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The influence of housing condition on autotomy following dorsal rhizotomy in rats
Pain, 13 (1982) 307-311
307
Elsevier ~omedical Press
The Influence of Housing Condition on Autotomy Following Dorsal Rhizotomy in Rats Doreen Berman and Barbara E. Rodin 2 Department of Psychology, Queens College, Flushing, N. Y. 11367 (U.S.A. )
(Received 13 July 1981,accepted23 December1981)
Summary Forty-four male rats were subjected to unilateral intradural section of dorsal roots TI3-L6. Of these, 10 were housed alone and 34 were housed with female rats. Each of the 10 animals housed alone self-mutilated to an extreme degree, with 7 cannibalizing the denervated limb. Only one of the animals housed with a female showed any sign of self-biting, and this was a minor, isolated incident. These results are discussed with particular reference to dorsal rhizotomy in rats serving as a model of chronic pain.
Autotomy (self-biting) occurring in animals after dorsal rhizotomy (DR) has been interpreted to reflect a dysesthesic [3,6] or even painful [2,8,11,17] condition. Whether this interpretation is valid is a matter of considerable importance. First, dorsal rhizotomized animals are used in a number of experimental contexts. If such animals are indeed suffering pain, this needs to be known so that a reasoned judgment can be made of lines of research in which they are used, considering costs and benefits to both animals and humans. Second, if the underlying basis of autotomy is pain, then the dorsal rhizotomized animal could well provide the model so vitally needed to advance our understanding of certain human pain states [13,14]. One approach to an understanding of the mechanisms underlying post-dorsal rhizotomy autotomy is to consider t h o ~ variables which affect its expression. Several of these are already known, an~ include extent and locus of rhizotomy [1 l],
' Supportedin part by PSC-BHEAward No. 13019. 2 Dr. Rodin's present address is Department of Anatomy, School ~f Medicine, UCLA, Los Angeles, Calif. 90024, U.S.A. 0304-3959/82/0000-0000/$02.75 © 1982 ElsevierBiomedicalPress
30g
as well as presence or absence of presumably pain-producing stimuli before deafferentation [4]. We now report that the simple expedient of changing housing condition can radically alter the incidence and severity of autotomy after dorsal rhizotomy in rats. Forty-four male rats (Sprague-Dawley hooded, 250-300g) were subjected to intradural DR. They were maintained in individual wire mesh cages until one week prior to surgery and, thereafter, in plastic breeding cages (40 cm × 23 cm × 20 cm) lined with Sanichips bedding, either alone (n = 10) or with a similar weight female (n = 34). Surgery was carried out under sodium pentobarbital anesthesia with ether as a sttpplement at the time of root section. After laminectomy T1 I-L1, dorsal roots T! 3-I..6 on the left were cut, care being taken to spare radicular vessels. A section of each root, severa! millimeters in length, was removed. Surgery was performed under 10 × magnification and completeness of lesion was checked under 20 × magnification. Table I summarizes the conditions of the experiment. Some animals in each of the housing conditions were trained before and/or after surgery in a shock avoidance paradigm; some served as yoked controls. Two animals housed alone and one housed with a female were left untrained. Regardless of housing condition, all animals were given a 30 day postoperative recovery period during which no training took place. Animals were examined every 48 h after surgery. They were checked for possible residual sensitivity to pinprick and pressure. The exact location and extent of lesions were drawn on a diagram of the body surface and lesions were scored in accordance with the classification shown in Table II. We found that a score of I (biting of nails)
TABLE I INCIDENCE, DAY OF ONSET, AND SEVERITY OF AUTOTOMY Group
Housing condition
N
Training Pre-op
I
Alone
II
With female
2 8 1 12 4 12 5
None Avoidance None None None Avoidance Yoked-control
Autotomy Post-op a
None None None Avoidance Yoked-control Avoidance Yoked-control
Incidence
Day of onset
(~)
(~)
100 100 0 0 0 0 0
9 (SD= 1) 6 (SD=5)
Severity b (X)
6 ( S D = 1) 7 ( S D = i)
a After 30 day postoperative recovery period during which there was no testing. b Grade 1 lesions (damage to, or removal of, nails) are not included in this table as they were not predictive of subsequent self-mutilation.
