research C apsaicin, the pungent ingredient in peppers, has been used for ~ver two decades now as a tool for investigating various aspects of peripheral sensory fibres due to its selectivity of action on unmyelinated fibres 1'2. It continues to provide a means of investigating the connections and functions of these fibres, as shown by a recent report of evidence for the existence of a capsaicin receptor 3, and the description of a novel methodological advance using capsaicin to probe the terminations of C-fibres in the spinal cord 4. Because of its specificity of action on C-fibres, capsaicin has been attractive to those interested in the tracing and localization of the anatomical pathways and terminals of such fibres and the consequences of peripheral nerve damage. The relief of pain and other functions of C-fibres, such as the control of smooth muscle, are of interest, with investigations into inflammatory and respiratory disorders to the fore L2'4'5. A problem that has bedevilled attempts to trace the terminals of the unmyelinated C-fibres is their sheer small size, with the fibres having typical terminals of a few ~zmin diameter. It is fitting that the novel anatomical technique (Fig. 1) described by Jancs6 and Lawson 4 (in Hungary and the UK) is based on studies by Jancs6, Kiraly and Jancs6-G~bor5 who, over a decade ago, provided the original description of the action of capsaicin on sensory nerves. The technique depends on the ability of capsaicin to impair the C-fibres when applied at a high concentration onto a peripheral nerve in an adult animal. There has been some controversy as to the mechanism of this action, but the present 4 study shows by the use of silver staining that the functional deficit is due to degeneration of the C-fibres and not to depletion of peptides in the nerves. The authors provide evidence that the degeneration results from destruction of the dorsal root ganglion ceils and speculate that this may be due to capsaicin interfeting with the transport of nerve growth factor (NGF). This is based on findings of an earlier study by Otten et al. where the application of NGF gave partial TINS, Vol. 14, No. 7, 1991
news
Capsaidn:gaps in our knowledgestart to be filled protection against capsaicin neurotoxicity, and the authors proposed that capsaicin produced degeneration of the cell bodies of the sensory neurones by blocking retrograde transport of NGF 6. This is supported by other studies showing that the application of NGF can aid survival of damaged sensory neurones (for review see Ref. 7). The degeneration forms the basis for the technique (Fig. 1) and it can be observed 7-8 hours after capsaicin application onto a peripheral nerve - in this case the sciatic nerve. The trick is then to wait 1-3 months and then reapply capsaicin by the systemic route so as to affect all sensitive sensory neurones. After 7-8 hours, the degeneration of C-fibre terminals in the spinal terminal zones can be observed again with silver staining but in the midst of the argyrophilia is a twilight zone with no staining. This is the capsaicin gap, the area once occupied by the terminals of C-fibres in the sciatic nerve, previously permanently destroyed after the original application of capsaicin. The sciatic spinal projection zones can only degenerate once. Thus the gap shows the site of termination of these sciatic Cfibres in the dorsal horn of the spinal cord. As the authors point out, the technique is applicable to all other central C-fibre terminal areas. Interestingly, a similar approach that uses a completely different marker for the C-fibre terminals has been described, on the basis that the central terminals of C-fibres possess opioid receptors 8. Thus, if a series of rhizotomies are made around a spared dorsal root and then autoradiography is used to visualize opioid receptors on sections of the spinal cord spanning the rhizotomy, the sites seen represent the locations of terminals of the C-fibres from the spared root. These can be quantified, although a complication in the anatomical visualization of the terminals is the presence of post-synaptic opioid receptors. The second breakthrough in capsaicin research is the evidence, presented to the British Pharma-
cological Society3, for a specific receptor. A modification of the capsaicin molecule produces capsazepine, which acts as a competitive antagonist of the actions of capsaicin in a large number of models both in vitro and in vivo. The antagonism is observed against effects of capsaicin that range from smooth muscle contractions to antinociception, and in all the assays the antagonist alone has no effect. The receptor joins the benzodiazepine site and the cannabis receptor in awaiting the unequivocal identification of the endogenous ligands for the receptor sites. The antinociception produced by low doses of systemic capsaicin is not due to degeneration of the sensory neurones and thus differs completely from the mechanisms behind the formation of the capsaicin gap. This capsaicin antinociception is reversible, is probably due to a spinal action of the chemical on the central terminals of C-fibres and is produced by doses much lower than those needed to elicit the neurotoxicity9. This reversible antinociception forms the basis for the development of potential novel analgesic drugs. Capsaicin research has therefore been given impetus by the
~
Degeneration
Anthony H. Dickenson
Deptof Pharmacology, UniversityCollege London,London WCIE6BT,UK.
The CapsaicinG a p
I
Fig. 1. The effect of capsaicin on the sciatic nerve is shown in (A), where the local application of capsaicin produces
discrete degeneration. Three months later, the administration of systemic capsaicin produces degeneration throughout the spinal cord with the exception of the area of degenerated terminals - the capsaicin gap (!}).
