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Sensory basis of autotomy in rats
Pain, 45 (1991) 109-110 c 1991 Elsevier Science Publishers
109 B.V. 0304-3959/91/$03.50
PAIN 01780
Guest Editorial
Sensory basis of autotomy in rats Marshall
Devor
Life Sctences Institute, Hebrew University of Jerusnlem. Jerusulem (Israel)
(Accepted 22 October 1990)
Chronic neuropathic pain syndyomes, pains associated with injury or disease affecting the nervous system, are among the most intractable encountered in clinical practice. After all, cutting sensory conduction pathways ought to eliminate sensation, not trigger it! Researchers interested in this problem have long realized the importance of establishing animal models of neuropathic conditions. Such models would provide not only an arena for examining the physiological mechanisms involved, but would also permit testing of new treatment ideas. Just over a decade ago Patrick Wall and I, together with other collaborators working in London and Jerusalem, announced that we thought we had found such a model. This was based on the observation that some time after major denervation of a limb, some animals begin to lick and bite the limb, eventually injuring one or more toes. We termed this behavioral peculiarity ‘autotomy’ and proposed that it results from unpleasant and perhaps painful paresthesias referred to the denervated limb [5]. Since then, numerous research articles have been published using the autotomy model. Many were designed to test the validity of the model by checking if autotomy in rats has the same clinical profile as denervation pain in man. In many respects it does. A few were aimed at investigating mechanisms and testing drug treatments. Unfortunately, however, this latter experimental mode has been slow in developing. An important reason for this is a nagging concern that no one could resolve with certainty. Is it possible that autotomy is the reaction of a rat to a totally numb insensitive limb and, actually, has nothing at all to do with neuropathic paresthesia or pain? How can we know what a rat is really feeling? This type of problem is not so acute for all pain models, for example those in which there is allodynia and hyperalgesia. However, it is ever present when the
Correspondence lo: Marshall DeGor, Life Sciences Institute. University of Jerusalem, Jerusalem, Israel.
Hebrew
subject is spontaneous pain (e.g., anesthesia dolorosa, or phantom limb sensation). A partial answer was provided by Basbaum [l], and more recently by SaadP: et al. [4], who showed that lesions of certain spinal cord tracts reduce autotomy. Were autotomy a reflection of the absence of normal sensory input, cutting spinal tracts should have exacerbated it. not relieved it. The conclusion that autotomy is a reaction to a positive sensory experience is further strengthened by the article by Blumenkopf and Lipman which appears in this issue of Pain. The authors reasoned that if autotomy is something that rats do to a chronically numb limb, in the absence of associated unpleasant sensations, then autotomy ought also to be triggered by chronic nerve block using local anesthetics. Experimentally, producing a total nerve block for weeks on end is easier said than done. The approach used by Blumenkopf and Lipman involved implantation of an osmotic mini-pump draining into a nerve cuff. Total anesthesia of the limb indicated that impulse conduction had indeed been blocked. The result: chronic nerve block did not trigger autotomy. The simple absence of sensation from the limb is apparently not enough to induce autotomy. This study may have significant impact on future research on neuropathic pain both by adding to our confidence in the validity of the autotomy model, and by introducing a useful new research tool. Indeed, Blumenkopf and Lipman went on to show that a lidocaine block central to the nerve end neuroma did not prevent autotomy. Assuming that metabolic disruption associated with this block [e.g., 31 did not in itself introduce spurious afferent signals, it seems reasonable to conclude that ectopic neuroma activity isnot necessary to trigger autotomy, although it may still be sufficient. It still needs to be determined if the lidocaine superfusion method is really innocuous to the nerve and as completely reversible as the authors inferred on the basis of behavioral observations. Other studies in the literature suggest that long-term lidocaine superfusion
1 I(1
ought to have toxic effects on nerve, among them at least partial block of axoplasmic transport [e.g., 31. If so. this would undermine the authors’ suggestion of an important role for axoplasmicaily transported substances. or rather their absence, in the development of autotomy. Autotomy in rats, like neuropathic pain states in man. probably involves a combination of interacting PNS and CNS processes. These need now to be defined and unraveled. The ultimate goal is the development of better treatment modalities for currently intractable neuropathic pain problems. Blumenkopf and Lipman’s work has likely brought us somewhat closer to realizing that goal. When all is said and done, this is the scientific, and the ethical, justification of experimental work using animal models of chronic pain.
References Bashaum. ‘4.1.. f-.ffccts of central lestons on dtsorders produced multiple dorsal rhizotomy Fink,
B.R.
transport (1976)
and
Kish,
in rats. Exp. Neural.,
S.J., Reversible
in viva by lidocaine
inhibitor
of rapid
axonal
Anesthesiology.
hydrochloride.
bti
42 (1974) 490. Sill 44
139-146.
Fink. B.R., Kenny, G.E. and Simpson, W.E.,
Depression of oxygen
uptake in cell culture by volatile, barbiturate
and local anesthetics.
Anesthesiology. Saadt.
N.E..
1SO--162.
30 (1969)
Atweh,
SF..
lesions m the anteriolateral self-mutilation Wall,
P.D..
Jabbur,
S.J. and Wall,
columns
behavior in rats, Pain, 42 (1990)
Devor,
M..
Inbal.
R., Scadding,
Seltzer, Z. and Tomkiewicz.
M.M.,
nerve lesions: experimental
anaesthesia
103-113.
PD.,
and dorsolateral
Autotomy
Effects 01 funiculi
on
313- 321. J.W.,
Schonfeld.
