Spine

Spine. 2005 May 1;30(9):1014-8.

Effect of noxious electrical stimulation of the peroneal nerve on stretch reflex activity of the hamstring muscle in rats: possible implications of neuronal mechanisms in the development of tight hamstrings in lumbar disc herniation.

Hirayama J, Yamagata M, Takahashi K, Moriya H.

Center for Spinal Disorder and Low Back Pain, Department of Orthopedic Surgery, Chiba Rosai Hospital, Chiba, Japan. j-hiraya@bk9.so-net.ne.jp

STUDY DESIGN: The effect of noxious electrical stimulation of the peroneal nerve on the stretch reflex electromyogram activity of the hamstring muscle (semitendinous) was studied. OBJECTIVE: To verify the following hypothetical mechanisms underlying tight hamstrings in lumbar disc herniation: stretch reflex muscle activity of hamstrings is increased by painful inputs from an injured spinal nerve root and the increased stretch reflex muscle activity is maintained by central sensitization. SUMMARY OF BACKGROUND DATA: It is reported that stretch reflex activity of the trunk muscles is induced by noxious stimulation of the sciatic nerve and maintained by central sensitization. METHODS: In spinalized rats (transected spinal cord), the peroneal nerve was stimulated electrically as a conditioning stimulus. Stretch reflex electromyogram activity of the semitendinous muscle was recorded before and after the conditioning stimulus. RESULTS: Even after electrical stimulation was terminated, an increased stretch reflex activity of the hamstring muscle was observed. CONCLUSIONS: It is likely that a central sensitization mechanism at the spinal cord level was involved in the increased reflex activity. Central sensitization may play a part in the neuronal mechanisms of tight hamstrings in lumbar disc herniation.

Spine. 2001 Mar15;26(6):602-9.

Effects of electrical stimulation of the sciatic nerve on background electromyography and static stretch reflex activity of the trunk muscles in rats: possible implications of n euronal mechanisms in the development of sciatic scoliosis.

Hirayama J, Takahashi Y, Nakajima Y, Takahashi K, Yamagata M, Moriya H.

Physiology, School of Medicine, Chiba University, Chiba, Japan. j-hiraya@bk9.so-net.ne.jp

STUDY DESIGN: The effects of electrical stimulation of the sciatic nerve on background electromyographic and static stretch reflex activity of the trunk muscles were studied. OBJECTIVES: To verify the hypotheses that sciatic scoliosis is induced reflexively by radiculopathic pain, and that scoliosis might be maintained by prolonged asymmetric alteration of the trunk muscle tonus caused by central sensitization of the spinal neurons that constitute the postural reflex pathways. SUMMARY OF BACKGROUND DATA: Sciatic scoliosis usually occurs with convexity to the side of the herniated disc. The neuronal mechanism of sciatic scoliosis has not been well clarified. Recently, prolonged alteration of motor function in the hindlimbs of animals caused by central sensitization has been reported. METHODS: In spinalized rats (transection of the spinal cord), the sciatic nerve was stimulated electrically as a conditioning stimulus. Muscle stretch elicited by bending of the lumbar spine was applied as a test stimulus. Background and stretch reflex activities of the bilateral oblique abdominal, psoas, and quadratus lumborum muscles were recorded. Rats in which MK-801, an N-methyl-d-aspartate antagonist, was preadministered also were used. RESULTS: The conditioning stimulus enhanced background electromyographic activity in bilateral oblique abdominal, contralateral psoas, and quadratus lumborum muscles. Furthermore, the conditioning stimulus induced prolonged facilitation and depression of stretch reflex activity of the contralateral psoas and quadratus lumborum, and ipsilateral psoas and quadratus lumborum muscles, respectively. Preadministration of MK-801 reduced these excitatory and inhibitory effects. CONCLUSION: It was found that the pattern of electromyographic activity of the trunk muscles evoked by sciatic nerve stimulation coincided with the typical direction of sciatic scoliosis in patients with lumbar disc herniation. It was supposed that the prolonged asymmetric alteration of the trunk muscle tonus was caused by central sensitization, and that central sensitization of spinal neurons may underlie the neuronal mechanism of sciatic scoliosis.

3: Brain Res. 1985 Feb 25;328(1):23-32.

Effects of a distant noxious stimulation on A and C fibre-evoked flexion reflexes and neuronal activity in the dorsal horn of the rat.

Schouenborg J, Dickenson A.

In the halothane-anaesthetized rat, the responses of 49 neurons in the lumbo-sacral cord and the reflex discharge in the common peroneal nerve following electrical stimulation of the sural nerve were recorded in order to study possible relations between neuronal events and reflex nerve discharges. A distant noxious stimulus (to activate Diffuse Noxious Inhibitory Controls (DNIC) of Le Bars et al.) was used as a conditioning stimulus. Only the responses of neurons receiving an input from both A and C fibres were studied. The neurons were classified as class 1 (low threshold mechanoreceptive input only, n = 2), class 2 (nonnoxious and noxious inputs, n = 34) or class 3 (responding to noxious stimuli only, n = 13). During conditioning stimulation the C fibre evoked discharge was inhibited in 32 out of 34 class 2 neurons. The A fibre-evoked discharge was simultaneously inhibited in 29 of these neurons. The main effect of the distant noxious stimulation on the C fibre evoked neuronal discharge was to decrease the discharge by a constant number of spikes, independent of the level of evoked activity. Only one class 3 neuron was inhibited during conditioning stimulation and none of the class 1 cells were influenced by DNIC. During conditioning stimulation the late and prolonged C fibre evoked reflex nerve discharge (latency 160-200 ms, duration up to several hundred ms) was strongly depressed. Concomitantly, a short-lasting reflex nerve discharge appeared over the interval 115-160 ms. This released reflex nerve discharge (RR) had a constant latency. There was no simultaneous change of the A beta evoked reflex nerve discharge. After the end of the distant noxious stimulation the late C fibre evoked reflex nerve discharge (latency 160-200 ms) recovered. Concomitantly, the RR disappeared. The possibility that the class 2 neurons and the class 3 neurons are intercalated in different reflex pathways is discussed.

4: Spine. 2002 Feb 1;27(3):E56-63.

Electrophysiologic evidence for an intersegmental reflex pathway between lumbar paraspinal tissues.

Kang YM, Choi WS, Pickar JG.

Department of Biomedical Engineering, University of Iowa and the Iowa Spine Research Center, Iowa City, USA.