309 TABLE 11 CLASSIFICATION OF LESIONS ACCORDING TO SEVERITY !
2 3 4 5 6 7
Nail(s) damaged or removed Digit(s) chewed or removed Skin removed over areas other than digits Muscle damage, localized and/or superficial Muscle damage, widespread and/or deep Self-cannibalization of paw Self-cannibalization of fimb
was not predictive of further biting. Therefore, only severity scores of 2 or greater are included in the data summary. Following surgery, the affected limb was held in an extended position and, initially, was not incorporated into the locomotory sequence. However, when the animal was held so that it struggled or was turned on its back, flexion at the hip and knee was brisk. Over the ensuing weeks function was regained so that, by 3-4 weeks after surgery, locomotion was near normal except for occasional misplacement or dragging of the limb. There was no responsivity to pinprick or to deep pressure applied with a clamp over the affected limb for the entire 6 month period of observation. The paw on the operated side tended to become edematous and somewhat glazed after surgery. If biting did not occur, the edema usually subsided within 3 weeks. Incidence and latency to onset of autotomy are shown in Table I. Each of the 10 rats housed alone self-mutilated to an extreme degree, regardless of whether or not they had been subjected to behavioral training before surgery (severity scores: untrained X = 6; trained X = 7). Biting began within 10 days of DR (before any postoperative training) and usually started at the digits. In 3 cases, the subsequent course of autotomy was distoproximal; in 7, the initial damage to the digits was followed by biting in the thigh area. In 5 of the 10 animals, autotomy progressed until there was cannibalization of the limb to the knee or above; in two, the entire limb was removed to the pelvis. The 3 animals that did not actually cannibalize the limb nevertheless produced such extensive damage that bones were exposed and the rats had to be sacrificed. The two animals that had not been subjected to any training procedures did not differ in type or degree of autotomy from the eight that were trained before surgery. There was no evidence of trauma to body parts other than the rhizotomized leg and its immediately contiguous body area. The animals gained weight at the expected rate and did not show evidence of discomfort, except in two cases in which, when autotomy was far advanced, the animals lost weight aad became lethargic. These animals were euthanized. Responsivity remained intact in the limb contralateral to surgery, and there was no sign of it being scratched [2] or of a hyperalgesic 'mirror' [ 11]. Only one of the animals housed with females showed any sign of trauma to the
310
affected limb during the 6 month period of postoperative observation. This occurred 2 weeks after surgery in the one rat that was not subjected to behavioral training and consisted of an isolated episode of biting the ventral surface of the toes (severity score 1). The wound healed rapidly and no new wounds appeared. Two animals that had been housed with females were separated from their cagemates 4 and 6 months after surgery respectively. Both started to self-mutilate within 28 days of being housed alone, and both cannibalized the leg to the knee. Post-mortem, spinal cords were reexamined microscopically, but no spared fibers were found in any animal. There are several alternative explanations for our results. The first rests on two assumptions: that animals housed alone are under more stress than are those wi,h cagemates and that higher levels of stress increase the incidence of autotomy. There is evidence in support of the first assumption [7]. As far as the second is concerned, stressors have been reported to reduce autotomy after dorsal rhizotomy [1] but to increase the autotomy that follows peripheral nerve section [16]. In the present study, all animals that were housed alone self-mutilated, regardless of whether or not they were subjected to the additional stress of avoidance training or serving as yoked controls before surgery. Among the operated animals housed with females, however, none self-mutilated. The only example of self-biting was quite minor. One of two conclusions seems warranted: either stress does not, in fact, influence autotomy after dorsal rhizotomy or, more likely, a female cagemate counteracts the adverse effects of stress. A second possible explanation for our results is that the presence of a female inhibits self-aggression, which otherwise would result in attack on an insensate body part. Such a pheromonally mediated effect has been demonstrated for outwardly directed aggression, at least in mice [5]. A third interpretation is based on the view that the hyperact, ,':ty which has been observed in dorsal horn [9] and other central [12] neurons following DR is accompanied by dysesthesias, and that these dysesthesias are the basis for autotomy [3]. Autotomy is delayed in the unilaterally deafferented rat, compared with the bilateral preparation, and it has been suggested that this is due to inhibition of dorsal horn neuronal hyperactivity by input to the contralateral intact limb [3,6]. This view is supported by the finding that electrical stimulation of the intact limb in unilaterally dorsal rhizotomized rats further retards the onset of autotomy [10]. It can be argued, then, that the presence of a female cagemate provides body contact to the operated male and this high level of tactile input to intact body areas suppresses the aberrant neuronal activity, thereby attenuating the dysesthesias. Tactile contact between animals was not measured in the ~ :esent study, but casual observation indicated a high level of 'cuddling', and the rate of impregnation of females was sufficient to provide subjects for many other experiments. The suggestion that autotomy is a response to pain induced by deafferentation has been criticized [13]. Certainly, such an interpredation does not fit the behaviors that we describe. Our rats were active, put on weight at an appropriate rate, and remained well groomed, save for the affected leg. They did not show the behavioral depression or lack of appetite that is to be expected from an animal in chronic pain.
