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Clustering of primary afferent fibers in peripheral nerve fascicles by sensory modality
Brain Research, 370 (1986) 149-152 Elsevier
149
BRE 21457
Clustering of primary afferent fibers in peripheral nerve fascicles by sensory modality W.J. ROBERTS and S.M. ELARDO
Neurological Sciences Institute of Good Samaritan Hospital and Medical Center, Portland, OR 97209 (U.S. A.) (Accepted November 26th, 1985)
Key words: cutaneous mechanoreceptor - - peripheral nerve - - sensory modality
The spatial organization of cutaneous afferent fibers in the cat saphenous nerve was studied by recording from functionally identified units in split filaments. It was found that within each fascicle, fibers tend to be clustered together with others of like modality; they are not randomly distributed. These results suggest that the sensory modality of primary afferent neurons is determined prior to their innervation of the skin.
The spatial organization of primary afferent fibers in peripheral nerves has been studied previously with respect to the fascicular grouping of fibers 14 and with respect to the contribution of fibers from several dorsal root ganglia to form a single nerve 6. In the present study the organization of small clusters of afferents in a cutaneous nerve was examined as a function of their sensory modalities. It was expected that the modalities expressed in each small cluster would be numerically representative of the set of all sensory fibers in that nerve, based on the assumption that the nerve would be somatotopically organized. The results were not consistent with this expectation; rather, they showed that fibers with the same modality tend to be clustered together. Data were o b t a i n e d from afferent units in the saphenous nerve of 6 adult cats anesthetized with sodium pentobarbital (40 mg/kg). The nerve was exposed at mid-thigh, a p p r o x i m a t e l y 120 m m distal to the dorsal root ganglion, and placed over a small platform for stabilization. A bipolar stimulating electrode.was placed under the nerve 2 cm distal to the platform. The nerve was covered with warm mineral oil, and a single fascicle was partially d e s h e a t h e d under x 3 0 magnification. A very small nerve filament was dissected in continuity and placed over a silver h o o k electrode for recording action potentials. Most fila-
ments contained just one active m y e l i n a t e d or a few unmyelinated afferent fibers. Filaments containing two or more units not electrophysiologically and functionally distinguishable were split. The conduction velocity of each unit was d e t e r m i n e d by stimulating the intact nerve 18-20 m m distal to the recording site and noting the response latency. A f t e r determining the sensory modality of a unit (see below), that filament was cut and discarded. A n o t h e r filament was then selected under x 30 magnification, choosing one as near as possible to the previous filament. This process was r e p e a t e d until a cluster of 10 or m o r e units had been identified before beginning with another fascicle. All data to be p r e s e n t e d were o b t a i n e d from mechanoreceptors functionally identified with mechanical stimulation of the skin and/or hairs. The identification criteria are summarized below. Slowly-adapting type I (SAI): (a) responsive to small forces (<100 mg) applied to one or m o r e touch domes visible at ×15 magnification; (b) sustained discharge with irregular interspike intervals to maintained pressure; (c) insensitive to hair m o v e m e n t or to pressure between domesS. 12. Slowly-adapting type H (SAIl): (a) single receptive field with indistinct borders for compressive stimuli; (b) excitatory response to skin stretch in one
Correspondence: W.J. Roberts, Neurological Sciences Institute, 1120 NW 20th Ave., Portland, OR 97209, U.S.A. 0006-8993/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
150 direction, inhibition with stretch perpendicular to that: (c) sustained discharge with regular interspike intervals during maintained stretch or compression4.9. G-Hair: (a) rapidly adapting response to small step stimuli applied to hair or skin; (b) no response to hand tremor; (c) insensitive to air puffs if hair has been clipped to 1-2 mm length 9.15. This class includes units labeled by others as field receptors 15. D-Hair: (a) rapidly adapting response to step-stimuli; (b) responsive to hand tremor; (c) responsive to air puffs directed toward hairs clipped to 1-2 mml.13; (d) conduction velocity in the 10-50 m/s range.