STUDY DESIGN: Electrophysiologic recordings were obtained from a lumbar paraspinal nerve or muscle in the anesthetized cat while electrically stimulating a paraspinal nerve or facet capsule in an adjacent lumbar segment. A variety of approaches were used to demonstrate the reflex nature of both the nerve and the muscle response. OBJECTIVE: The primary purpose of this study was to seek electrophysiologic evidence for the presence of intersegmental reflexes between adjacent lumbar vertebral segments. A second purpose of this study was to confirm a previous procedure used to evoke paraspinal reflexes. This previous work had shown that electrical stimulation of the L1-L2 facet joint capsule elicits electromyographic activity from multifidus muscle one to two vertebral segments caudal to the stimulated facet in a porcine preparation. SUMMARY OF BACKGROUND DATA: Biomechanical approaches have stressed the need for spinal stability to avoid conditions that could give rise to low back dysfunction. It seems reasonable to believe that reflex interactions between vertebral segments contribute to the sensorimotor integration of lumbar paraspinal tissues. It also seems reasonable to believe that alterations or abnormal elicitation of these reflexes could contribute to biomechanical changes associated with low back pain and paraspinal muscle spasm. METHODS: Experiments were performed on 23 alpha-chloralose anesthetized adult cats. In eight cats the L3, L4, and L5 medial branch from each dorsal ramus was exposed and placed on a bipolar hook electrode. In six cats the L4 medial branch was stimulated and a compound action potential was recorded from the L3 medial branch. In three of the six cats the L5 medial branch was stimulated and a compound action potential was recorded from the L3 medial branch. In one cat the L4 medial branch was stimulated and a compound action potential was recorded from the L5 medial branch. In one cat the L3 medial branch was stimulated and a compound action potential was recorded from the L5 medial branch. At the end of each protocol the medial branch was cut just proximal to the stimulating electrode to confirm that the compound action potential was reflexive in nature and not initiated by volume conduction. In 15 cats three approaches were used to confirm that multifidus electromyographic activity evoked by electrical stimulation of a lumbar facet capsule was reflexive in nature: 1) by anesthetizing the site of the sensory endings, i.e., the facet capsule, 2) by injecting lidocaine intrathecally to block neural conduction centrally, i.e., within the spinal canal, or 3) by cutting the afferent pathway, i.e., the medial branch of the dorsal ramus. RESULTS: Electrical stimulation of the medial branch of the dorsal ramus innervating the medial-most lumbar paraspinal tissues evoked a compound action potential in the medial branch innervating the medial-most paraspinal tissues one and two segments away. Stimulating voltages between 2 and 70 V were necessary to evoke the compound action potential. Each compound action potential was reflexive in nature because cutting the lumbar medial branch proximal to its contact with the stimulating electrode abolished each compound action potential. The conduction velocity of the reflex ranged from 3.5 to 6.1 m/sec. Electrical stimulation of a lumbar facet capsule evoked lumbar multifidus muscle electromyographic activity. However, injecting lidocaine intrathecally or transecting the medial branch of the dorsal ramus had no effect on electromyographic activity. Injecting lidocaine into the facet or into the multifidus muscle around the facet joint (near the stimulating electrode) significantly decreased the magnitude of the multifidus electromyography. CONCLUSION: These results indicate that afferent impulses conveyed by the medial branch of the dorsal ramus reflexly altered efferent activity to an adjacent lumbar segment. This intersegmental paraspinal reflex may span at least one or two vertebral segments. The data suggest that electrical stimulation of the facet joint capsule may not have reflexly elicited multifidus activity because neither chemical interruption (intrathecal lidocaine) nor physical interruption (nerve transection) of the presumed reflex pathway diminished or abolished the electromyographic response. Volume conduction of the stimulating currents likely elicited multifidus activity during electrical stimulation of the facet capsule. When using electrical stimulation of neural paraspinal tissues to evoke reflex muscle activity, appropriate control experiments must be performed to clearly demonstrate the reflexive nature of the response.

5: Brain Res. 1996 Nov 11;739(1-2):263-75.

Spinal NK1 receptors contribute to the increased excitability of the nociceptive flexor reflex during persistent peripheral inflammation.

Parsons AM, Honda CN, Jia YP, Budai D, Xu XJ, Wiesenfeld-Hallin Z, Seybold VS.

Department of Cell Biology and Neuroanatomy, University of Minnesota, Minneapolis 55455, USA.

Hyperalgesia is a characteristic of inflammation and is mediated, in part, by an increase in the excitability of spinal neurons. Although substance P does not appear to mediate fast synaptic events that underlie nociception in the spinal cord, it may contribute to the hyperalgesia and increased excitability of spinal neurons during inflammation induced by complete Freund's adjuvant. We examined the role of endogenous substance P in changes in the excitability of spinal neurons during adjuvant-induced, peripheral inflammation by determining the effect of a selective NK1 receptor antagonist (RP67580) on the nociceptive flexor reflex in adult rats. Experiments were conducted 2 or 3 days after injection of adjuvant. Animals exhibited moderate thermal hyperalgesia at this time. The flexor reflex was evoked by electrical stimulation of the sural nerve and was recorded in the ipsilateral hamstring muscles. The flexor reflex ipsilateral to the inflamed hindpaw was enhanced approximately two-fold compared to the flexor reflex evoked in untreated animals as determined by the number of potentials and the duration of the reflex. The enhanced reflex in adjuvant-treated animals was most likely due to an increase in the excitability of spinal interneurons because short-latency activity in the hamstring muscles did not differ between untreated animals and adjuvant-treated animals following electrical stimulation of the L5 dorsal root or the nerve innervating the muscle with a stimulus that was 1.3-1.5 times the threshold for excitation of A-fibers. Intrathecal administration of RP67580 (2.3 and 6.8 nmol) attenuated the flexor reflex evoked in adjuvant-treated animals, but had no effect in untreated animals. Intravenous or intraplantar injection of RP67580 (6.8 nmol) did not affect the flexor reflex in adjuvant-treated animals indicating a spinal action of the drug following intrathecal administration. RP68651, the enantiomer of RP67580, was without effect at doses up to 6.8 nmol, indicating that the effects of comparable doses of RP67580 were due to an action of the drug at NK1 receptors. However, intrathecal administration of 23 nmol of both drugs attenuated the reflex in adjuvant-treated and control animals indicating that effects of RP67580 at this dose were not mediated entirely by its action at NK1 receptors. Overall, these data suggest that endogenous substance P has a role in the increased excitability of spinal interneurons observed during persistent inflammation and support the hypothesis that substance P released in the spinal cord contributes to the hyperalgesia that accompanies adjuvant-induced persistent, peripheral inflammation.

6: Spine. 1998 Sep 1;23(17):1853-8; discussion 1859.

Regional correspondence between the ventral portion of the lumbar intervertebral disc and the groin mediated by a spinal reflex. A possible basis of discogenic referred pain.

Takahashi Y, Sato A, Nakamura SI, Suseki K, Takahashi K.

Department of Orthopaedic Surgery, School of Medicine, Chiba University, Japan.

