999) observed that intracutaneous histamine injection was sometimes accompanied by an additional sensation of pain. They postulated that histamine acts not only on itch transducing afferents but also on peripheral nociceptors. Such an histamineinduced activation of cutaneous nociceptive afferents might led to additional pain after histamine application during capsaicin-induced deep muscle pain in the present study. However, none of the subject noticed any pain sensation during control-iontophoresis of
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histamine in our experiments. Furthermore, the subjects noticed an increase in deep muscle pain following histamine application nor with any change in pain quality neither with any additional sensation of superficial pain. Therefore, it is unlikely that a summation of different peripheral pains is responsible for the histamine-induced increase in muscle pain in the present study. Histamine-induced pain has been also observed in patients suffering from postherpetic neuralgia when histamine was applied in hyperalgesic skin (Baron et al., 2001). It is suggested that irritable primary afferent nociceptors have changed their peripheral transduction processes after zoster inflammation, e.g. they might start to express novel histamine receptors at their membranes. Alternatively, specific primary afferent histamine sensitive C-fibers may gain synaptical access to pain signalling second order neurons in the spinal cord (Baron et al., 2001). A similar spinal interaction may be involved in the increase of muscle pain following histamine in the present study. It is suggested that activity in primary afferent histamine-sensitive fibers facilitates activity in second order muscle nociceptors (Fig. 4). It may be speculated that these central nociceptors are wide-dynamic range (WDR) neurons that were sensitized following capsaicin-induced primary sensitization of peripheral muscle nociceptive afferents. A projection originating from central itch conducting fibers on central nociceptive afferents is unlikely, because the activity of the central itch fibers is nearly completely abolished by the influence from central muscle nociceptors as described above. Interestingly, also referred pain, a common phenomenon in experimentally induced muscle pain, defined as a pain distinct from the pain at the injection site seems to depend on cutaneous sensory input. Laursen et al. (1997) observed that pretreatment of the referred pain area with a local anaesthetic cream decreased intensity of electrically induced referred muscle pain. It should be noted that there was no spontaneous activity from the skin which could be blocked. However, in the present study the investigated skin and muscle areas are located within the same dermatome and myotome, respectively, so that the underlying mechanisms might differ from that in referred pain areas. In conclusion, the present bi-directional effect of histamine-induced itch and capsaicin-induced muscle pain points to a spinal mechanism. It is suggested that inhibitory projections from nociceptive neurons in the dorsal horn project on itch mediating pathways. Furthermore, activity in primary itch fibers facilitates activity in central nociceptors (Fig. 4). Whether the described interactions are pre- or postsynaptic processes and whether interneurons are involved cannot be answered by this study. Further research is needed to investigate the presented findings in more detail.
Acknowledgements We appreciate the technical assistance of Nicoleta Blunck. We also thank Dr. Lars Friege from the Department of Psychiatry, University Kiel, for editing the statistical analysis. This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1-2), the Bundesministerium f€ ur Bildung und Forschung (BMBF Forschungsverbund ‘‘Neuropathischer Schmerz’’) and the German-Danish exchange programme of the Christian-Albrechts-Universit€at Kiel.
References Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001;4:72–7. Atanassoff PG, Brull SJ, Zhang J, Greenquist K, Silverman DG, Lamotte RH. Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Mot Res 1999;16:291–8. Baron R, Schwarz K, Kleinert A, Schattschneider J, Wasner G. Histamine-induced itch converts into pain in neuropathic hyperalgesia. NeuroReport 2001;12:3475–8. Baron R, Wasner G, Borgstedt R, et al. Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation. Neurology 1999;52:923–32. Bickford MJ. Experiments relation to the itch sensation – its peripheral mechanism, and central pathways. Clin Sci 1937;3:377–86. Brull SJ, Atanassoff PG, Silverman DG, Zhang J, Lamotte RH. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res 1999;16:299–303. Graham DT, Goodell H, Woolf HG. Neural mechanisms involved in itch, itchy skin, and tickle sensations. J Clin Invest 1951;30: 37–49. Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS. Experimental muscle pain: a quantitative study of local and referred pain in humans following injection of hypertonic saline. J Musculoskeletal Pain 1997;5:49–69. Heyer G, Hornstein OP, Handwerker HO. Skin reactions and itch sensation induced by epicutaneous histamine application in atopic dermatitis and controls. J Invest Dermatol 1989;93: 492–6. Hollins M, Sigurdsson A, Fillingim L, Goble AK. Vibrotactile threshold is elevated in temporomandibular disorders. Pain 1996;67:89–96. Laitinen LV. Inhibition of cutaneous nociception by deep musculoskeletal pain. A clinical observation. Pain 1982;13:373–7. LaMotte RH, Lundberg LE, Torebj€ ork HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol (Lond) 1992;448:749–64. Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L. Referred pain is denpendent on sensory input from the periphery: a psychophysiological study. Eur J Pain 1997;1:261–7. Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain 1997;71:49–55. Saville DJ. Multiple comparison procedures: the practical solution. Am Statist 1990;44:174–80. Schmelz M. A neural pathway for itch. Nat Neurosci 2001;4:9–10. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE. Specific C-receptors for itch in human skin. J Neurosci 1997;17:8003–8.
G. Wasner et al. / European Journal of Pain 8 (2004) 179–185 Stohler CS, Kowalski CJ, Lund JP. Muscle pain inhibits cutaneous touch perception. Pain 2001;92:327–33. Svensson P, Graven-Nielsen T, Arendt-Nielsen L. Mechanical hyperesthesia of human facial skin induced by tonic painful stimulation of jaw muscles. Pain 1998;74:93–100. Travell JG, Simons DG. In: Myofascial pain and dysfunction The trigger point manual, vol. 1. Baltimore: Williams & Williams; 1982. Voerman VF, van Egmond J, Crul BJ. Elevated detection thresholds for mechanical stimuli in chronic pain patients: support for a central mechanism. Arch Phys Med Rehabil 2000;81: 430–5.
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Interaction between histamine-induced itch and experimental muscle pain G. Wasner
a,*
, K. Schwarz a, J. Schattschneider a, A. Binder a, T.S. Jensen b, R. Baron
a
a Klinik f€ur Neurologie, Christian-Albrechts-Universit€at Kiel, Kiel, Germany Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark
b
Received 28 October 2002; accepted 29 July 2003
Abstract Itch sensation can be inhibited by simultaneously applied cutaneous pain at the same skin site via a central mechanism. Deep muscle pain is often associated with sensory changes in the corresponding dermatome. We investigated whether experimentally induced muscle pain has any influence on histamine-induced itch and vice versa in a double blind placebo-controlled study. Experiments were performed in 18 healthy subjects. In nine individuals control iontophoresis of histamine into the forearm produced a distinct itch sensation. Another nine individuals participated in an additional experiment in which histamine and saline were iontophoresed on the forearm in a randomized double-blinded two-way crossover design after intramuscular injection of capsaicin into the ipsilateral brachioradial muscle. Capsaicin-induced muscle pain reduced itch sensation significantly. In contrast, capsaicininduced muscle pain increased significantly after cutaneous histamine application compared to muscle pain after iontophoresis of saline (placebo). These novel data indicate that muscle pain inhibits itch and histamine increases muscle pain. A bi-directional interaction between cutaneous histamine-sensitive afferents and nociceptive muscle afferents via central mechanisms is suggested. Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Capsaicin; Histamine; Itch; Nociceptor; Skeletal muscle pain
1. Introduction Cutaneous application of histamine induces an itch sensation due to activation of histamine-sensitive C-fiber afferents (Schmelz et al., 1997). The evidence for itchspecific central afferent neurons suggested the existence of a seperate neural system mediating itch-sensations (Andrew and Craig, 2001; Schmelz, 2001). Interestingly, cutaneous pain inhibits itch if both sensations are applied to the same skin site (Bickford, 1937; Graham et al., 1951). It has been demonstrated that painful chemical or electrical stimulation of the skin can reduce histamine induced itch locally for hours (Ward et al., 1996; Nilsson et al., 1997; Brull et al., 1999; Baron et al., 2001). This phenomenon is explained by the effect of central inhibitory projections from cutaneous nocicep*
Corresponding author. Tel.: +49-431-597-2633; fax: +49-431-5972712. E-mail address: [email protected] (G. Wasner).