A-mechano-heat (AMH) and high-threshold mechanoreceptors (HTM): (a) receptive field consists of two or more spots (<1 mm diameter) separated by areas of insensitivity; (b) conduction velocity >10 m/s; (c) transient response to mechanical step-stimuli; (d) mechanical threshold can be very low (0.2 g von Frey filament) or high (Pinch)3,5,1°. No attempt was made in the present study to distinguish between units unresponsive to heat (HTM) and units responsive to heat (AMH). Pacinian corpuscle afferents (PC): (a) single, indistinct receptive field; (b) very rapidly adapting response to mechanical stimuli; (c) one-to-one following of high frequency vibration (128 Hz); (d) conduction velocity >50 m/s (ref. 7). Non-myelinated mechanoreceptors (C-Mech): (a) conduction velocity <1 m/s; (b) low-mechanical threshold and prolonged afterdischarge to gentle stroking of the skin; (c) marked fatigue with repeated stimuli H . An ordered set of functionally identified primary afferent units was collected for each of 12 fascicles. These sets were then analyzed statistically to test whether the numbers of units of each modality recorded from individual fascicles were representative of the larger population of units from all fascicles recorded in these experiments. A contingency table was prepared to examine the association between the observed number of each type of unit in each fascicle and the expected number, assuming a random distribution of units throughout each facicle. A g2-test was performed on the data to establish the statistical significance of the results. A total of 225 mechanoreceptors were functionally identified in sets of 10-27 neighboring units in 12 fas-
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........,....,,,......... "...."...'" 331414.5%6.1% 21 9.2% 50 21.9% 9240.4% 6 2.6% 12 5.3% 6A 6B
Fig. 1. Sensory modality of individual mechanoreceptors recorded from small clusters of cutaneous nerve fibers. Each dot represents one afferent fiber. The position of each dot indicates both the modality of the afferent and the sequential order in which it was recorded relative to others in that cluster (see text). Data from separate fascicles are separated by vertical lines. The numbers at the lower right indicate the number of each modality recorded in all fascicles and the percentage of the total. cicles from 6 cats. The receptive fields of the afferent units were found to be located 70-180 mm distal to the recording site. Each afferent unit was functionally identified and placed in one of the 7 modality classes. The data from all units are presented in Fig. 1 in which each dot represents one identified unit. The modality of each unit is indicated by the row in which it is located. The first unit recorded in each fascicle is placed at the left of that set, with subsequent units presented in sequence to the right. The set of units encountered in each of the 12 fascicles is labeled with both a number assigned to the cat and a letter for each separate fascicle. The total number of units of each modality in all fascicles is shown numerically at the lower right. In these samples of cutaneous afferents, two findings stand out. One is that neighboring axons, recorded sequentially in this study, often have the same sensory modality. Note in Fig. 1, cat 1, fascicle B that 4 A M H - H T M afferents were followed by 7 D-hair units. Many other examples are apparent in other fascicles, although the modalities in some sets, such as 2B, appear to be rather randomly organized.
151 The second finding, related to the first, is that units of a particular sensory modality are often over- or underrepresented in the small sample of adjacent units from a single fascicle. For example, no SAIs were encountered in the 38 units of cat 4, fascicles A and B; but in fascicle C in the same cat, 6 of 23 units (26%) were SAIs. Other examples are plentiful, such as the abundance of SAils in cat 1, fascicle A and a paucity of G-hairs in fascicle B of the same cat (5%) even though G-hairs are relatively abundant in the total population (22%). The significance of these differences between the observed number of unit types in individual fascicles and the expected number, assuming that the units were randomly distributed throughout each fascicle, was determined using a 2~2-test. In this analysis the Cmechanoreceptors and pacinian corpuscle afferents were deleted because their expected frequencies in each small cluster were too low for this statistical test. The resulting value of Z2 was 96.8, with 44 degrees of freedom, which is statistically significant beyond the 0.001 level. Thus, it is highly unlikely that the observed arrangement of fibers was random. These results undoubtedly underestimate the actual degree of segregation of afferents because of the imprecision involved in trying to select adjacent filaments. Although the technique used did allow the sampling of a cluster of filaments from one small sector in each fascicle, it was impossible to be sure of selecting adjacent axons in sequence. This finding that afferent fibers are clustered by sensory modality is in agreement with the unpublished observations of experienced sensory physiologists (Drs. B.H. Pubols and E.R. Perl, personal communications). The proportions of the different classes of myelinated afferents observed in the present study are very similar to those reported by others, with one exception: a higher percentage of the hair afferents in the present study were classified as D-hair relative to G-hair (including field receptors). The percentages of myelinated afferents classified as D- and G-hairs in this study are 43% and 23%, respectively, compared with earlier studies which reported 16% and 34% (ref. 2) or 18% and 41% (ref. 1). These numerical differences are likely the result of the identification criteria used. In the earlier studies cited, single guard and down hairs were stimu-