STUDY DESIGN: Lumbar peripheral nerves were examined to determine whether they were responsive to electrical stimulation of the ventral portion of the lumbar disc in anesthetized rats. OBJECTIVES: To confirm by electrophysiologic means the neural correspondence between the ventral portion of the lumbar disc and the groin. SUMMARY OF BACKGROUND DATA: Patients with a degenerated lumbar disc occasionally report groin pain. However, its pathogenesis has not been investigated. The authors of the current study found that chemical stimulation of the ventral portion of rat lumbar disc caused cutaneous plasma extravasation in the groin, and thereby hypothesize the neural relation between the lumbar disc and the groin. METHODS: The ventral portion of rat L5-L6 disc was electrically stimulated, and the elicited action potentials were recorded from the iliohypogastric, genitofemoral, lateral femoral cutaneous, sural, and sciatic nerves. The roles of the lumbar sympathetic trunks and spinal cord in the generation of the action potentials were examined. RESULTS: Action potentials were elicited principally in the genitofemoral nerve; the action potentials of the genitofemoral nerve were not influenced by transection of the cervical spinal cord, whereas they disappeared immediately after death, which indicates that they are induced by a spinal reflex. The action potentials were reduced considerably after destruction of the lumbar sympathetic trunks, suggesting that they comprise an afferent path of the reflex. CONCLUSIONS: The ventral portion of the lumbar disc had spatial relation to the groin area via a spinal reflex. Such a relation suggests that a disorder in the ventral portion of the lumbar disc may be a possible source of groin referred pain.

7: Spine. 2000 Feb 15;25(4):411-7.

Electrical stimulation of the rat lumbar spine induces reflex action potentials in the nerves to the lower abdomen.

Takahashi Y, Hirayama J, Nakajima Y, Ohtori S, Takahashi K.

Department of Orthopaedic Surgery, School of Medicine, Chiba University, Japan. BXM06740@nifty.ne.jp

STUDY DESIGN: The distribution of the nerve action potentials reflexively elicited by electrical stimulation of the lumbar spine was investigated in rats. OBJECTIVES: To elucidate the relation between the lumbar spine and other body regions that compose the spinal reflex. SUMMARY OF BACKGROUND DATA: The hypothesis was that the ventral portion of the L5-L6 disc spatially corresponds to the groin. METHODS: In Experiments 1 and 2, wire electrodes were placed 1) in the ventral and dorsal portions of the disc, facet joint, and muscle fascia at L5-L6, and 2) in the ventral portions of L3-L4, L4-L5, L5-L6, and L6-S discs. A needle electrode was inserted in the L5-L6 disc by 0.4-mm increments, and action potentials were serially recorded from the genitofemoral nerve. RESULTS: Experiments 1 and 2: Reflex action potentials were elicited in the iliohypogastric (T13 and L1), ilioinguinal (L1), and genitofemoral (L2) nerves. Experiment 1: Stimulation of the disc induced reflex discharges significantly more frequently than stimulation of the facet joint and muscle fascia. Experiment 2: The more cranial the disc stimulated, the more frequently the reflex discharge was induced in the iliohypogastric nerve. Experiment 3: The depth of stimulation did not influence the size of the reflex action potential. CONCLUSIONS: Electrical stimulation of the lumbar disc and facet joint induced reflex discharges in the nerves to the lower abdominal regions. It was postulated that the reflex discharges are related to muscle contraction resulting in referred pain in the loin and groin.

8: Eur J Pain. 2001;5(2):175-85.

The spatial organization of central sensitization of hind limb flexor reflexes in the decerebrated, spinalized rabbit.

Clarke RW, Harris J.

Division of Animal Physiology, School of Bioscience, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK. robert.clarke@nottingham.ac.uk

This study was designed to investigate the relationship between the location of a noxious stimulus and the magnitude and duration of the plastic effects induced by that stimulus in withdrawal reflexes acting about the knee and the ankle, in rabbits. Reflexes were evoked in the nerves to the anterior tibial and semitendinosus flexor muscles by electrical stimulation at the toes. Repetitive, high intensity electrical stimulation of nerve trunks (sural, medial gastrocnemius, superficial peroneal, tibial, 100 pulses, 20 V, 1 ms at 0.5 Hz) was generally found to be a poor method for inducing central sensitization in these flexor reflexes. 'Natural' noxious stimulation induced more reliable enhancement of both reflexes. Mechanical (clamp) or chemical (mustard oil) stimulation of the heel induced prolonged (median duration >30 min) increases in reflexes to both muscles. Mechanical (clamp and superficial pinch) or chemical (mustard oil) stimulation of the toes, and injection of bradykinin into the gastrocnemius muscles or into the soft tissues of the sole of the foot, also led to enhancement of both reflexes, with the median duration of potentiation between 7 and 30 min. The effects obtained from deep tissue stimulation were generally weaker than those obtained after stimulation of superficial structures. These data show that there were no major differences in the effects obtained from the heel vs the toes, or between the two reflexes. It appears that the spatial organization of the spinal mechanisms underlying central sensitization of flexor withdrawal reflexes is rather more crudely drawn than that pertaining to the reflexes themselves. Furthermore, the data indicate that in the present preparation, afferents from deep tissues are no more effective in generating central sensitization than those from superficial structures. Copyright 2001 European Federation of Chapters of the International Association for the study of pain.

9: J Physiol. 1999 Oct 15;520 Pt 2:591-604.

Voluntary and reflex control of human back muscles during induced pain.

Zedka M, Prochazka A, Knight B, Gillard D, Gauthier M.

Division of Neuroscience, University of Alberta, Edmonton, Canada. zedka@lnf.cnrs-mrs.fr

1. Back pain is known to change motor patterns of the trunk. The purpose of this study was to examine the motor output of the erector spinae (ES) muscles during pain in the lumbar region. First, their voluntary activation was assessed during flexion and re-extension of the trunk. Second, effects of cutaneous and muscle pain on the ES stretch reflex were measured, since increased stretch reflex gain has been suggested to underlie increased muscle tone in painful muscles. 2. The trunk movement and electromyographical (EMG) signals from the right and left ES during pain were compared with values before pain. Controlled muscle pain was induced by infusion of 5 % saline into the right lumbar ES. Cutaneous pain was elicited by mechanical or electrical stimulation of the dorsal lumbar skin. The stretch reflex was evoked by rapidly indenting the right lumbar ES with a servo-motor prodder. 3. The results from the voluntary task show that muscle pain decreased the modulation depth of ES EMG activity. This pattern was associated with a decreased range and velocity of motion of the painful body segment, which would normally serve to avoid further injury. Interestingly, when subjects overcame this guarding tendency and made exactly the same movements during pain as before pain, the EMG modulation depth was still reduced. The results seem to reconcile the controversy of previous studies, in which both hyper- and hypoactivity of back muscles in pain have been reported. 4. In the tapped muscle, the EMG response consisted of two peaks (latency 19.3 +/- 2.1 and 44.6 +/- 2.5 ms, respectively) followed by a trough. On the contralateral side the first response was a trough (26.2 +/- 3.2 ms) while the second (46.4 +/- 4.3 ms) was a peak, similar to the second peak on the tapped side. Cutaneous pain had no effect on the short-latency response but significantly increased the second response on the tapped side. Surprisingly, deep muscle pain had no effect on the stretch reflex. A short-latency reciprocal inhibition exists between the right and left human ES. 5. It is concluded that deep back pain does not influence the stretch reflexes in the back muscles but modulates the voluntary activation of these muscles.