tive neurons on itch mediating pathways and might be utilized for treatment in patients suffering from itch (Nilsson et al., 1997; Schmelz, 2001). It is not clear whether also pain from other tissues like deep muscle pain interferes with cutaneous itch sensation. A classical clinical feature of musculo-skeletal pain disorders is the occurrence of cutaneous sensory changes in the skin overlying the painful muscle and in referred pain areas (Travell and Simons, 1982). Besides the development of referral pain areas, alterations of cutaneous perception were also observed in the area of primary muscle pain. In patients with temporomandibular disorders and cervicobrachialgia an increased mechanical threshold was found (Hollins et al., 1996; Voerman et al., 2000). Laitinen (1982) described cutaneous hypalgesia in a patient with deep musculo-skeletal pain. The disappearance of the sensory deficit in this patient after inhibition of muscle pain by local anesthesia points to a central functional interaction between nociceptive muscle and sensory afferents.
1090-3801/$30 Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/S1090-3801(03)00099-5
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After experimentally induced muscle pain by intramuscular injection of hypertonic saline cutaneous hypoesthesia to pinprick and touch stimulation developed around the site of applicated saline (Graven-Nielsen et al., 1997; Stohler et al., 2001). It was suggested that muscle nociceptors activated central inhibitory pathways suppressing transmission from cutaneous afferents (Stohler et al., 2001). Interestingly, no significant cutaneous sensory changes to nociceptive C-fiber stimulation by heat were found (Graven-Nielsen et al., 1997). On the other hand cutaneous hyperalgesia has also been observed in both experimental muscle pain and in patients with muskulo-skeletal pain disorders (Travell and Simons, 1982; Svensson et al., 1998). Taken together these findings suggest an interaction between activity in small fibers from deep and superficial tissue. In this study we hypothesize that the sensory perception by activation of cutaneous itch fibers is modulated by activity in deep muscle nociceptive afferents. Furthermore, we investigated whether the muscle pain is affected by the activated itch fibers. Hence, muscle pain and itch sensation were measured during cutaneous histamine application after intramuscular injection of capsaicin in a placebo controlled double-blind study.
rating the intensity on a numeric rating scale (NRS 0–10, with 0 representing ‘‘Õno pain’’ and 10 being ‘‘the maximum pain that can be imagined’’) for 10 min by asking the subjects every minute to rate the pain. Quality of muscle pain was documented by using the following descriptors from the McGill pain questionnaire: burning, cramping, dull, itching, like sore muscle, shooting, stinging, tingling, throbbing, and wrenching. The term ‘‘like sore muscle’’ was added because of the experience in other investigations (Wasner et al., 2002). 2.3. Induction and assessment of itch sensation Itch sensation was induced by iontophoretic intracutaneous application of histamine (histamine hydrochlorid 1%, charge 14 mC: 700 lA for 20 s) about 2–3 cm medial from the site of capsaicin-injection. Iontophoresis of 0.9% saline was performed as placebo control for histamine application during muscle pain (see Section 2.4). Intensity of sensations due to iontophoresis of histamine and placebo were quantified on a numeric rating scale (NRS 0–10) for 7 min by asking the subjects every minute for rating. Furthermore, individuals noted the quality of histamine-evoked sensations by using descriptors from the McGill pain questionnaire (see Section 2.2).