© 1991. EJsevierSciencePublishersLtd. (UK) 0166- 2236/91/$02.00
265
development of tools such as capsazepine as probes for the physiological function of the receptor; this in turn raises the question as to what the endogenous ligands for the site are. The anatomical tracing of the terminals of unmyelinated C-fibres innervating tissues throughout the body should be considerably aided by the description of the capsaicin gap tech-
nique. The importance of capsaicin as a research tool and as a model for the development of novel therapeutic agents will no doubt continue.
Selected references 1 Fitzgerald, M. (1983) Pain 15,109-130 2 Lynn, B. (1990) Pa/n 41, 61-69 3 8evan, S. eta/. (1991) Br. J. Pharmaco/. (in press)
Colorand the integrationof motionsignals Thomas D.
Albright Salk Institute for Biological Studtes, La Jolla, San Diego, CA 92138, USA.
266
everal lines of evidence indicate that there are at least two stages of motion processing in the primate visual cortex. The first stage involves 'local' measurements of image motion. Motiondetecting neurons at this stage are characterized by marked orientation selectivity and a limited spatial field. Orientation selectivity restricts the contribution of individual detectors to one-dimensional motion signals, i.e. motion is detected only along the axis perpendicular to the preferred orientation. All motion-sensitive neurons in primary visual cortex (area V1) and a substantial fraction of cells in the middle temporal visual area (area MT) of the macaque have properties characteristic of this first stage of motion processing 1. At the second stage these local motion signals are integrated to construct a representation of the 'global' two-dimensional velocity field - a representation consistent with the integrity of our perceptual experience of motion. This second stage is embodied by a small subset (about 25%) of MT neuronsl'2. The nature of this motion signal integration process has been the subject of intense research in the past decade and a fairly coherent story has begun to emerge. Much of the story centers on the use of 'plaid' stimuli (Fig. 1) developed by Adelson and Movshon 3, which afford a conceptually straightforward means to probe the integration process both physiologically and psychophysically. These stimuli are produced by the superimposition of two drifting gratings. Individually the gratings stimulate detectors at the first stage of motion processing. These early signals are then integrated by the
S
second stage to yield the percept of a coherently moving plaid pattern. In the real world it is commonly the case that multiple motion signals arise from approximately the same region of the visual field. Sometimes these signals are produced by different parts of a single moving object. In other instances they may arise from different objects drifting past one another. Successful motion processing is, of course, critically dependent upon integrating only those signals common to each object. By using moving plaid patterns as visual stimuli, a central objective has been to explore the 'rules' that govern motion signal integration. Typically, similarity of the two component gratings is manipulated along some dimension and subjects are asked to indicate whether their dominant percept is that of a coherently moving plaid pattern or of two gratings sliding past one another. In seminal experiments Adelson and Movshon 3 showed that the coherent motion percept was less likely if the two gratings differed sufficiently in either spatial frequency or contrast. More recently it has been found that coherence is markedly reduced if the gratings are in different stereoscopic depth planes 4 or if one grating is perceived to be transparent and overlying the other 5. These results seem to suggest that any of a variety of cues for image segmentation have the capacity to 'gate' the motion integration process. To put it another way, it seems that motion signals that are likely to have originated from the same object - j u d g i n g from image segmentation cues are most likely to be integrated. New results addressing the
© 1991, ElsevierSciencePubhshersLtd, (UK) 0166- 2236191/$0200
4 Jancs6, G. and Lawson, S. N. (1990) Neuroscience 39, 501-511 5 Jancs6, G., Kiraly, E. and Jancs6-G,~,bor, A. (1977) Nature 270, 741-743 6 0 t t e n , U., Lorez, H. P. and Businger, F. (1983) Nature 301,515-517 7 Johnson, E. M., Rich, K. M. and Yip, H. K. (1986) Trends Neurosci. 9, 33-37 8 Besse, D., Lombard, M. C. and Besson, J-M. (1990) Pain (Suppl.) 5, $122 9 Dickenson, A., Ashwood, N., Sullivan, A. F., James, I. and Dray. A. (1990) Eur. J. Pharmacol. 187. 225-233