10: Eur Spine J. 1997;6(6):398-401.

Spinal manipulation results in immediate H-reflex changes in patients with unilateral disc herniation.

Floman Y, Liram N, Gilai AN.

Spine Surgery Unit, Hadassah University Hospital, Jerusalem, Israel. Yizhar@cc.huji.ac.il

The aim of this clinical investigation was to determine whether the abnormal H-reflex complex present in patients with S1 nerve root compression due to lumbosacral disc herniation is improved by single-session lumbar manipulation. Twenty-four patients with unilateral disc herniation at the L5-S1 level underwent spinal H-reflex electro-physiological evaluation. This was carried out before and after single-session lumbar manipulation in the side-lying position. Eligibility criteria for inclusion in the study were: predominant sciatica, no motor or sphincteric involvement, unilateral disc herniation at the L5-S1 level on CT or MR imaging, age between 20 and 50 years. H-reflex responses were recorded bilaterally from the gastrosoleous muscle following stimulation of tibial sensory fibers in the popliteal fossa. H-reflex amplitude in millivolts (HR-A) and H-reflex latency in milliseconds (HR-L) were measured from the spinal reflex response. Pre- and post-manipulation measurements were compared between the affected side and the healthy side. Statistical evaluation was performed by the Wilcoxon matched-pairs test (SPSS). Thirteen patients displayed abnormal H-reflex parameters prior to lumbar manipulation, indicating an S1 nerve root lesion. The mean amplitude was found to be significantly lower on the side of disc herniation than on the normal, healthy side (P = 0.0037). Following manipulation, the abnormal HR-A increased significantly on the affected side while the normal HR-A on the healthy side remained unchanged (P = 0.0045). There was a significant difference between latencies on the affected side and those on the healthy side (P = 0.003). Following manipulation there was a trend toward decreased HR-L. However, this trend did not reach statistical significance (P = 0.3877). Eight patients displayed no H-reflex abnormalities before or after manipulation. Their respective HR-A and HR-L values did not change significantly following manipulation. Three additional patients were excluded due to technical difficulties in achieving manipulation or measuring spinal reflex. These observations may lend physiological support for the clinical effects of manipulative therapy in patients with degenerative disc disease.

11: Exp Brain Res. 1988;72(2):305-15.

Do muscle afferents contribute to the cervical response evoked by electrical stimulation of the median nerve in man?

Reni L, Ratto S, Abbruzzese G, Abbruzzese M, Favale E.

Department of Neurology, University of Genova, Italy.

The possible contribution of low threshold muscle afferents to the postsynaptic component (N13) of the cervical response evoked by electrical stimulation of the median nerve (MN) was investigated in normal subjects. Electroneurographic (ENG) and electromyographic (EMG) correlates of the reflex motoneuronal discharge (RMND) were recorded simultaneously. A. No reflex activity could be elicited by stimulation of the MN at the wrist, at least in the resting subjects, while well developed ENG (P2 efferent volley) and EMG (H reflex) monosynaptic responses occurred following stimulation of the MN at the elbow at suitable strengths. In neither case could a surface correlate of interneuronal activity evoked by muscle afferents be demonstrated. B. Recruitment curves showed that at stimulus intensities above maximal for the H reflex both P2 and H responses started to decrease until they completely disappeared, while N13 showed further enhancement. C. Subthreshold conditioning stimulation of the MN enhanced both P2 and H responses, while vibratory muscle stimuli provoked a clearcut suppression of these two responses. In contrast, N13 was completely unaffected by either manoeuvre. D. No cervical evoked activity could be detected following tendon tapping of the anterior forearm muscles in spite of the appearance of well developed cortical responses and the ENG and EMG correlates of the T reflex. E. Conditioning volleys elicited by tendon taps of the anterior forearm muscles suppressed both P2 and H responses following stimulation of the MN at the elbow without affecting the related N13 component. Conditioning supramaximal stimulation of the MN at the wrist suppressed the N13 component of the cervical response evoked by stimulation of the MN at the elbow without affecting the related reflex responses. No component chronologically related to the RMND could be recorded at the posterior neck region during suppression of N13, thus ruling out the possibility that failure to detect the RMND (as well as its interneuronal concomitants) with cervical electrodes is due to a masking effect of the N13 component. G. Conditioning tendon taps of anterior forearm muscles provoked a clearcut reduction of the primary cortical response to finger stimulation without affecting the postsynaptic component of the related cervical response. It is concluded that neither segmental (motoneuronal or interneuronal in origin) nor ascending postsynaptic impulses generated in the spinal cord by stimulation of low threshold muscle afferents contribute to N13, the latter being probably due to activation of both short and long axoned spinal neurons by cutaneous afferents.

Clin Neurophysiol. 2004 Dec;115(12):2798-810.

Expansion of nociceptive withdrawal reflex receptive fields in spinal cord injured humans.

Andersen OK, Finnerup NB, Spaich EG, Jensen TS, Arendt-Nielsen L.

Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7, D3, Aalborg DK-9220, Denmark. oka@hst.aau.dk

OBJECTIVE: In spinal cord injured (SCI) subjects, exaggerated withdrawal reflexes associated with a dominant flexor pattern irrespective of stimulation site have been reported. In the present study, withdrawal reflex receptive field (RRF) was determined in complete SCI subjects (N=9). METHODS: Distributed electrical stimulation was applied to the sole of the foot, and reflexes in tibialis anterior, soleus, biceps femoris, and vastus lateralis muscles were recorded together with knee and ankle movement trajectories. A group of spinally intact subjects (N=10) were included as controls. With the subjects in supine position, stimulation was applied to 10 different sites on the foot sole. Based on the tibialis anterior reflex threshold for stimulation on the mid foot sole, two stimulus intensities (1.1 times the reflex threshold and 1.4 times the reflex threshold) were used for all 10 sites. RESULTS: In SCI subjects, dorsi-flexion dominated independent of stimulus site and the tibialis anterior RRF covered the entire foot sole in contrast to a well-defined tibialis anterior receptive field at the medial, distal foot sole in the spinally intact subjects. Further, the soleus RRF also covered the entire sole in the SCI subjects. The reflexes in biceps femoris and vastus lateralis muscles were small and associated with weak knee flexion at all 10 sites in the SCI subjects and in the controls. CONCLUSIONS: The RRF of the ankle flexor and the ankle extensor muscles both covered the entire sole of the foot indicating an expansion of the RRFs following spinal cord injury. The expansion is most likely due to lack of descending inhibitory control and/or increased sensitivity of the spinal reflex loop in the SCI subjects. SIGNIFICANCE: The study improves the understanding of spinal reflex control in spinal intact and spinal cord injured subjects.