2. Materials and methods 2.4. Experimental protocol 2.1. Individuals Eighteen healthy volunteers participated in the experiments. The individuals were tested in supine position at room temperature (24 °C). In nine individuals (two women, seven men; mean age 30.2 2.6 years) control application of histamine was performed, in another nine sex and aged matched individuals (two women, seven men; mean age 30.9 2.7 years) histamine and saline (placebo) were given during capsaicin-induced muscle pain. The aim of the study and the nature of the tests were explained to the individuals according to the Helsinki Declaration. The study was approved by the local ethical committee. All volunteers gave their informed consent to participate in the study. 2.2. Induction and assessment of experimental muscle pain Muscle pain was induced by intramuscular injection of 50 ll of a solution containing 25 lg capsaicin into the brachioradial muscle 5 cm below the elbow (Witting et al., 2000; Wasner et al., 2002). Capsaicin was prepared by pharmacists (Kieler Hofapotheke, Kiel, Germany) as described previously (LaMotte et al., 1992; Baron et al., 1999). Intramuscular capsaicin injection induced a deep muscle pain at the injection site that was quantified by
Nine individuals rated itch sensation during control histamine application in the forearm. In another nine individuals capsaicin injection was performed twice in each individual in a randomized double-blinded twoway crossover procedure: (1) into one brachioradial muscle followed by cutaneous iontophoresis of histamine after three minutes and (2) into the contralateral brachioradial muscle followed by cutaneous iontophoresis of 0.9% saline (placebo) after 3 min. Neither the individuals nor the investigators were aware whether histamine or saline was iontophoresed first, because substances were encoded by a technical assistent. Areas of iontophoresis were covered in order to avoid detection of flare reaction as a sign for application of histamine. The right and left forearm were alternated for the first injection in each experiment. The intertrial interval between the two capsaicin injections was 30 min. There was no remaining spontaneous pain when the second injection was performed. 2.5. Data acquisation and analysis Intensity (NRS 0–10) and quality (McGill pain questionnaire) of histamine-induced sensations and capsaicin-induced local muscle pain were documented at 1 min intervals. Data are given as mean values SEM.
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The U test was used to compare the intensity of sensations during control iontophoresis of histamine with the intensity of histamine-induced sensations during capsaicin-evoked deep muscle pain on the one hand and with the intensity of saline-induced sensations during capsaicin-evoked deep muscle pain on the other hand (unpaired data). The Wilcoxon-test was used to compare the intensity of histamine-induced sensations during capsaicin-evoked deep muscle pain with the intensity of saline-induced sensations during capsaicinevoked deep muscle pain and for the comparison between the intensity of capsaicin-evoked deep muscle pain following cutaneous iontophoresis of histamine and the intensity of capsaicin-evoked deep muscle pain following iontophoresis of saline (paired data). p values of <0.05 were regarded as statistically significant.
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iontophoresis of histamine. Five individuals reported a moderate tingling and only one felt a slight itch sensation. Sensations decreased rapidly after application. On average, the intensity of histamine-induced sensations was significantly decreased during deep muscle pain in comparison to control iontophoresis of histamine (p < 0:001). The differences ranged from NRS 3.3 0.4 (control histamine) versus NRS 1.0 0.3 (histamine following capsaicin) to NRS 1.3 0.3 (control histamine) versus NRS 0 (histamine following capsaicin) (Fig. 1). Intensity of histamine-induced sensation during muscle pain was not significantly different from sensory changes due to iontophoresis of saline that served as placebo control (Fig. 1). Furthermore, quality of sensations were almost identical: four individuals had no cutaneous sensation following saline-application during muscle pain, four noticed a moderate tingling and one felt a slight itch.