lated to help classify units, whereas sensitivity to air puffs, gentle stroking of many hairs and responsiveness to tremor were used to differentiate between Gand D-units in the present study. The conduction velocities of our units showed the expected difference between G- and D-hairs (mean velocities of 45 and 24 m/s, respectively). This classification issue is not critical in the demonstration of clustering of afferents, because the deviation from randomness is statistically significant whether the G- and D-hair units are combined or are treated separately. Clustering of primary afferents in peripheral nerves is of obvious practical significance to sensory physiologists who wish to study units of a particular sensory modality. Furthermore, clustering of afferents may also lead to specific sensory deficits in some but not all modalities of mechanical sensibility after partial nerve injuries. Developmentally, the existence of modality segregation of axons distal (120 mm) to the dorsal root ganglia (DRG) suggests that the sensory modality of individual D R G neurons is determined prior to the developmental stage at which the primary afferents reach the skin. Once they reach the skin the growing afferent fibers may be guided to appropriate target tissues, or they may induce the development of associated sensory cells 16. If afferent specificity was instead induced by target tissues encountered by chance, then one would expect to find a random organization within the fascicle, not clustering by sensory modality. The present findings are thus consistent with reports, based on spatial targeting of primary afferents in the chick, that the outgrowth of these axons is not random and that the afferent projections are not established by selective cell death after the axons reach the skin 6. It remains to be determined whether the observed spatial segregation of afferent nerve fibers is causally related to the clustering of cell bodies in the D R G 6 or results from other developmental influences. The authors are grateful for comments on the manuscript from Drs. Marcia Honig, Benjamin H. Pubols, Jr., and Dean Smith, and from Mark Foglesong. Financial support was received from Good Samaritan Hospital and from the USPHS (NS 13447).
152 1 Brown, A.G. and Iggo, A., A quantitative study of cutaneous receptors and afferent fibres in the cat and rabbit, J. Physiol. (London), 193 (1967)707-733. 2 Burgess, P.R., Petit, D. and Warren, R.M., Receptor types in cat hairy skin supplied by myelinated fibers, J. Neurophysiol.. 31 (1968) 833-848. 3 Burgess, P.R. and Perl, E.R., Cutaneous mechanoreceptors and nociceptors. In A. Iggo (Ed.), The Somatosensorv System, Vol. 2, Springer, Berlin, 1973, pp. 29-78. 4 Chambers, M.R., Andres, K.H., Duering, M.V. and Iggo, A., The structure and function of the slowly adapting type I! mechanoreceptor in hairy skin, Q. J. Exp. Physiol., 57 (1972) 417-445. 5 Georgopoulos, A.P., Functional properties of primary afferent units probably related to pain mechanisms in primate glabrous skin, J. Neurophysiol., 39 (1976) 71-83. 6 Honig, M.G., The development of sensory projection patterns in embryonic chick hind limb, J. Physiol. (London), 330 (1982) 175-202. 7 Hunt, C.C., On the nature of vibration receptors in the hind limb of the cat, J. Physiol. (London), 155 (1981) 175-186. 8 Iggo, A. and Muir, A.R., The structure and function of a slowly adapting touch corpuscle in hairy skin, J. Physiol. (London), 200 (1969) 763-796.
9 Pierce, J.P. and Roberts, W.J., Sympathetically induced changes in the responses of guard hair and type II receptors in the cat, J. Physiol. (London), 314 (1981) 411-428. 10 Roberts, W.J. and Elardo, S.M., Sympathetic activation of A-delta nociceptors, Somatosensory Res., in press. ll Roberts, W.J. and Elardo, S.M., Sympathetic activation of unmyelinated mechanoreceptors in cat skin, Brain Research, 339 (1985) 123-125. 12 Roberts, W.J., Elardo, S.M. and King, K.A., Sympathetically induced changes in the responses of slowly adapting type I receptors in cat skin, Somatosensory Res., 2 (1985) 223-236. 13 Roberts, W.J. and Levitt, G.R., Histochemical evidence for sympathetic innervation of hair receptor afferents in cat skin, J. Comp. Neurol., 210 (1982) 204-209. 14 Sunderland, S., The intraneural topography of the radial, median and ulnar nerves, Brain, 68 (1945) 177-299. 15 Tuckett, R.P., Horch, K.W. and Burgess, P.R., Response of cutaneous hair and field mechanoreceptors in cat to threshold stimuli, J. Neurophysiol., 41 (1978) 138-149. 16 Zelena, J., The role of sensory innervation in the development of mechano-receptors, Prog. Brain Res, 43 (1976) 59-64.