2: Brain Res Brain Res Rev. 2004 Oct;46(2):163-72.

The organization of motor responses to noxious stimuli.

Clarke RW, Harris J.

School of Biosciences and Institute of Neuroscience, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire LE12 5RD, United Kingdom. Robert.clarke@nottingham.ac.uk

Withdrawal reflexes are the simplest centrally organized responses to painful stimuli, making them popular models for the study of nociception. Until recently, it was believed that withdrawal was a single reflex response involving excitation of all flexor muscles in a limb with concomitant inhibition of extensors. However, recent findings suggest that withdrawal reflexes are tailored to produce the most appropriate movement according the site at which the stimulus is applied, which could require extensors to act as the primary movers. This idea is supported by new evidence obtained from the direct measurement of limb movements, although these data indicate that differentiation of withdrawal reflexes is most readily seen from stimuli applied to the plantar surface of the foot. Injurious stimuli augment the protective function of reflexes by enhancing (sensitizing) reflexes that protect the injured site and inhibiting those reflexes that might exacerbate the insult. The areas from which a reflex can be sensitized closely match those from which the reflex itself can be evoked, provided that the spinal cord is intact. If descending pathways are interrupted, sensitization can be evoked from a much wider area. Thus, the exact movement made in a withdrawal reflex is determined by the location of the evoking stimulus and whether the reflex sensitized or inhibited after an injury depends on the relationship between the site of the injury and the movement made by the reflex. The factors should be borne in mind when designing experiments in which reflexes are used as the end point in studies of nociception.

3: J Neurophysiol. 2004 Dec;92(6):3375-84. Epub 2004 Jul 14.

Contribution of muscle afferents to prolonged flexion withdrawal reflexes in human spinal cord injury.

Hornby TG, < a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Tysseling%2DMattiace+VM%22%5BAuthor%5D" title="Click to search for citations by this author.">Tysseling-Mattiace VM, Benz EN, Schmit BD.

Department of Physical Therapy, University of Illinois, Chicago, Illinois 60612, USA. tgh@uic.edu

The contribution of force-sensitive muscular afferents to prolonged flexion withdrawal reflexes, or flexor spasms, after human spinal cord injury (SCI) was investigated. In three separate experimental conditions, flexion reflexes were triggered in subjects with SCI using trains of electrocutaneous stimuli delivered at the foot and lower leg and compared with reflexes elicited via intramuscular (i.m.) electrical stimuli. In the first experiment, flexion reflexes were elicited using i.m. stimuli to the tibialis anterior (TA) in the majority of subjects tested. The ratio of peak isometric ankle to hip torques during i.m.-triggered reflexes were proportionally similar to those evoked by electrocutaneous foot or shank stimulation, although the latency to onset and peak flexion torques were significantly longer with i.m. stimulation. In the second experiments, the amplitude and frequency of i.m. TA stimulation were varied to alter the stimulus-induced muscle torque. Peak ankle and hip torques generated during the flexion reflex responses were correlated to a greater extent with stimulus-induced muscle torques as compared with the modulated stimulus parameters. In the third experimental series, i.m. stimuli delivered to the gastrocnemius (GS) elicited flexion reflexes in approximately half of the subjects tested. The combined data indicate a potentially prominent role of the stimulus-induced muscle contraction to the magnitude and latency of flexor reflex behaviors after i.m. TA stimulation. Results after i.m. GS stimulation indicate multi-joint flexion reflexes can also be elicited, although to a lesser extent than i.m. TA stimulation.

4: J Physiol. 2003 Jan 1;546(Pt 1):251-65.

Organisation of sensitisation of hind limb withdrawal reflexes from acute noxious stimuli in the rabbit.

Harris J, Clarke RW.

Division of Animal Physiology, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK.

Spatial aspects of central sensitisation were investigated by studying the effects on three hind limb withdrawal reflexes of an acute noxious stimulus (20 % mustard oil) applied to a number of locations around the body in decerebrate and in anaesthetised rabbits. Reflex responses to electrical stimulation of the toes were recorded from the ankle flexor tibialis anterior (TA) and the knee flexor semitendinosus (ST), whereas responses to stimulation of the heel were recorded from the ankle extensor medial gastrocnemius (MG). In non-spinalised, decerebrated, pentobarbitone-sedated preparations, flexor reflexes were facilitated significantly from sites on the plantar surface of the ipsilateral foot but were either inhibited or unaffected by stimulation of sites away from this location. The heel-MG reflex was facilitated from the ipsilateral heel and was inhibited from a number of ipsilateral, contralateral and off-limb sites. In decerebrated, spinalised, pentobarbitone-sedated animals, mustard oil applied to any site on the ipsilateral hind limb enhanced both flexor reflexes, whereas the MG reflex was enhanced only after stimulation at the ipsilateral heel and was inhibited after stimulation of the toe tips or TA muscle. Mustard oil on the contralateral limb had no effect on any reflex. In rabbits anaesthetised with pentobarbitone and prepared with minimal surgical interference, the sensitisation fields for the heel-MG and toes-TA reflexes were very similar to those in non-spinal decerebrates whereas that for toes-ST was more like the pattern observed in spinalised animals. In no preparation was sensitisation or inhibition of reflexes related to the degree of motoneurone activity generated in direct response to the sensitising stimulus. This study provides for the first time a complete description of the sensitisation fields for reflexes to individual muscles. Descending controls had a marked effect on the area from which sensitisation of flexor reflexes could be obtained, as the sensitisation fields for the flexor reflexes evoked from the toes were larger in spinalised compared to decerebrated, non-spinalised animals. The intermediate sizes of sensitisation fields in anaesthetised animals suggests that the area of these fields can be dynamically controlled from the brain. On the other hand, the sensitisation field for the heel-MG reflex varied little between preparations and appears to be a function of spinal neurones.

5: Eur J Pain. 2001;5(2):175-85.

The spatial organization of central sensitization of hind limb flexor reflexes in the decerebrated, spinalized rabbit.

Clarke RW, Harris J.