rules and mechanisms underlying motion signal integration have been obtained from an elegant and strikingly simple psychophysical experiment reported by Krauskopf and Farell in a recent issue of Nature 6. Their findings are of particular interest as they also bear on the contribution of color to motion processing - a subject that has of late given rise to considerable debate. Before describing the result it is worthwhile briefly reviewing some salient features of the way color is encoded at early stages in the primate visual system. The primate retina contains three types of cone photoreceptors, which are maximally sensitive to long (L), middle (M) or short (S) wavelengths of light. Signals arising from L, M, and S cones are combined at subsequent stages to render three channels that define a 'color space' with three principal axes (Fig. 2) 7-9. Activity in the first of these post-receptoral channels is proportional to the difference between the activation of L and M cones (Fig. 3). This channel is one of two purely chromatic channels and it encodes, roughly speaking, the relative intensities of long and mid-spectral light, but is insensitive to absolute levels of illuminatio1:. Activity in the second channel is proportional to the difference between the activation of S cones and the combined activation of L and M cones, i.e. S - ( L + M ) . This second channel is also purely chromatic since it encodes, roughly speaking, the relative intensities of short and non-short (i.e. long and mid-spectral) wavelengths of light. Activity in the third channel is proportional to the summed activity of L and M cones. This channel thus encodes overall luminance within the broad range of spectral frequencies that excite L and M cones. However, this TINS, 9'oi. 14, No. 7, 1991
news
Capsaidn:gaps in our knowledgestart to be filled protection against capsaicin neurotoxicity, and the authors proposed that capsaicin produced degeneration of the cell bodies of the sensory neurones by blocking retrograde transport of NGF 6. This is supported by other studies showing that the application of NGF can aid survival of damaged sensory neurones (for review see Ref. 7). The degeneration forms the basis for the technique (Fig. 1) and it can be observed 7-8 hours after capsaicin application onto a peripheral nerve - in this case the sciatic nerve. The trick is then to wait 1-3 months and then reapply capsaicin by the systemic route so as to affect all sensitive sensory neurones. After 7-8 hours, the degeneration of C-fibre terminals in the spinal terminal zones can be observed again with silver staining but in the midst of the argyrophilia is a twilight zone with no staining. This is the capsaicin gap, the area once occupied by the terminals of C-fibres in the sciatic nerve, previously permanently destroyed after the original application of capsaicin. The sciatic spinal projection zones can only degenerate once. Thus the gap shows the site of termination of these sciatic Cfibres in the dorsal horn of the spinal cord. As the authors point out, the technique is applicable to all other central C-fibre terminal areas. Interestingly, a similar approach that uses a completely different marker for the C-fibre terminals has been described, on the basis that the central terminals of C-fibres possess opioid receptors 8. Thus, if a series of rhizotomies are made around a spared dorsal root and then autoradiography is used to visualize opioid receptors on sections of the spinal cord spanning the rhizotomy, the sites seen represent the locations of terminals of the C-fibres from the spared root. These can be quantified, although a complication in the anatomical visualization of the terminals is the presence of post-synaptic opioid receptors. The second breakthrough in capsaicin research is the evidence, presented to the British Pharma-
cological Society3, for a specific receptor. A modification of the capsaicin molecule produces capsazepine, which acts as a competitive antagonist of the actions of capsaicin in a large number of models both in vitro and in vivo. The antagonism is observed against effects of capsaicin that range from smooth muscle contractions to antinociception, and in all the assays the antagonist alone has no effect. The receptor joins the benzodiazepine site and the cannabis receptor in awaiting the unequivocal identification of the endogenous ligands for the receptor sites. The antinociception produced by low doses of systemic capsaicin is not due to degeneration of the sensory neurones and thus differs completely from the mechanisms behind the formation of the capsaicin gap. This capsaicin antinociception is reversible, is probably due to a spinal action of the chemical on the central terminals of C-fibres and is produced by doses much lower than those needed to elicit the neurotoxicity9. This reversible antinociception forms the basis for the development of potential novel analgesic drugs. Capsaicin research has therefore been given impetus by the
~
Degeneration
Anthony H. Dickenson
Deptof Pharmacology, UniversityCollege London,London WCIE6BT,UK.
The CapsaicinG a p
I
Fig. 1. The effect of capsaicin on the sciatic nerve is shown in (A), where the local application of capsaicin produces
discrete degeneration. Three months later, the administration of systemic capsaicin produces degeneration throughout the spinal cord with the exception of the area of degenerated terminals - the capsaicin gap (!}).
© 1991. EJsevierSciencePublishersLtd. (UK) 0166- 2236/91/$02.00
265
development of tools such as capsazepine as probes for the physiological function of the receptor; this in turn raises the question as to what the endogenous ligands for the site are. The anatomical tracing of the terminals of unmyelinated C-fibres innervating tissues throughout the body should be considerably aided by the description of the capsaicin gap tech-
nique. The importance of capsaicin as a research tool and as a model for the development of novel therapeutic agents will no doubt continue.
Selected references 1 Fitzgerald, M. (1983) Pain 15,109-130 2 Lynn, B. (1990) Pa/n 41, 61-69 3 8evan, S. eta/. (1991) Br. J. Pharmaco/. (in press)
Colorand the integrationof motionsignals Thomas D.