311
Even the two animals that did, finally, become lethargic had been in good health during several prior weeks of autotomy. Furthermore, it should be noted that autotomy is not a beha~,ior that is typically associated with pain. On the other hand, dysesthesias, such as itch, provoke many counter-stimulating behaviors and biting would be, for the rat, an expected form of response. It appears less likely that a relatively simple environmental change, housing condition, could affect pain than that it could modify an animal's response to other, less distressing, sensations. If, however, autotomy is indeed an index of a chronic pain state, then a determination of how housing condition alters the incidence of autotomy is important in the context of possible approaches to the treatment of pain.
References 1 Albe-Fessard, D. and Lombard, M.C., Animal models for pain due to central deafferentation. Methods of protection against this syndrome, Pain, Suppl. ! (! 981) 80. 2 Albe-Fessard, D., Nashold, Jr., B.S., Lombard, M.C., Yamaguchi, Y. and Bouneau, F., Rat after dorsal rhizotomy, a possible animal model for chronic pain. In: J.J. Bonica (Ed.), Advances in Pain Research and Therapy, Vol. 2, Raven Press, New York, 1979, pp. 761-766. 3 Basbaum, A.I., Effects of central lesions on disorders produced by multiple dorsal rhizotomy in rats, Exp. Neurol., 42 (1974) 490-501. 4 Dennis, S.G. and Melzack, R., Self-mutilation after dorsal rhizotomy in rats: effects of prior pain and pattern of root lesions, Exp. Neurol., 65 (1979) 412-421. 5 Dixon, A.K. and Mackintosh, J.H., Effects of female urine upon the social behavior of adult male mice, Anita. Behav., 19 (1971) 138-140. 6 Duckrow, R.B. and Taub, A., The effect of diphenylhydantoin on self-mutilation in rats produced by unilateral multiple dorsal rhizotomy, Exp. Neurol., 54 (1977) 33-41. 7 Hatch, A., Wiberg, G., Bah~zs,T. and Grice, H., Long-term isolation stress in rats, Science, 142 (1963) 507. 8 Levitt, M. and Heybach, J.P., The deafferentation syndrome in genetically blind rats: a model of the painful phantom limb syndrome, Pain, 10 (1980) 67-73. 9 Loeser, J.D. and Ward, A.A., Some effects of deafferentation on neurons of the cat spinal cord, Arch. Neurol. (Chic.), 17 (1967) 629-636. • 10 Lombard, M.C., Larabi, Y. and Albe-Fessard, D., Electrophysiological study of cervical dorsal horn cells in partially deafferented rats, Pain, Suppl. 1 (1981) 129. i I Lombard, M.C., Nashold, Jr., B.S., Aibe-Fessard, D., Salman, N. and Sakr, C., Deafferentation supersensitivity in the rat after dorsal rhizotomy: a possible animal model of chronic pain. P~n, 6 (1979) 163-174. 12 Lombard, M.C., Nashold, Jr., B.S. and Pelissier, T., Thalamic recordings in rats with hyperalgesia. In: J.J. Bonica (Ed.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 767-772. 13 Sweet, W.H., Animal models of chronic pain: their possible validation from human experience with posterior rhizotomy and congenital analgesia, Pain, 10 (1981) 275-295. 14 Sweet, W.H. and Wepsi¢, J.G., Treatment of chronic pain by stimulation of fibers of primary afferent neuron, Trans. Amer. neurol. Ass., 10 (1969) 103-107. 15 Wall, P.D. and Sternbach, R.A., The need for an animal model of chronic pain, Pain, 2 (1976) 1-4. 16 Wiesenfeld, Z. and Hallin, R.G., Stress-related behavior in rats with peripheral nerve injuries, Pain, 8 (I 980) 279-284. 17 Wiesenfeld, S. and Lindblom, U., Behavioral and electrophysiological eifects of various types of peripheral nerve lesions in the rat: a comparison of possible models for chronic pain, Pain, 8 (1980) 285-298.