Division of Animal Physiology, School of Bioscience, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK. robert.clarke@nottingham.ac.uk

This study was designed to investigate the relationship between the location of a noxious stimulus and the magnitude and duration of the plastic effects induced by that stimulus in withdrawal reflexes acting about the knee and the ankle, in rabbits. Reflexes were evoked in the nerves to the anterior tibial and semitendinosus flexor muscles by electrical stimulation at the toes. Repetitive, high intensity electrical stimulation of nerve trunks (sural, medial gastrocnemius, superficial peroneal, tibial, 100 pulses, 20 V, 1 ms at 0.5 Hz) was generally found to be a poor method for inducing central sensitization in these flexor reflexes. 'Natural' noxious stimulation induced more reliable enhancement of both reflexes. Mechanical (clamp) or chemical (mustard oil) stimulation of the heel induced prolonged (median duration >30 min) increases in reflexes to both muscles. Mechanical (clamp and superficial pinch) or chemical (mustard oil) stimulation of the toes, and injection of bradykinin into the gastrocnemius muscles or into the soft tissues of the sole of the foot, also led to enhancement of both reflexes, with the median duration of potentiation between 7 and 30 min. The effects obtained from deep tissue stimulation were generally weaker than those obtained after stimulation of superficial structures. These data show that there were no major differences in the effects obtained from the heel vs the toes, or between the two reflexes. It appears that the spatial organization of the spinal mechanisms underlying central sensitization of flexor withdrawal reflexes is rather more crudely drawn than that pertaining to the reflexes themselves. Furthermore, the data indicate that in the present preparation, afferents from deep tissues are no more effective in generating central sensitization than those from superficial structures. Copyright 2001 European Federation of Chapters of the International Association for the study of pain.

6: Neurosci Lett. 2001 May 18;304(1-2):120-2.

Adaptive changes in withdrawal reflexes after noxious stimulation at the heel and the toes in the decerebrated rabbit.

Clarke RW, Wych BE, Harris J.

Division of Animal Physiology, School of Biosciences, Sutton Bonington Campus, LE12 5RD, Loughborough, UK. robert.clarke@Nottingham.ac.uk

In decerebrated rabbits, reflexes evoked by electrical stimulation of the toes in the ankle flexor tibialis anterior were enhanced for > 30 min after application of 20% mustard oil to the base of the toes, whereas responses of the ankle extensor medial gastrocnemius to stimulation of the heel were depressed for > 20 min by the same stimulus. Applied to the heel, mustard oil had inconsistent effects on the flexor reflex but potentiated the extensor response for approximately 1 h. Intrathecal co-administration of naloxone (25 microg) with the selective alpha(2)-adrenoceptor antagonist RX 821002 (200 microg) enhanced both reflexes to more than twice pre-drug values and reduced or abolished all effects of mustard oil. These data confirm that the location of a noxious stimulus is an important determinant of the subsequent adaptive changes in reflexes, and indicate roles for endogenous opioids and noradrenaline in these processes.

7: Exp Brain Res. 2001 Feb;136(3):303-12.

Withdrawal reflex organisation to electrical stimulation of the dorsal foot in humans.

Sonnenborg FA, Andersen OK, Arendt-Nielsen L, Treede RD.

Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Denmark.

The present study investigated excitatory reflex receptive fields for various muscle reflex responses and reflex mediated ankle joint movements using randomised electrical stimulation of the dorsal and plantar surface of the foot in 12 healthy subjects. Eleven electrodes (0.5-cm2 cathodes) were mounted on the dorsal side and three on the plantar side of the foot. A low (1.5 times pain threshold) and a high (2.3 times pain threshold) stimulus intensity were used to elicit the reflexes. EMG signals were recorded from tibialis anterior (TA), gastrocnemius medialis (GM), soleus (SO), biceps femoris (BF), and rectus femoris (RF) muscles together with the ankle movement measured by a goniometer. The withdrawal pattern evoked from the dorsal side consisted of two separate responses with different receptive fields: (1) early EMG responses in GM and BF (50-120 ms) evoking knee flexion, probably of purely spinal origin, and (2) a late response in GM and SO (120-200 ms) that may be under supraspinal control. The ankle flexor TA was significantly activated in both time windows, but in 11 of 12 subjects its contraction was too small to cause significant dorsal flexion. In the ankle joint inversion was the most dominant movement. Stimulation of the plantar side resulted in activation of TA when stimulating the forefoot and in activation of triceps surae when stimulating the heel. These observations show that painful stimuli activate appropriate muscles depending on stimulus location to initiate the adequate withdrawal. For proximal muscles (e.g. knee flexors) the receptive field covers almost the entire foot (dorsal and plantar sides) while more distal muscles have a smaller receptive field covering only a part of the foot. This adequate withdrawal movement suggests a more refined withdrawal reflex organisation than a stereotyped flexion of all joints to avoid tissue damage.

8: Neurosci Res. 2000 May;37(1):79-82.

Neither a general flexor nor a withdrawal pattern of nociceptive reflexes evoked from the human foot.

Ellrich J, Steffens H, Schomburg ED.

Institute of Physiology, University of Erlangen, D-91054, Erlangen, Germany.

In humans motor reactions to noxious radiant heat stimulation of the sole and the dorsum of the foot do not resemble a locally specific pattern of multiple modular withdrawal reflexes but rather a general flexion reflex pattern with a few exceptions which did neither fit a withdrawal nor a flexion reflex pattern. The partly observed excitatory feed back to foot extensors from nociceptive afferents of the foot sole is functionally discussed as a foot stabilizing mechanism under particular conditions.

9: Muscle Nerve. 1999 Nov;22(11):1520-30.

Modular organization of human leg withdrawal reflexes elicited by electrical stimulation of the foot sole.

Andersen OK, Sonnenborg FA, Arendt-Nielsen L.

Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Fredrik Bajers Vej 7, D3, DK-9220, Aalborg, Denmark. oka@smi.auc.dk

Human withdrawal reflex receptive fields were determined for leg muscles by randomized, electrical stimulation at 16 different positions on the foot sole. Tibialis anterior, gastrocnemius medialis, peroneus longus, soleus, rectus femoris, and biceps femoris reflexes, and ankle joint angle changes were recorded from 14 subjects in sitting position. Tibialis anterior reflexes were evoked at the medial, distal foot and correlated well with ankle dorsal flexion. Gastrocnemius medialis reflexes were evoked on the heel and correlated with plantar flexion. Stimulation on the distal, medial sole resulted in inversion (correlated best with tibialis anterior activity), whereas stimulation of the distal, lateral sole evoked eversion. Biceps femoris reflexes were evoked on the entire sole followed by a small reflex in rectus femoris. A detailed withdrawal reflex organization, in which each lower leg muscle has its own receptive field, may explain the ankle joint responses. The thigh activity consisted primarily of flexor activation.

10: Pain. 1994 Aug;58(2):141-55.

Sensitization of high mechanothreshold superficial dorsal horn and flexor motor neurones following chemosensitive primary afferent activation.

Woolf CJ, Shortland P, Sivilotti LG.

Department of Anatomy and Developmental Biology, University College London, UK.