149
BRE 21457
Clustering of primary afferent fibers in peripheral nerve fascicles by sensory modality W.J. ROBERTS and S.M. ELARDO
Neurological Sciences Institute of Good Samaritan Hospital and Medical Center, Portland, OR 97209 (U.S. A.) (Accepted November 26th, 1985)
Key words: cutaneous mechanoreceptor - - peripheral nerve - - sensory modality
The spatial organization of cutaneous afferent fibers in the cat saphenous nerve was studied by recording from functionally identified units in split filaments. It was found that within each fascicle, fibers tend to be clustered together with others of like modality; they are not randomly distributed. These results suggest that the sensory modality of primary afferent neurons is determined prior to their innervation of the skin.
The spatial organization of primary afferent fibers in peripheral nerves has been studied previously with respect to the fascicular grouping of fibers 14 and with respect to the contribution of fibers from several dorsal root ganglia to form a single nerve 6. In the present study the organization of small clusters of afferents in a cutaneous nerve was examined as a function of their sensory modalities. It was expected that the modalities expressed in each small cluster would be numerically representative of the set of all sensory fibers in that nerve, based on the assumption that the nerve would be somatotopically organized. The results were not consistent with this expectation; rather, they showed that fibers with the same modality tend to be clustered together. Data were o b t a i n e d from afferent units in the saphenous nerve of 6 adult cats anesthetized with sodium pentobarbital (40 mg/kg). The nerve was exposed at mid-thigh, a p p r o x i m a t e l y 120 m m distal to the dorsal root ganglion, and placed over a small platform for stabilization. A bipolar stimulating electrode.was placed under the nerve 2 cm distal to the platform. The nerve was covered with warm mineral oil, and a single fascicle was partially d e s h e a t h e d under x 3 0 magnification. A very small nerve filament was dissected in continuity and placed over a silver h o o k electrode for recording action potentials. Most fila-
ments contained just one active m y e l i n a t e d or a few unmyelinated afferent fibers. Filaments containing two or more units not electrophysiologically and functionally distinguishable were split. The conduction velocity of each unit was d e t e r m i n e d by stimulating the intact nerve 18-20 m m distal to the recording site and noting the response latency. A f t e r determining the sensory modality of a unit (see below), that filament was cut and discarded. A n o t h e r filament was then selected under x 30 magnification, choosing one as near as possible to the previous filament. This process was r e p e a t e d until a cluster of 10 or m o r e units had been identified before beginning with another fascicle. All data to be p r e s e n t e d were o b t a i n e d from mechanoreceptors functionally identified with mechanical stimulation of the skin and/or hairs. The identification criteria are summarized below. Slowly-adapting type I (SAI): (a) responsive to small forces (<100 mg) applied to one or m o r e touch domes visible at ×15 magnification; (b) sustained discharge with irregular interspike intervals to maintained pressure; (c) insensitive to hair m o v e m e n t or to pressure between domesS. 12. Slowly-adapting type H (SAIl): (a) single receptive field with indistinct borders for compressive stimuli; (b) excitatory response to skin stretch in one
Correspondence: W.J. Roberts, Neurological Sciences Institute, 1120 NW 20th Ave., Portland, OR 97209, U.S.A. 0006-8993/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
150 direction, inhibition with stretch perpendicular to that: (c) sustained discharge with regular interspike intervals during maintained stretch or compression4.9. G-Hair: (a) rapidly adapting response to small step stimuli applied to hair or skin; (b) no response to hand tremor; (c) insensitive to air puffs if hair has been clipped to 1-2 mm length 9.15. This class includes units labeled by others as field receptors 15. D-Hair: (a) rapidly adapting response to step-stimuli; (b) responsive to hand tremor; (c) responsive to air puffs directed toward hairs clipped to 1-2 mml.13; (d) conduction velocity in the 10-50 m/s range.