3. Results 3.2. Effect of histamine on capsaicin-induced muscle pain 3.1. Effect of muscle pain on histamine-induced sensations
NRS (histamine/saline-induced sensations)
Control iontophoresis of histamine in the forearm produced a distinct itch sensation in all individuals that decreased continuously after application (Fig. 1). Additionally, six individuals described an initial short lasting tingling sensation that was probably due to the current of iontophoresis. These results are in good correlation with data in the literature describing the effect of histamine iontophoresis (Heyer et al., 1989; Schmelz et al., 1997; Baron et al., 2001). Histamine-induced sensations changed during capsaicin-evoked deep muscle pain: Three of the nine individuals had no cutaneous sensation at all following
Immediately after capsaicin-injection into the brachioradial muscle individuals felt a deep pain described as dull, stinging and sore at the site of capsaicin injection. Additionally, three individuals felt an initial short lasting burning sensation, probably due to cutaneous stimulation by a small amount of capsaicin during syringe penetration through the skin. Deep muscle pain decreased continuously after capsaicin injection. However, cutaneous iontophoresis of histamine three minute after intramuscular capsaicin had an enhancing effect on deep muscle pain (Figs. 2 and 3): pain intensity increased significantly by a value of about NRS 1.5 in
* **
4
2
0 0
1
min
7
Histamine/Saline
Fig. 1. Histamine-induced sensations in controls and during deep muscle pain. In controls (rhombuses, n ¼ 9) iontophoresis of histamine (arrow) induced a distinct itch sensation that decreased continuously after application. Intensity of histamine-evoked sensations decreased significantly during capsaicin-induced muscle pain (squares, n ¼ 9), but were not significant different from saline-induced sensations (triangles, n ¼ 9) during deep muscle pain. NRS, numeric rating scale. Mean SEM. ***p < 0:001.
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multiple comparison procedure, because the findings are due to a post hoc analysis (Saville, 1990). Changes in pain quality were not observed neither after cutaneous histamine nor after saline.
NRS (muscle pain)
8
*
* 4
4. Discussion
0
5
0
Capsaicin
min
10
Histamine/Saline
Fig. 2. Effect of histamine on capsaicin-induced muscle pain. Intramuscular injection of capsaicin (arrow-capsaicin) induced a deep muscle pain that decreased continuously after application. Three minutes after capsaicin histamine (squares) or saline (triangles) were iontophoresed (arrow-histamine/saline) in a randomized double-blinded two-way crossover design. Histamine led to a moderate, but significant increase in muscle pain for a few minutes whereas pain was not effected by saline. NRS, numeric rating scale. Mean SEM. *p < 0:05.
*
NRS-changes in % (muscle pain)
250
200
100
0
5
0
Capsaicin
min
10
Histamine/Saline
Fig. 3. Effect of histamine on capsaicin-induced muscle pain expressed by percentual changes of numeric rating scale (NRS) values. The individual pain ratings in the ‘‘capsaicin + histamine series’’ (squares) were expressed as percentage compared to the ratings in the ‘‘capsaicin + saline’’ series that were set 100% as baseline (dotted line). Intramuscular injection of capsaicin (arrow-capsaicin) induced a deep muscle pain that was not significant different during both series until histamine/saline was iontophorized (arrow). Histamine iontophoresis was followed by a significant increase in muscle pain for a few minutes compared to muscle pain following saline application. Mean SEM. *p < 0:05.
the first minutes after histamine application compared to muscle pain after iontophoresis of saline (p < 0:05) (Fig. 2). This corresponded to an averaged percentual increase of NRS values of about 100%, when the individual pain ratings in the ‘‘capsaicin + saline’’ series was set 100% as baseline (Fig. 3). These results are based on the Wilcoxon-test without performing an additional
The experiments resulted in two different findings: First, histamine-induced cutaneous itch sensation was abolished by capsaicin-evoked deep muscle pain. Secondly, intensity of deep muscle pain increased after cutaneous histamine application. This indicates a bi-directional interaction between cutaneous histaminesensitive afferents and nociceptive muscle afferents. 