Nociceptive primary afferents have the capacity to induce a state of increased excitability or central sensitization in dorsal horn neurones. This contributes to the mechanical hypersensitivity (allodynia) which occurs after peripheral tissue injury where low-mechanothreshold primary afferent activation begins to elicit pain. The relative susceptibility of dorsal horn cells with an apparent exclusive nociceptive input (nociceptive-specific (NS) or high-threshold (HT) cells) and those with a convergent input from low- and high-threshold mechanoreceptors (wide-dynamic-range (WDR) or multireceptive neurones) to sensitivity changes has been disputed. We have examined whether high-mechanothreshold neurones in the superficial dorsal and the ventral horn can modify their sensitivity following cutaneous application of the chemical irritant mustard oil. This produced both a prolonged reduction in the mechanical threshold of the cutaneous flexion withdrawal reflex, recorded from semitendinosus alpha-motor neurones, and an increase in the activity evoked in these neurones by low-intensity touch stimuli to the glabrous skin. Eight NS or HT only cells, defined in terms of their cutaneous mechanoreceptive field properties, were recorded in the superficial dorsal horn before and after cutaneous application of mustard oil. Mustard oil was applied outside of the mechanical receptive field of the cells and produced a transient increase in action potential discharge in 4 cells but increased the mechanoreceptive field size in all cells for 30-60 min. Mechanical thresholds declined in 6 cells to levels associated with low-threshold (LT) and WDR cells, and this was accompanied by recruitment of a novel brush/touch response in 5 cells. The responses evoked by graded electrical stimulation of the sural nerve were tested in 5 cells. Only 1 cell failed to show any change after mustard oil. In 3 cells, an increase in the response to A-fibre afferents occurred, a novel A-fibre response was recruited in 2 cells and the C-fibre response increased in 2 cells. Cells in the superficial dorsal horn of the rat spinal cord that are normally NS can begin, therefore, to respond to LT primary afferent mechanoreceptors after an increase in central excitability produced by activation of peripheral chemoreceptors. Sensitization of these, as well as of WDR cells, may contribute to the generation of post-injury mechanical pain and reflex hypersensitivity.

11: J Neurosci. 1986 May;6(5):1433-42.

Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat.

Woolf CJ, Wall PD.

Changes in the excitability of the hamstring flexor withdrawal reflex produced by conditioning stimuli applied to C-afferent fibers of different origins have been examined in the decerebrate spinal rat. In the absence of conditioning stimuli, the flexor reflex elicited by a standard suprathreshold mechanical stimulus to the toes is stable when tested repeatedly for hours. Three categories of conditioning stimuli have been used in an attempt to modify the excitability of the flexor reflex; electrical stimulation of a cutaneous (sural) nerve or a muscle (gastrocnemius-soleus) nerve at C-fiber strength; the application of mustard oil, a chemical irritant that activates chemosensitive C-afferents, to the skin or injected intramuscularly and intraarticularly; and the indirect activation of high-threshold muscle afferents by fused tetanic contractions of the tibial muscles. Conditioning stimuli of an intensity sufficient to activate C-afferent fibers result in a heterosynaptic facilitation of the flexor motoneuronal response to the standard test input, which lasts from 3 min to more than 3 hr, depending on the stimulus and the C-afferents activated. Pretreatment of the sciatic nerve with the C-fiber neurotoxin capsaicin abolishes all the postconditioning facilitations, which is an indication that it is likely that it is C-afferents that are primarily responsible for the facilitatory effects of the conditioning stimuli, although some A delta afferents may contribute. Capsaicin pretreatment does not modify the reflex response to the test stimulus. The most prolonged increase in the excitability of the flexor reflex resulted from intraarticular injections of 5 microliter mustard oil. Using the subsequent injection of lignocaine intraarticulary, it was found that the prolonged facilitation of the reflex is triggered by the afferent input generated by the conditioning stimulus and does not require an ongoing input for its maintenance. These results indicate that there is a spectrum of central changes in the stimulus response relations of the spinal cord resulting from the activation of C-fibers of different origins. The prolonged duration of some of these changes means that the peripheral activation of C-afferents will modify the functional response of the spinal cord to other inputs applied long after the conditioning input, and this may be responsible for some of the sensory and motor alterations found after peripheral tissue injury.

12: Neuroscience. 1985 Oct;16(2):395-404.

Injury-induced plasticity of the flexor reflex in chronic decerebrate rats.

Woolf CJ, McMahon SB.

The hindlimb-flexor-withdrawal reflex elicited by stimulation of the skin of the hindpaw has been examined in chronic decerebrate rats. This flexor reflex manifests as a typical phasic avoidance response when measured either behaviourally in the decerebrate rat or electrophysiologically in the decerebrate-spinal preparation. Once the threshold of the cutaneous flexor-reflex afferents in the skin have been exceeded a brief burst of activity with only a short afterdischarge occurs in the flexor motoneurones. The response to sustained stimuli adapts rapidly. In the absence of any treatment to the hindlimb the threshold, duration and responsiveness of the reflex remains stable when tested repeatedly. Thermal or chemical stimuli of sufficient intensity to produce tissue injury and prolonged local inflammation in a hindpaw of the chronic decerebrate rat result in marked and long-lasting (several weeks) alterations in the ipsilateral withdrawal reflex. The mechanical threshold necessary to elicit the reflex by stimulation of the hindpaw falls so that light touch or brush can now elicit a response instead of the firm pressure or pinch required pre-injury. Suprathreshold stimuli to the inflamed skin generate a sustained oscillating pattern of flexion in contrast to the brief flicking movement found in control animals. Electromyographic recordings from the hamstring flexor muscles ipsilateral to the inflamed hindpaw show decreased mechanothresholds, increased spontaneous activity, prolonged afterdischarges to brief stimuli and a slowly adapting tonic response to sustained stimulation. Populations of single cutaneous mechanoreceptive C-primary afferents recorded both from untreated decerebrate rats and from rats with an inflamed hindpaw are indistinguishable in terms of their response properties. There is no difference in threshold, spontaneous activity or afterdischarge between the two populations. The possible mechanisms responsible for the conversion of the high threshold phasic flexor reflex into a low threshold tonic reflex are discussed as are the possible implications for sensory disorders that accompany chronic injury in man.

13: J Physiol. 1985 Jul;364:249-63.

Cutaneous receptive field and morphological properties of hamstring flexor alpha-motoneurones in the rat.

Cook AJ, Woolf CJ.