D..
foliowing peripheral
dolornsa.
Pain.
7 (1979)
109 B.V. 0304-3959/91/$03.50
PAIN 01780
Guest Editorial
Sensory basis of autotomy in rats Marshall
Devor
Life Sctences Institute, Hebrew University of Jerusnlem. Jerusulem (Israel)
(Accepted 22 October 1990)
Chronic neuropathic pain syndyomes, pains associated with injury or disease affecting the nervous system, are among the most intractable encountered in clinical practice. After all, cutting sensory conduction pathways ought to eliminate sensation, not trigger it! Researchers interested in this problem have long realized the importance of establishing animal models of neuropathic conditions. Such models would provide not only an arena for examining the physiological mechanisms involved, but would also permit testing of new treatment ideas. Just over a decade ago Patrick Wall and I, together with other collaborators working in London and Jerusalem, announced that we thought we had found such a model. This was based on the observation that some time after major denervation of a limb, some animals begin to lick and bite the limb, eventually injuring one or more toes. We termed this behavioral peculiarity ‘autotomy’ and proposed that it results from unpleasant and perhaps painful paresthesias referred to the denervated limb [5]. Since then, numerous research articles have been published using the autotomy model. Many were designed to test the validity of the model by checking if autotomy in rats has the same clinical profile as denervation pain in man. In many respects it does. A few were aimed at investigating mechanisms and testing drug treatments. Unfortunately, however, this latter experimental mode has been slow in developing. An important reason for this is a nagging concern that no one could resolve with certainty. Is it possible that autotomy is the reaction of a rat to a totally numb insensitive limb and, actually, has nothing at all to do with neuropathic paresthesia or pain? How can we know what a rat is really feeling? This type of problem is not so acute for all pain models, for example those in which there is allodynia and hyperalgesia. However, it is ever present when the
Correspondence lo: Marshall DeGor, Life Sciences Institute. University of Jerusalem, Jerusalem, Israel.
Hebrew
subject is spontaneous pain (e.g., anesthesia dolorosa, or phantom limb sensation). A partial answer was provided by Basbaum [l], and more recently by SaadP: et al. [4], who showed that lesions of certain spinal cord tracts reduce autotomy. Were autotomy a reflection of the absence of normal sensory input, cutting spinal tracts should have exacerbated it. not relieved it. The conclusion that autotomy is a reaction to a positive sensory experience is further strengthened by the article by Blumenkopf and Lipman which appears in this issue of Pain. The authors reasoned that if autotomy is something that rats do to a chronically numb limb, in the absence of associated unpleasant sensations, then autotomy ought also to be triggered by chronic nerve block using local anesthetics. Experimentally, producing a total nerve block for weeks on end is easier said than done. The approach used by Blumenkopf and Lipman involved implantation of an osmotic mini-pump draining into a nerve cuff. Total anesthesia of the limb indicated that impulse conduction had indeed been blocked. The result: chronic nerve block did not trigger autotomy. The simple absence of sensation from the limb is apparently not enough to induce autotomy. This study may have significant impact on future research on neuropathic pain both by adding to our confidence in the validity of the autotomy model, and by introducing a useful new research tool. Indeed, Blumenkopf and Lipman went on to show that a lidocaine block central to the nerve end neuroma did not prevent autotomy. Assuming that metabolic disruption associated with this block [e.g., 31 did not in itself introduce spurious afferent signals, it seems reasonable to conclude that ectopic neuroma activity isnot necessary to trigger autotomy, although it may still be sufficient. It still needs to be determined if the lidocaine superfusion method is really innocuous to the nerve and as completely reversible as the authors inferred on the basis of behavioral observations. Other studies in the literature suggest that long-term lidocaine superfusion
1 I(1
ought to have toxic effects on nerve, among them at least partial block of axoplasmic transport [e.g., 31. If so. this would undermine the authors’ suggestion of an important role for axoplasmicaily transported substances. or rather their absence, in the development of autotomy. Autotomy in rats, like neuropathic pain states in man. probably involves a combination of interacting PNS and CNS processes. These need now to be defined and unraveled. The ultimate goal is the development of better treatment modalities for currently intractable neuropathic pain problems. Blumenkopf and Lipman’s work has likely brought us somewhat closer to realizing that goal. When all is said and done, this is the scientific, and the ethical, justification of experimental work using animal models of chronic pain.
References Bashaum. ‘4.1.. f-.ffccts of central lestons on dtsorders produced multiple dorsal rhizotomy Fink,
B.R.
transport (1976)
and
Kish,
in rats. Exp. Neural.,
S.J., Reversible
in viva by lidocaine
inhibitor
of rapid
axonal
Anesthesiology.
hydrochloride.
bti
42 (1974) 490. Sill 44
139-146.
Fink. B.R., Kenny, G.E. and Simpson, W.E.,
Depression of oxygen
uptake in cell culture by volatile, barbiturate
and local anesthetics.
Anesthesiology. Saadt.
N.E..
1SO--162.
30 (1969)
Atweh,
SF..
lesions m the anteriolateral self-mutilation Wall,
P.D..
Jabbur,
S.J. and Wall,
columns
behavior in rats, Pain, 42 (1990)
Devor,
M..
Inbal.
R., Scadding,
Seltzer, Z. and Tomkiewicz.
M.M.,
nerve lesions: experimental
anaesthesia
103-113.
PD.,
and dorsolateral
Autotomy
Effects 01 funiculi
on
313- 321. J.W.,
Schonfeld.
D..
foliowing peripheral
dolornsa.
Pain.
7 (1979)