4.1. Inhibition of itch sensation by muscle pain Iontophoresis of histamine into the skin of the forearm in healthy volunteers evoked a distinct itch sensation that was nearly completely absent during capsaicin-induced muscle pain in the brachioradial muscle. Until now the phenomenon of an inhibited itch sensation was described exclusively when cutaneous pain was applied to the same skin site (Bickford, 1937; Graham et al., 1951). Histamine-induced itch was significantly reduced during chemical activation of cutaneous nociceptors by topical application of mustard oil and capsaicin also when histamine was applied in the area of primary and secondary hyperalgesia (Ward et al., 1996; Brull et al., 1999; Wasner et al., 1999; Baron et al., 2001). Ward et al. (1996) found a decreased itch sensation due to noxious heat stimuli. Furthermore, stimulation of nociceptive C-fibers by cutaneous field stimulation abolished ipsilateral itch significantly for many hours (Nilsson et al., 1997). There is strong evidence from recent research that itch and pain are conducted in seperate peripheral and central pathways (Schmelz et al., 1997; Andrew and Craig, 2001; Schmelz, 2001). It is suggested that a specialized subset of itch-mediating C-units (mechanoinsensitive and heat-sensitive fibers) are the primary afferents that exclusively respond to histamine (Schmelz et al., 1997). Therefore, a peripheral mechanism that might cause an inhibition of itch by pain can be ruled out and an interaction within the central nervous system, probably at spinal cord level, has been suggested, though a supraspinal coupling might be also possible (Ward et al., 1996; Brull et al., 1999; Baron et al., 2001). It is postulated that inhibitory projections from nociceptive neurons in the dorsal horn project on itch mediating pathways (Fig. 4). The present data demonstrated that such an interaction seems to exist not only between afferents originating from the same tissue, but also between muscle pain and cutaneous itch. Therefore, it is hypothesized that nociceptive input from different
G. Wasner et al. / European Journal of Pain 8 (2004) 179–185 Itch
Muscle pain Central afferents
Dorsal horn
Peripheral afferents
Histamine Capsaicin
Fig. 4. Schematic drawing illustrating the interaction between activated cutaneous itch fibers and muscle nociceptors. Itch conducting specific primary afferents were activated by histamine (left side) and primary muscle nociceptors were activated by capsaicin (right side). Both project to their spinal secondary order afferents in the dorsal horn. Level of neuronal activity is illustrated by different flash sizes. Activity in central nociceptive muscle afferents inhibits the discharge of central itch conducting fibers in the dorsal horn (dark arrow). Activity in primary itch fibers facilitates activity in spinal nociceptors (bright arrow).
tissues might project on the same central inhibitory pathway that suppresses activity in itch-mediating fibers. A spinal inhibition seems to be also the origin for the reduced perception of other sensory qualities induced by muscle pain in patients and experimental pain models (Laitinen, 1982; Travell and Simons, 1982; Hollins et al., 1996; Graven-Nielsen et al., 1997; Voerman et al., 2000; Stohler et al., 2001). However, it is not clear, whether the same spinal neuronal pathways are responsible for decreasing itch sensation and the other sensory deficits. The observation from Graven-Nielsen et al. (1997) that heat perception by activation of heat sensitive C-fibers is not changed during muscle pain argues against such a common pathway and favors a special interaction between itch-mediating C-units and nociceptors from deep tisssue. 4.2. Histamine-induced increase in muscle pain Cutaneous iontophoresis of histamine in the forearm three minutes after intramuscular injection of capsaicin into the brachioradial muscle led to a significant increase in deep muscle pain compared to pain after iontophoresis of saline. This is the first evidence that activity in cutaneous sensory afferents enhances local muscle pain. However, because the effect was moderate and lasted for only a few minutes, several methodological issues need to be discussed before this notion is accepted:
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(1) Rating of intensity of sensations is a psychophysiological approach. Therefore, distraction is an important factor influencing perception, especially when two different sensations were rated simultaneously (deep muscle pain and histamine/saline-induced sensations). However, distraction by iontophoresis of histamine/saline would rather have led to a decreased intensity of deep muscle pain than to an increased perception (Ward et al., 1996). Furthermore, both histamine and saline were iontophoresed in a randomized double-blinded procedure and had therefore probably the same effect of distraction. (2) Another aspect is the difficulty to distinguish between two different sensations presented at the same time so that the supposed increase in muscle pain might be an added histamine-evoked direct cutaneous sensation. The affirmation of all individuals of the present study that they rated a pure deep muscle pain that was not altered in quality after histamine application and that could have been clearly distinguished from additional superficial sensations after histamine argues against this suggestion. Likewise, itch and pain sensations were clearly distinguishable also in other studies when they were presented simultaneously (Ward et al., 1996; Nilsson et al., 1997; Brull et al., 1999; Wasner et al., 1999). (3) Finally, blinding concerning iontophoresis of