307
Elsevier ~omedical Press
The Influence of Housing Condition on Autotomy Following Dorsal Rhizotomy in Rats Doreen Berman and Barbara E. Rodin 2 Department of Psychology, Queens College, Flushing, N. Y. 11367 (U.S.A. )
(Received 13 July 1981,accepted23 December1981)
Summary Forty-four male rats were subjected to unilateral intradural section of dorsal roots TI3-L6. Of these, 10 were housed alone and 34 were housed with female rats. Each of the 10 animals housed alone self-mutilated to an extreme degree, with 7 cannibalizing the denervated limb. Only one of the animals housed with a female showed any sign of self-biting, and this was a minor, isolated incident. These results are discussed with particular reference to dorsal rhizotomy in rats serving as a model of chronic pain.
Autotomy (self-biting) occurring in animals after dorsal rhizotomy (DR) has been interpreted to reflect a dysesthesic [3,6] or even painful [2,8,11,17] condition. Whether this interpretation is valid is a matter of considerable importance. First, dorsal rhizotomized animals are used in a number of experimental contexts. If such animals are indeed suffering pain, this needs to be known so that a reasoned judgment can be made of lines of research in which they are used, considering costs and benefits to both animals and humans. Second, if the underlying basis of autotomy is pain, then the dorsal rhizotomized animal could well provide the model so vitally needed to advance our understanding of certain human pain states [13,14]. One approach to an understanding of the mechanisms underlying post-dorsal rhizotomy autotomy is to consider t h o ~ variables which affect its expression. Several of these are already known, an~ include extent and locus of rhizotomy [1 l],
' Supportedin part by PSC-BHEAward No. 13019. 2 Dr. Rodin's present address is Department of Anatomy, School ~f Medicine, UCLA, Los Angeles, Calif. 90024, U.S.A. 0304-3959/82/0000-0000/$02.75 © 1982 ElsevierBiomedicalPress
30g
as well as presence or absence of presumably pain-producing stimuli before deafferentation [4]. We now report that the simple expedient of changing housing condition can radically alter the incidence and severity of autotomy after dorsal rhizotomy in rats. Forty-four male rats (Sprague-Dawley hooded, 250-300g) were subjected to intradural DR. They were maintained in individual wire mesh cages until one week prior to surgery and, thereafter, in plastic breeding cages (40 cm × 23 cm × 20 cm) lined with Sanichips bedding, either alone (n = 10) or with a similar weight female (n = 34). Surgery was carried out under sodium pentobarbital anesthesia with ether as a sttpplement at the time of root section. After laminectomy T1 I-L1, dorsal roots T! 3-I..6 on the left were cut, care being taken to spare radicular vessels. A section of each root, severa! millimeters in length, was removed. Surgery was performed under 10 × magnification and completeness of lesion was checked under 20 × magnification. Table I summarizes the conditions of the experiment. Some animals in each of the housing conditions were trained before and/or after surgery in a shock avoidance paradigm; some served as yoked controls. Two animals housed alone and one housed with a female were left untrained. Regardless of housing condition, all animals were given a 30 day postoperative recovery period during which no training took place. Animals were examined every 48 h after surgery. They were checked for possible residual sensitivity to pinprick and pressure. The exact location and extent of lesions were drawn on a diagram of the body surface and lesions were scored in accordance with the classification shown in Table II. We found that a score of I (biting of nails)
TABLE I INCIDENCE, DAY OF ONSET, AND SEVERITY OF AUTOTOMY Group
Housing condition
N
Training Pre-op
I
Alone
II
With female
2 8 1 12 4 12 5
None Avoidance None None None Avoidance Yoked-control
Autotomy Post-op a
None None None Avoidance Yoked-control Avoidance Yoked-control
Incidence
Day of onset
(~)
(~)
100 100 0 0 0 0 0
9 (SD= 1) 6 (SD=5)
Severity b (X)
6 ( S D = 1) 7 ( S D = i)
a After 30 day postoperative recovery period during which there was no testing. b Grade 1 lesions (damage to, or removal of, nails) are not included in this table as they were not predictive of subsequent self-mutilation.