Albright Salk Institute for Biological Studtes, La Jolla, San Diego, CA 92138, USA.
266
everal lines of evidence indicate that there are at least two stages of motion processing in the primate visual cortex. The first stage involves 'local' measurements of image motion. Motiondetecting neurons at this stage are characterized by marked orientation selectivity and a limited spatial field. Orientation selectivity restricts the contribution of individual detectors to one-dimensional motion signals, i.e. motion is detected only along the axis perpendicular to the preferred orientation. All motion-sensitive neurons in primary visual cortex (area V1) and a substantial fraction of cells in the middle temporal visual area (area MT) of the macaque have properties characteristic of this first stage of motion processing 1. At the second stage these local motion signals are integrated to construct a representation of the 'global' two-dimensional velocity field - a representation consistent with the integrity of our perceptual experience of motion. This second stage is embodied by a small subset (about 25%) of MT neuronsl'2. The nature of this motion signal integration process has been the subject of intense research in the past decade and a fairly coherent story has begun to emerge. Much of the story centers on the use of 'plaid' stimuli (Fig. 1) developed by Adelson and Movshon 3, which afford a conceptually straightforward means to probe the integration process both physiologically and psychophysically. These stimuli are produced by the superimposition of two drifting gratings. Individually the gratings stimulate detectors at the first stage of motion processing. These early signals are then integrated by the
S
second stage to yield the percept of a coherently moving plaid pattern. In the real world it is commonly the case that multiple motion signals arise from approximately the same region of the visual field. Sometimes these signals are produced by different parts of a single moving object. In other instances they may arise from different objects drifting past one another. Successful motion processing is, of course, critically dependent upon integrating only those signals common to each object. By using moving plaid patterns as visual stimuli, a central objective has been to explore the 'rules' that govern motion signal integration. Typically, similarity of the two component gratings is manipulated along some dimension and subjects are asked to indicate whether their dominant percept is that of a coherently moving plaid pattern or of two gratings sliding past one another. In seminal experiments Adelson and Movshon 3 showed that the coherent motion percept was less likely if the two gratings differed sufficiently in either spatial frequency or contrast. More recently it has been found that coherence is markedly reduced if the gratings are in different stereoscopic depth planes 4 or if one grating is perceived to be transparent and overlying the other 5. These results seem to suggest that any of a variety of cues for image segmentation have the capacity to 'gate' the motion integration process. To put it another way, it seems that motion signals that are likely to have originated from the same object - j u d g i n g from image segmentation cues are most likely to be integrated. New results addressing the
© 1991, ElsevierSciencePubhshersLtd, (UK) 0166- 2236191/$0200
4 Jancs6, G. and Lawson, S. N. (1990) Neuroscience 39, 501-511 5 Jancs6, G., Kiraly, E. and Jancs6-G,~,bor, A. (1977) Nature 270, 741-743 6 0 t t e n , U., Lorez, H. P. and Businger, F. (1983) Nature 301,515-517 7 Johnson, E. M., Rich, K. M. and Yip, H. K. (1986) Trends Neurosci. 9, 33-37 8 Besse, D., Lombard, M. C. and Besson, J-M. (1990) Pain (Suppl.) 5, $122 9 Dickenson, A., Ashwood, N., Sullivan, A. F., James, I. and Dray. A. (1990) Eur. J. Pharmacol. 187. 225-233
rules and mechanisms underlying motion signal integration have been obtained from an elegant and strikingly simple psychophysical experiment reported by Krauskopf and Farell in a recent issue of Nature 6. Their findings are of particular interest as they also bear on the contribution of color to motion processing - a subject that has of late given rise to considerable debate. Before describing the result it is worthwhile briefly reviewing some salient features of the way color is encoded at early stages in the primate visual system. The primate retina contains three types of cone photoreceptors, which are maximally sensitive to long (L), middle (M) or short (S) wavelengths of light. Signals arising from L, M, and S cones are combined at subsequent stages to render three channels that define a 'color space' with three principal axes (Fig. 2) 7-9. Activity in the first of these post-receptoral channels is proportional to the difference between the activation of L and M cones (Fig. 3). This channel is one of two purely chromatic channels and it encodes, roughly speaking, the relative intensities of long and mid-spectral light, but is insensitive to absolute levels of illuminatio1:. Activity in the second channel is proportional to the difference between the activation of S cones and the combined activation of L and M cones, i.e. S - ( L + M ) . This second channel is also purely chromatic since it encodes, roughly speaking, the relative intensities of short and non-short (i.e. long and mid-spectral) wavelengths of light. Activity in the third channel is proportional to the summed activity of L and M cones. This channel thus encodes overall luminance within the broad range of spectral frequencies that excite L and M cones. However, this TINS, 9'oi. 14, No. 7, 1991