histamine and saline that served as placebo might be insufficient. However, by encoding substances for iontophoresis by a technical assistent and by covering the areas of iontophoresis in order to avoid detection of histamine-induced flare reaction neither the individuals nor the investigators were aware whether histamine or saline was iontophoresed. Even estimation of cutaneous sensations after iontophoresis gave no evidence which substance was given, because intensity and quality of histamine- and saline-evoked sensations were not significantly different during deep muscle pain. In summary, it is unlikely that methodological issues are responsible for the increased muscle pain after histamine. However, an additional multiple comparison procedure was not performed in the statistical analysis, because the findings are the result of a post hoc analysis (Saville, 1990). Therefore, the design of further studies to investigate the present findings in more detail have to include the use of a multiple comparison procedure. Atanassoff et al. (1999) observed that intracutaneous histamine injection was sometimes accompanied by an additional sensation of pain. They postulated that histamine acts not only on itch transducing afferents but also on peripheral nociceptors. Such an histamineinduced activation of cutaneous nociceptive afferents might led to additional pain after histamine application during capsaicin-induced deep muscle pain in the present study. However, none of the subject noticed any pain sensation during control-iontophoresis of
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histamine in our experiments. Furthermore, the subjects noticed an increase in deep muscle pain following histamine application nor with any change in pain quality neither with any additional sensation of superficial pain. Therefore, it is unlikely that a summation of different peripheral pains is responsible for the histamine-induced increase in muscle pain in the present study. Histamine-induced pain has been also observed in patients suffering from postherpetic neuralgia when histamine was applied in hyperalgesic skin (Baron et al., 2001). It is suggested that irritable primary afferent nociceptors have changed their peripheral transduction processes after zoster inflammation, e.g. they might start to express novel histamine receptors at their membranes. Alternatively, specific primary afferent histamine sensitive C-fibers may gain synaptical access to pain signalling second order neurons in the spinal cord (Baron et al., 2001). A similar spinal interaction may be involved in the increase of muscle pain following histamine in the present study. It is suggested that activity in primary afferent histamine-sensitive fibers facilitates activity in second order muscle nociceptors (Fig. 4). It may be speculated that these central nociceptors are wide-dynamic range (WDR) neurons that were sensitized following capsaicin-induced primary sensitization of peripheral muscle nociceptive afferents. A projection originating from central itch conducting fibers on central nociceptive afferents is unlikely, because the activity of the central itch fibers is nearly completely abolished by the influence from central muscle nociceptors as described above. Interestingly, also referred pain, a common phenomenon in experimentally induced muscle pain, defined as a pain distinct from the pain at the injection site seems to depend on cutaneous sensory input. Laursen et al. (1997) observed that pretreatment of the referred pain area with a local anaesthetic cream decreased intensity of electrically induced referred muscle pain. It should be noted that there was no spontaneous activity from the skin which could be blocked. However, in the present study the investigated skin and muscle areas are located within the same dermatome and myotome, respectively, so that the underlying mechanisms might differ from that in referred pain areas. In conclusion, the present bi-directional effect of histamine-induced itch and capsaicin-induced muscle pain points to a spinal mechanism. It is suggested that inhibitory projections from nociceptive neurons in the dorsal horn project on itch mediating pathways. Furthermore, activity in primary itch fibers facilitates activity in central nociceptors (Fig. 4). Whether the described interactions are pre- or postsynaptic processes and whether interneurons are involved cannot be answered by this study. Further research is needed to investigate the presented findings in more detail.
Acknowledgements We appreciate the technical assistance of Nicoleta Blunck. We also thank Dr. Lars Friege from the Department of Psychiatry, University Kiel, for editing the statistical analysis. This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1-2), the Bundesministerium f€ ur Bildung und Forschung (BMBF Forschungsverbund ‘‘Neuropathischer Schmerz’’) and the German-Danish exchange programme of the Christian-Albrechts-Universit€at Kiel.
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