309 TABLE 11 CLASSIFICATION OF LESIONS ACCORDING TO SEVERITY !
2 3 4 5 6 7
Nail(s) damaged or removed Digit(s) chewed or removed Skin removed over areas other than digits Muscle damage, localized and/or superficial Muscle damage, widespread and/or deep Self-cannibalization of paw Self-cannibalization of fimb
was not predictive of further biting. Therefore, only severity scores of 2 or greater are included in the data summary. Following surgery, the affected limb was held in an extended position and, initially, was not incorporated into the locomotory sequence. However, when the animal was held so that it struggled or was turned on its back, flexion at the hip and knee was brisk. Over the ensuing weeks function was regained so that, by 3-4 weeks after surgery, locomotion was near normal except for occasional misplacement or dragging of the limb. There was no responsivity to pinprick or to deep pressure applied with a clamp over the affected limb for the entire 6 month period of observation. The paw on the operated side tended to become edematous and somewhat glazed after surgery. If biting did not occur, the edema usually subsided within 3 weeks. Incidence and latency to onset of autotomy are shown in Table I. Each of the 10 rats housed alone self-mutilated to an extreme degree, regardless of whether or not they had been subjected to behavioral training before surgery (severity scores: untrained X = 6; trained X = 7). Biting began within 10 days of DR (before any postoperative training) and usually started at the digits. In 3 cases, the subsequent course of autotomy was distoproximal; in 7, the initial damage to the digits was followed by biting in the thigh area. In 5 of the 10 animals, autotomy progressed until there was cannibalization of the limb to the knee or above; in two, the entire limb was removed to the pelvis. The 3 animals that did not actually cannibalize the limb nevertheless produced such extensive damage that bones were exposed and the rats had to be sacrificed. The two animals that had not been subjected to any training procedures did not differ in type or degree of autotomy from the eight that were trained before surgery. There was no evidence of trauma to body parts other than the rhizotomized leg and its immediately contiguous body area. The animals gained weight at the expected rate and did not show evidence of discomfort, except in two cases in which, when autotomy was far advanced, the animals lost weight aad became lethargic. These animals were euthanized. Responsivity remained intact in the limb contralateral to surgery, and there was no sign of it being scratched [2] or of a hyperalgesic 'mirror' [ 11]. Only one of the animals housed with females showed any sign of trauma to the
310
affected limb during the 6 month period of postoperative observation. This occurred 2 weeks after surgery in the one rat that was not subjected to behavioral training and consisted of an isolated episode of biting the ventral surface of the toes (severity score 1). The wound healed rapidly and no new wounds appeared. Two animals that had been housed with females were separated from their cagemates 4 and 6 months after surgery respectively. Both started to self-mutilate within 28 days of being housed alone, and both cannibalized the leg to the knee. Post-mortem, spinal cords were reexamined microscopically, but no spared fibers were found in any animal. There are several alternative explanations for our results. The first rests on two assumptions: that animals housed alone are under more stress than are those wi,h cagemates and that higher levels of stress increase the incidence of autotomy. There is evidence in support of the first assumption [7]. As far as the second is concerned, stressors have been reported to reduce autotomy after dorsal rhizotomy [1] but to increase the autotomy that follows peripheral nerve section [16]. In the present study, all animals that were housed alone self-mutilated, regardless of whether or not they were subjected to the additional stress of avoidance training or serving as yoked controls before surgery. Among the operated animals housed with females, however, none self-mutilated. The only example of self-biting was quite minor. One of two conclusions seems warranted: either stress does not, in fact, influence autotomy after dorsal rhizotomy or, more likely, a female cagemate counteracts the adverse effects of stress. A second possible explanation for our results is that the presence of a female inhibits self-aggression, which otherwise would result in attack on an insensate body part. Such a pheromonally mediated effect has been demonstrated for outwardly directed aggression, at least in mice [5]. A third interpretation is based on the view that the hyperact, ,':ty which has been observed in dorsal horn [9] and other central [12] neurons following DR is accompanied by dysesthesias, and that these dysesthesias are the basis for autotomy [3]. Autotomy is delayed in the unilaterally deafferented rat, compared with the bilateral preparation, and it has been suggested that this is due to inhibition of dorsal horn neuronal hyperactivity by input to the contralateral intact limb [3,6]. This view is supported by the finding that electrical stimulation of the intact limb in unilaterally dorsal rhizotomized rats further retards the onset of autotomy [10]. It can be argued, then, that the presence of a female cagemate provides body contact to the operated male and this high level of tactile input to intact body areas suppresses the aberrant neuronal activity, thereby attenuating the dysesthesias. Tactile contact between animals was not measured in the ~ :esent study, but casual observation indicated a high level of 'cuddling', and the rate of impregnation of females was sufficient to provide subjects for many other experiments. The suggestion that autotomy is a response to pain induced by deafferentation has been criticized [13]. Certainly, such an interpredation does not fit the behaviors that we describe. Our rats were active, put on weight at an appropriate rate, and remained well groomed, save for the affected leg. They did not show the behavioral depression or lack of appetite that is to be expected from an animal in chronic pain.