A-mechano-heat (AMH) and high-threshold mechanoreceptors (HTM): (a) receptive field consists of two or more spots (<1 mm diameter) separated by areas of insensitivity; (b) conduction velocity >10 m/s; (c) transient response to mechanical step-stimuli; (d) mechanical threshold can be very low (0.2 g von Frey filament) or high (Pinch)3,5,1°. No attempt was made in the present study to distinguish between units unresponsive to heat (HTM) and units responsive to heat (AMH). Pacinian corpuscle afferents (PC): (a) single, indistinct receptive field; (b) very rapidly adapting response to mechanical stimuli; (c) one-to-one following of high frequency vibration (128 Hz); (d) conduction velocity >50 m/s (ref. 7). Non-myelinated mechanoreceptors (C-Mech): (a) conduction velocity <1 m/s; (b) low-mechanical threshold and prolonged afterdischarge to gentle stroking of the skin; (c) marked fatigue with repeated stimuli H . An ordered set of functionally identified primary afferent units was collected for each of 12 fascicles. These sets were then analyzed statistically to test whether the numbers of units of each modality recorded from individual fascicles were representative of the larger population of units from all fascicles recorded in these experiments. A contingency table was prepared to examine the association between the observed number of each type of unit in each fascicle and the expected number, assuming a random distribution of units throughout each facicle. A g2-test was performed on the data to establish the statistical significance of the results. A total of 225 mechanoreceptors were functionally identified in sets of 10-27 neighboring units in 12 fas-
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........,....,,,......... "...."...'" 331414.5%6.1% 21 9.2% 50 21.9% 9240.4% 6 2.6% 12 5.3% 6A 6B
Fig. 1. Sensory modality of individual mechanoreceptors recorded from small clusters of cutaneous nerve fibers. Each dot represents one afferent fiber. The position of each dot indicates both the modality of the afferent and the sequential order in which it was recorded relative to others in that cluster (see text). Data from separate fascicles are separated by vertical lines. The numbers at the lower right indicate the number of each modality recorded in all fascicles and the percentage of the total. cicles from 6 cats. The receptive fields of the afferent units were found to be located 70-180 mm distal to the recording site. Each afferent unit was functionally identified and placed in one of the 7 modality classes. The data from all units are presented in Fig. 1 in which each dot represents one identified unit. The modality of each unit is indicated by the row in which it is located. The first unit recorded in each fascicle is placed at the left of that set, with subsequent units presented in sequence to the right. The set of units encountered in each of the 12 fascicles is labeled with both a number assigned to the cat and a letter for each separate fascicle. The total number of units of each modality in all fascicles is shown numerically at the lower right. In these samples of cutaneous afferents, two findings stand out. One is that neighboring axons, recorded sequentially in this study, often have the same sensory modality. Note in Fig. 1, cat 1, fascicle B that 4 A M H - H T M afferents were followed by 7 D-hair units. Many other examples are apparent in other fascicles, although the modalities in some sets, such as 2B, appear to be rather randomly organized.
151 The second finding, related to the first, is that units of a particular sensory modality are often over- or underrepresented in the small sample of adjacent units from a single fascicle. For example, no SAIs were encountered in the 38 units of cat 4, fascicles A and B; but in fascicle C in the same cat, 6 of 23 units (26%) were SAIs. Other examples are plentiful, such as the abundance of SAils in cat 1, fascicle A and a paucity of G-hairs in fascicle B of the same cat (5%) even though G-hairs are relatively abundant in the total population (22%). The significance of these differences between the observed number of unit types in individual fascicles and the expected number, assuming that the units were randomly distributed throughout each fascicle, was determined using a 2~2-test. In this analysis the Cmechanoreceptors and pacinian corpuscle afferents were deleted because their expected frequencies in each small cluster were too low for this statistical test. The resulting value of Z2 was 96.8, with 44 degrees of freedom, which is statistically significant beyond the 0.001 level. Thus, it is highly unlikely that the observed arrangement of fibers was random. These results undoubtedly underestimate the actual degree of segregation of afferents because of the imprecision involved in trying to select adjacent filaments. Although the technique used did allow the sampling of a cluster of filaments from one small sector in each fascicle, it was impossible to be sure of selecting adjacent axons in sequence. This finding that afferent fibers are clustered by sensory modality is in agreement with the unpublished observations of experienced sensory physiologists (Drs. B.H. Pubols and E.R. Perl, personal communications). The proportions of the different classes of myelinated afferents observed in the present study are very similar to those reported by others, with one exception: a higher percentage of the hair afferents in the present study were classified as D-hair relative to G-hair (including field receptors). The percentages of myelinated afferents classified as D- and G-hairs in this study are 43% and 23%, respectively, compared with earlier studies which reported 16% and 34% (ref. 2) or 18% and 41% (ref. 1). These numerical differences are likely the result of the identification criteria used. In the earlier studies cited, single guard and down hairs were stimu-
