letters 'Silent' nociceptors in the skin SIR:
In their recent review, McMahon and Koltzenburg 1 propose that a large population of 'silent' afferent neurones awaits the infrequent occurrence of prolonged tissue injury or inflammation. This is an idea that requires very critical examination, since it rests largely on negative findings - the failure to activate many C-fibre afferents with mechanical stimulation. The difficulty of carrying out experiments where thorough testing is performed for every isolated C-fibre should not be underestimated, especially for regions such as the joints or the more inaccessible parts of visceral organs. It is hardly surprising that, in such tissues, many more afferent units will be excited with the available stimuli when they have become sensitized by inflammatory mediators. In the skin the situation is more straightforward, since the tissue is readily accessible by a wide range of stimuli. Despite this, there is no agreement about the number of inexcitable C-fibres (i.e. putative 'silent' nociceptors). In the first published survey of cutaneous C-fibres, Bessou and Perl 2 found that only 10% of their sample from the skin was inexcitable. Our studies have found up to 28% inexcitable units in nerves from rat skin 3'4. Approximately 20% of C-fibres in the nerves studied are known to be sympathetic efferents 5. Our studies therefore provide no evidence for significant numbers of inexcitable afferent C-fibres and, as such, disagree completely with the studies cited by McMahon and Koltzenburg ~. The reasons for the disagreement are not clear and further careful experimental work is needed to sort out this key issue. Until then, it is important to keep an open mind about 'silent' nociceptors from the skin. The case for 'silent' nociceptors from deep structures such as the joint and the bladder is stronger but, as mentioned earlier, does rest heavily on negative findings. In afferent physiology, including the study of cutaneous C-fibres, TINS, Vol. 14, No. 3, 1991
there is a long and salutary history of incorrect conclusions based on negative results. So at this time we would do well to retain a certain scepticism about the concept of the 'silent' nociceptive afferent. Bruce Lynn Dept of Physiology, University College London, Gower St, London WCfE 6BT, UK.
Selectedreferences 1 McMahon, S. B. and Koltzenburg, M. (1990) Trends Neurosci. 13, 199-201 2 Bessou, P. and Perl, E. R. (1969) J. Neurophysiol. 32, 1025-1043 3 Lynn, B. and Carpenter, S. E. (1982) Brain Res. 238, 29-43 4 Pini, A., Baranowski, R. and Lynn, B. (1990) Eur. J. Neurosci. 2, 89-97 5 Baron, R., Janig, W. and Kollmann, W. (1988) J. Comp. Neurol. 175, 460-468
Reply SIR:
The aim of our article was to draw attention to recent findings that show that, in mammals, a population of primary sensory neurones exists that is not excited by a host of acutely damaging stimuli, but becomes active after a sustained perturbation of the tissue, notably during an inflammatory reaction. Importantly, this transition of afferents into an active state has not been indirectly inferred, nor is it based on negative findings as suggested by Lynn. Rather, the changing receptive properties of single identified C-fibres have been directly witnessed over the initial hours of an acute inflammation affecting a joint I or the urinary bladder 2. Moreover, several independent groups have reported similar findings for the skin 3'4. Regarding the exact percentage of silent, nociceptors, several studies have rigorously tested the excitability of C-fibres recorded from the dorsal root and have demonstrated that 30-50% of fibres in joint s and skeletal muscle 6, and 80-90% of fibres in certain visceral nerves are unresponsive 7. In skin, the prevalence of unresponsive fibres varies between laboratories and species 3,4,8,9.
to the editor
There are several complicating features of the interpretation of the work on skin. First, many recordings have been made from the peripheral nerves where the presence of sympathetic efferents, which are assumed to have no mechanosensitivity, introduces uncertainty. Second, skin faces external assaults and there is theoretically no limit for the stimulus intensity that might b e usefully signalled, i.e. it is difficult to decide exactly what 'mechanically unresponsive' means in this context. Third, repeated noxious stimuli (used to identify afferents) might eventually precipitate injury and inflammation and interfere with the excitability of unmyelinated fibres. We therefore agree with Lynn that, for the very specific question of the exact percentage of silent nociceptors in rat saphenous nerve, the data are ambiguous and the issue is open for debate. However, we should avoid throwing the baby out with the bathwater because of the difficulty in detecting large quantities of silent nociceptors in one specific preparation.
Stephen McMahon Sherrington School of Physiology, St Thomas's Hospita/ Medical School Campus, Lambeth Palace Road, London SE1 7EH, UK.
Martin Koltzenburg Institut for Physiologie und Biokybernetik der Universit~t EHangen-NOrnber#, Universita'tstrasse 17, D-8520 Edangen, FRO.