311
Even the two animals that did, finally, become lethargic had been in good health during several prior weeks of autotomy. Furthermore, it should be noted that autotomy is not a beha~,ior that is typically associated with pain. On the other hand, dysesthesias, such as itch, provoke many counter-stimulating behaviors and biting would be, for the rat, an expected form of response. It appears less likely that a relatively simple environmental change, housing condition, could affect pain than that it could modify an animal's response to other, less distressing, sensations. If, however, autotomy is indeed an index of a chronic pain state, then a determination of how housing condition alters the incidence of autotomy is important in the context of possible approaches to the treatment of pain.
References 1 Albe-Fessard, D. and Lombard, M.C., Animal models for pain due to central deafferentation. Methods of protection against this syndrome, Pain, Suppl. ! (! 981) 80. 2 Albe-Fessard, D., Nashold, Jr., B.S., Lombard, M.C., Yamaguchi, Y. and Bouneau, F., Rat after dorsal rhizotomy, a possible animal model for chronic pain. In: J.J. Bonica (Ed.), Advances in Pain Research and Therapy, Vol. 2, Raven Press, New York, 1979, pp. 761-766. 3 Basbaum, A.I., Effects of central lesions on disorders produced by multiple dorsal rhizotomy in rats, Exp. Neurol., 42 (1974) 490-501. 4 Dennis, S.G. and Melzack, R., Self-mutilation after dorsal rhizotomy in rats: effects of prior pain and pattern of root lesions, Exp. Neurol., 65 (1979) 412-421. 5 Dixon, A.K. and Mackintosh, J.H., Effects of female urine upon the social behavior of adult male mice, Anita. Behav., 19 (1971) 138-140. 6 Duckrow, R.B. and Taub, A., The effect of diphenylhydantoin on self-mutilation in rats produced by unilateral multiple dorsal rhizotomy, Exp. Neurol., 54 (1977) 33-41. 7 Hatch, A., Wiberg, G., Bah~zs,T. and Grice, H., Long-term isolation stress in rats, Science, 142 (1963) 507. 8 Levitt, M. and Heybach, J.P., The deafferentation syndrome in genetically blind rats: a model of the painful phantom limb syndrome, Pain, 10 (1980) 67-73. 9 Loeser, J.D. and Ward, A.A., Some effects of deafferentation on neurons of the cat spinal cord, Arch. Neurol. (Chic.), 17 (1967) 629-636. • 10 Lombard, M.C., Larabi, Y. and Albe-Fessard, D., Electrophysiological study of cervical dorsal horn cells in partially deafferented rats, Pain, Suppl. 1 (1981) 129. i I Lombard, M.C., Nashold, Jr., B.S., Aibe-Fessard, D., Salman, N. and Sakr, C., Deafferentation supersensitivity in the rat after dorsal rhizotomy: a possible animal model of chronic pain. P~n, 6 (1979) 163-174. 12 Lombard, M.C., Nashold, Jr., B.S. and Pelissier, T., Thalamic recordings in rats with hyperalgesia. In: J.J. Bonica (Ed.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 767-772. 13 Sweet, W.H., Animal models of chronic pain: their possible validation from human experience with posterior rhizotomy and congenital analgesia, Pain, 10 (1981) 275-295. 14 Sweet, W.H. and Wepsi¢, J.G., Treatment of chronic pain by stimulation of fibers of primary afferent neuron, Trans. Amer. neurol. Ass., 10 (1969) 103-107. 15 Wall, P.D. and Sternbach, R.A., The need for an animal model of chronic pain, Pain, 2 (1976) 1-4. 16 Wiesenfeld, Z. and Hallin, R.G., Stress-related behavior in rats with peripheral nerve injuries, Pain, 8 (I 980) 279-284. 17 Wiesenfeld, S. and Lindblom, U., Behavioral and electrophysiological eifects of various types of peripheral nerve lesions in the rat: a comparison of possible models for chronic pain, Pain, 8 (1980) 285-298.