lated to help classify units, whereas sensitivity to air puffs, gentle stroking of many hairs and responsiveness to tremor were used to differentiate between Gand D-units in the present study. The conduction velocities of our units showed the expected difference between G- and D-hairs (mean velocities of 45 and 24 m/s, respectively). This classification issue is not critical in the demonstration of clustering of afferents, because the deviation from randomness is statistically significant whether the G- and D-hair units are combined or are treated separately. Clustering of primary afferents in peripheral nerves is of obvious practical significance to sensory physiologists who wish to study units of a particular sensory modality. Furthermore, clustering of afferents may also lead to specific sensory deficits in some but not all modalities of mechanical sensibility after partial nerve injuries. Developmentally, the existence of modality segregation of axons distal (120 mm) to the dorsal root ganglia (DRG) suggests that the sensory modality of individual D R G neurons is determined prior to the developmental stage at which the primary afferents reach the skin. Once they reach the skin the growing afferent fibers may be guided to appropriate target tissues, or they may induce the development of associated sensory cells 16. If afferent specificity was instead induced by target tissues encountered by chance, then one would expect to find a random organization within the fascicle, not clustering by sensory modality. The present findings are thus consistent with reports, based on spatial targeting of primary afferents in the chick, that the outgrowth of these axons is not random and that the afferent projections are not established by selective cell death after the axons reach the skin 6. It remains to be determined whether the observed spatial segregation of afferent nerve fibers is causally related to the clustering of cell bodies in the D R G 6 or results from other developmental influences. The authors are grateful for comments on the manuscript from Drs. Marcia Honig, Benjamin H. Pubols, Jr., and Dean Smith, and from Mark Foglesong. Financial support was received from Good Samaritan Hospital and from the USPHS (NS 13447).
152 1 Brown, A.G. and Iggo, A., A quantitative study of cutaneous receptors and afferent fibres in the cat and rabbit, J. Physiol. (London), 193 (1967)707-733. 2 Burgess, P.R., Petit, D. and Warren, R.M., Receptor types in cat hairy skin supplied by myelinated fibers, J. Neurophysiol.. 31 (1968) 833-848. 3 Burgess, P.R. and Perl, E.R., Cutaneous mechanoreceptors and nociceptors. In A. Iggo (Ed.), The Somatosensorv System, Vol. 2, Springer, Berlin, 1973, pp. 29-78. 4 Chambers, M.R., Andres, K.H., Duering, M.V. and Iggo, A., The structure and function of the slowly adapting type I! mechanoreceptor in hairy skin, Q. J. Exp. Physiol., 57 (1972) 417-445. 5 Georgopoulos, A.P., Functional properties of primary afferent units probably related to pain mechanisms in primate glabrous skin, J. Neurophysiol., 39 (1976) 71-83. 6 Honig, M.G., The development of sensory projection patterns in embryonic chick hind limb, J. Physiol. (London), 330 (1982) 175-202. 7 Hunt, C.C., On the nature of vibration receptors in the hind limb of the cat, J. Physiol. (London), 155 (1981) 175-186. 8 Iggo, A. and Muir, A.R., The structure and function of a slowly adapting touch corpuscle in hairy skin, J. Physiol. (London), 200 (1969) 763-796.
9 Pierce, J.P. and Roberts, W.J., Sympathetically induced changes in the responses of guard hair and type II receptors in the cat, J. Physiol. (London), 314 (1981) 411-428. 10 Roberts, W.J. and Elardo, S.M., Sympathetic activation of A-delta nociceptors, Somatosensory Res., in press. ll Roberts, W.J. and Elardo, S.M., Sympathetic activation of unmyelinated mechanoreceptors in cat skin, Brain Research, 339 (1985) 123-125. 12 Roberts, W.J., Elardo, S.M. and King, K.A., Sympathetically induced changes in the responses of slowly adapting type I receptors in cat skin, Somatosensory Res., 2 (1985) 223-236. 13 Roberts, W.J. and Levitt, G.R., Histochemical evidence for sympathetic innervation of hair receptor afferents in cat skin, J. Comp. Neurol., 210 (1982) 204-209. 14 Sunderland, S., The intraneural topography of the radial, median and ulnar nerves, Brain, 68 (1945) 177-299. 15 Tuckett, R.P., Horch, K.W. and Burgess, P.R., Response of cutaneous hair and field mechanoreceptors in cat to threshold stimuli, J. Neurophysiol., 41 (1978) 138-149. 16 Zelena, J., The role of sensory innervation in the development of mechano-receptors, Prog. Brain Res, 43 (1976) 59-64.