References 1 Schaible, H-G. and Schmidt, R. F. (1988) J. NeurophysioL 60, 2180-2195 2 Habler, H-J., Janig, W. and Koltzenburg, M. (1990)/. Physiol. 425, 545-562 3 Cohen,R. H., Meyer, R. A., Davis, K. D. Treede, T. D. and Campbell, J. N. (1989) Pain (Suppl. 5), $105 4 Handwerker, H. 0., Kilo, S. and Reeh, P. W. J. Physiol. (in press) 5 Grigg, P., Schaible, H-G. and Schmidt, R. F. (1986) J. NeurophysioL 55, 635-643 6 Kniffki, K-D., Mense, S. and Schmidt, R. F. (1976) Exp. Brain Res. 31, 511-522 7 Janig, W. and Koltzenburg, M. (1990) J. Auton. Nerv. Syst. 30, $89--$96 8 Lynn, B. and Carpenter, S. E. (1982) Brain Res. 238, 29-43 9 Welk, E., Fleischer,E., Petsche,U. and Handwerker, H. O. (1984) Pfl(Jgers Arch, 400, 66--71 95
In their recent review, McMahon and Koltzenburg 1 propose that a large population of 'silent' afferent neurones awaits the infrequent occurrence of prolonged tissue injury or inflammation. This is an idea that requires very critical examination, since it rests largely on negative findings - the failure to activate many C-fibre afferents with mechanical stimulation. The difficulty of carrying out experiments where thorough testing is performed for every isolated C-fibre should not be underestimated, especially for regions such as the joints or the more inaccessible parts of visceral organs. It is hardly surprising that, in such tissues, many more afferent units will be excited with the available stimuli when they have become sensitized by inflammatory mediators. In the skin the situation is more straightforward, since the tissue is readily accessible by a wide range of stimuli. Despite this, there is no agreement about the number of inexcitable C-fibres (i.e. putative 'silent' nociceptors). In the first published survey of cutaneous C-fibres, Bessou and Perl 2 found that only 10% of their sample from the skin was inexcitable. Our studies have found up to 28% inexcitable units in nerves from rat skin 3'4. Approximately 20% of C-fibres in the nerves studied are known to be sympathetic efferents 5. Our studies therefore provide no evidence for significant numbers of inexcitable afferent C-fibres and, as such, disagree completely with the studies cited by McMahon and Koltzenburg ~. The reasons for the disagreement are not clear and further careful experimental work is needed to sort out this key issue. Until then, it is important to keep an open mind about 'silent' nociceptors from the skin. The case for 'silent' nociceptors from deep structures such as the joint and the bladder is stronger but, as mentioned earlier, does rest heavily on negative findings. In afferent physiology, including the study of cutaneous C-fibres, TINS, Vol. 14, No. 3, 1991
there is a long and salutary history of incorrect conclusions based on negative results. So at this time we would do well to retain a certain scepticism about the concept of the 'silent' nociceptive afferent. Bruce Lynn Dept of Physiology, University College London, Gower St, London WCfE 6BT, UK.
Selectedreferences 1 McMahon, S. B. and Koltzenburg, M. (1990) Trends Neurosci. 13, 199-201 2 Bessou, P. and Perl, E. R. (1969) J. Neurophysiol. 32, 1025-1043 3 Lynn, B. and Carpenter, S. E. (1982) Brain Res. 238, 29-43 4 Pini, A., Baranowski, R. and Lynn, B. (1990) Eur. J. Neurosci. 2, 89-97 5 Baron, R., Janig, W. and Kollmann, W. (1988) J. Comp. Neurol. 175, 460-468
Reply SIR:
The aim of our article was to draw attention to recent findings that show that, in mammals, a population of primary sensory neurones exists that is not excited by a host of acutely damaging stimuli, but becomes active after a sustained perturbation of the tissue, notably during an inflammatory reaction. Importantly, this transition of afferents into an active state has not been indirectly inferred, nor is it based on negative findings as suggested by Lynn. Rather, the changing receptive properties of single identified C-fibres have been directly witnessed over the initial hours of an acute inflammation affecting a joint I or the urinary bladder 2. Moreover, several independent groups have reported similar findings for the skin 3'4. Regarding the exact percentage of silent, nociceptors, several studies have rigorously tested the excitability of C-fibres recorded from the dorsal root and have demonstrated that 30-50% of fibres in joint s and skeletal muscle 6, and 80-90% of fibres in certain visceral nerves are unresponsive 7. In skin, the prevalence of unresponsive fibres varies between laboratories and species 3,4,8,9.
to the editor
There are several complicating features of the interpretation of the work on skin. First, many recordings have been made from the peripheral nerves where the presence of sympathetic efferents, which are assumed to have no mechanosensitivity, introduces uncertainty. Second, skin faces external assaults and there is theoretically no limit for the stimulus intensity that might b e usefully signalled, i.e. it is difficult to decide exactly what 'mechanically unresponsive' means in this context. Third, repeated noxious stimuli (used to identify afferents) might eventually precipitate injury and inflammation and interfere with the excitability of unmyelinated fibres. We therefore agree with Lynn that, for the very specific question of the exact percentage of silent nociceptors in rat saphenous nerve, the data are ambiguous and the issue is open for debate. However, we should avoid throwing the baby out with the bathwater because of the difficulty in detecting large quantities of silent nociceptors in one specific preparation.
Stephen McMahon Sherrington School of Physiology, St Thomas's Hospita/ Medical School Campus, Lambeth Palace Road, London SE1 7EH, UK.
Martin Koltzenburg Institut for Physiologie und Biokybernetik der Universit~t EHangen-NOrnber#, Universita'tstrasse 17, D-8520 Edangen, FRO.
References 1 Schaible, H-G. and Schmidt, R. F. (1988) J. NeurophysioL 60, 2180-2195 2 Habler, H-J., Janig, W. and Koltzenburg, M. (1990)/. Physiol. 425, 545-562 3 Cohen,R. H., Meyer, R. A., Davis, K. D. Treede, T. D. and Campbell, J. N. (1989) Pain (Suppl. 5), $105 4 Handwerker, H. 0., Kilo, S. and Reeh, P. W. J. Physiol. (in press) 5 Grigg, P., Schaible, H-G. and Schmidt, R. F. (1986) J. NeurophysioL 55, 635-643 6 Kniffki, K-D., Mense, S. and Schmidt, R. F. (1976) Exp. Brain Res. 31, 511-522 7 Janig, W. and Koltzenburg, M. (1990) J. Auton. Nerv. Syst. 30, $89--$96 8 Lynn, B. and Carpenter, S. E. (1982) Brain Res. 238, 29-43 9 Welk, E., Fleischer,E., Petsche,U. and Handwerker, H. O. (1984) Pfl(Jgers Arch, 400, 66--71 95