Intracellular recordings have been made from twenty antidromically identified posterior biceps femoris/semitendinosus (p.b.s.t.) hamstring flexor alpha-motoneurones in the decerebrate-spinal rat. The hamstring motoneurones had either low or no spontaneous background activity. In nineteen of the twenty cells high-frequency phasic responses could be elicited by stimulation of the ipsilateral hind paw with firm pressure or pinch. There was no response to light touch or brush. Contralateral cutaneous mechanoreceptive fields with higher thresholds and weaker responses were present in 70% of the motoneurones. Noxious heating of the ipsilateral hind paw produced excitatory responses in six of eight cells tested and two of these cells also responded to heating of the contralateral hind paw. Stimulation of the ipsilateral sural nerve at graded strengths that successively activated A beta, A delta and C afferents produced excitatory post-synaptic potentials (e.p.s.p.s) at progressively longer latencies in the motoneurones. The C-fibre induced e.p.s.p. lasted up to 200 ms. Horseradish peroxidase was injected into ten motoneurones and in seven cases full reconstructions of dendritic field, cell body and axon could be made. In agreement with previous reports from studies in the cat, the dendritic fields of rat motoneurones are very extensive in the rostrocaudal, mediolateral and dorsoventral planes. The general pattern of dendritic branching for each motoneurone in this functionally homogeneous population was uniformly organized. Three major spatial orientations were always present: a rostrocaudally restricted series of dendrites emerging from the cell body and directed dorsolaterally towards the dorsolateral funiculus with branches in the lateral dorsal horn, a laterally, and a ventromedially directed series of branches arranged obliquely in the ventral horn, both of which were distributed rostrocaudally for equal distances from the cell body. Many of these dendritic branches terminated within the lateral and ventral white columns. Although the sizes of the rat flexor motoneurones' somas (51 +/- 4.9 micron, S.E., n = 10) were similar to those of cat lumbosacral alpha-motoneurones, the tip-to-tip rostrocaudal extent of their dendritic fields (1130 +/- 34 micron, S.E., n = 7) was half that reported in the cat. These results are discussed in terms of the organization of the cutaneous flexor withdrawal reflex in the rat.

14: Brain Res. 1984 Jun 15;303(2):299-312.

The cutaneous contribution to the hamstring flexor reflex in the rat: an electrophysiological and anatomical study.

Woolf CJ, Swett JE.

The location and properties of the cutaneous receptive fields responsible for detecting the flexor withdrawal reflex in the posterior head of biceps femoris (pBF) and semitendinosus (ST) components of the hamstring muscle have been examined in unanaesthetized decerebrate rats, spinalized at T10-T11. Single alpha-motoneurone efferents were recorded from the nerve to pBF and the principal head of ST and their responses to ipsi- and contralateral hindlimb skin stimulation investigated. The efferents to both muscles characteristically had a low or absent background discharge and they all had mechanoreceptive fields on the ipsilateral foot. The mechanical threshold of these fields was high with no response to light touch or brush. Fifty-four percent of these units also had a smaller and weaker contralateral mechanoreceptive field. The only apparent difference between ST and pBF efferents was that more ST efferents had contralateral fields than pBF units. Noxious, hot and cold thermal stimuli applied to the ipsilateral foot activated 56% of the efferents. Mustard oil, a chemical irritant, produced a long-lasting flexor response when applied to the ipsilateral foot. The responses of these efferents to stimulation of A beta, A delta and C cutaneous afferents in the sural nerve were also studied. Short latency reflexes were elicited in all efferents by A beta inputs, longer latency reflexes were elicited in 64% by A delta inputs and very long latency responses with long afterdischarges were found in 73% of the units to C inputs. Retrograde labelling of the hamstring motoneurones with WGA-HRP indicated that they lay in ventrolateral lamina IX extending from the caudal portion of the third lumbar segment to the junction of the 5th and 6th lumbar segments. Transganglionic labelling of small diameter primary afferent terminals in the dorsal horn of cutaneous nerves innervating the foot revealed that the longitudinal distribution corresponded closely with that of the hamstring motor nucleus. The flex-or reflex in the spinal rat provides a useful model therefore, for studying how the input in nociceptive afferents is processed and transformed within the spinal cord, to produce appropriate outputs.

15: Pain. 1984 Apr;18(4):325-43.

Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat.

Woolf CJ.

Chronic decerebrate rats have been prepared by the aspiration of all the cranial contents rostral to the mesencephalon. With careful nursing, body temperature control and orogastric tube feeding the rats survive for up to 4 months. The decerebrate rats have intact brain stem and spinal reflexes including locomotion, righting reflexes and grooming. Mild noxious cutaneous thermal and mechanical stimuli of an intensity which does not produce tissue damage evokes flexion withdrawal reflexes, vocalization, orientation to the site of the injury and generalized escape or attack responses, from the animals. These effects are transient and only occur during the application of the stimulus. The rats do not exhibit stress reactions, aggression or vocalization when handled before or after application of such noxious stimuli. The production of localized tissue injury by thermal or chemical means results in long term alterations (up to 6 weeks) in the thresholds and excitability of the flexor reflex, both ipsilateral and contralateral, to the site of the injury. It is proposed that the reduction in the flexor reflex threshold is analogous to the hyperalgesia and allodynia that follows tissue injury in man and that the long term alterations in the flexor reflex in the chronic decerebrate rat provide a model for the study of chronic pain, without the ethical problems associated with such studies in intact animals.

Jenkins S, Richarson B, Clarke RW

Effects of a selective 5-HT(1B/1D) receptor agonist on spinal and trigeminal reflexes in the anaesthetized rabbit.Br J Pharmacol. 2000 Nov;131(5):974-80.

Division of Animal Physiology, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD.

The effects of the 5-HT(1B/1D) receptor agonist L-741,604 on a trigeminally-mediated (jaw depressor) reflex and a spinally-mediated (flexion withdrawal) reflex have been compared between spinalized and intact, anaesthetized rabbits. L-741,604 depressed the jaw depressor reflex dose-dependently in all animals, to a median of 5% (inter-quartile range, IQR, 3 - 28%, n=18) of pre-drug levels after a cumulative dose of 3.1 micromol kg(-1) i.v. This effect was reversed by the 5-HT(1B/1D) antagonist GR 127,935 (1 - 2 micromol kg(-1) i.v.). The flexion withdrawal reflex was depressed by L-741, 604 in non-spinalized animals, to a median of 22% (IQR 10 - 36%, n=10) of pre-drug levels after the highest dose, an action that was reversed by GR 127,935. In spinalized rabbits, L-741,604 up to 0.3 micromol kg(-1) i.v. cumulative increased the flexion reflex to a median of 189% (IQR 169 - 198%, n=8) of pre-drug controls. With higher doses the reflex decreased, so that after 3.1 micromol kg(-1) it was 75% (IQR 55 - 96%) of pre-drug levels. Subsequent GR 127,935 increased reflexes to a median of 180% (IQR 136 - 219%) of controls. L-741,604 increased arterial blood pressure and decreased heart rate in both preparations, effects that were reversed by GR 127,935. Thus, when the spinal cord was intact L-741,604 inhibited spinal and trigeminal reflexes in the same way. Although spinalization enabled a non-5-HT(1B/1D)-mediated excitatory effect of L-741,604 on spinal reflexes, there was a clear inhibitory effect of the drug at high doses. These data suggest that L-741,604 inhibits spinal reflexes by increasing descending inhibition and by a direct action in the cord. The same processes could apply to inhibition of trigeminally-mediated events.