Peripheral nerve stimulation suppression of C-fiber-evoked flexion reflex in rats. Part 1: Parameters of continuous stimulation

Transcription

1 J Neurosurg 63: , 1985 Peripheral nerve stimulation suppression of C-fiber-evoked flexion reflex in rats Part 1: Parameters of continuous stimulation BENGT H. SJOLUND, M.D., PH.D. Science Branch, Medical Board of the Armed Forces, Karolinen, Karlstad, Sweden v" Transcutaneous electrical nerve stimulation (TENS) is now a well established clinical technique to alleviate chronic pain. Its mechanism of action remains unknown and the stimulation parameters used are based on subjective reports from patients. In the present study, a systematic investigation has been performed with conditioning stimulation of different parameters delivered to a dissected skin nerve in the lightly anesthetized rat, utilizing the size of a C-fiber-evoked flexion reflex as a measure of transmission from nociceptive afferent fibers in the spinal cord. A stimulation intensity that recruited both A-beta and A-delta fibers was more effective in depressing the C-fiber-evoked reflex at all frequencies studied than were intensities activating A- beta fibers only. A stimulation frequency of 80 Hz gave the most profound inhibition. The implications for clinical treatment are discussed. KEY WORDS 9 transcutaneous electrical nerve stimulation 9 C-fiber 9 pain 9 peripheral nerve stimulation 9 reflex suppression 9 rat F OR more than a decade, transcutaneous electrical nerve stimulation (TENS) has been used for the alleviation of chronic pain. 5'1~176 With the original technique (conventional TENS), mainly superficial nerve fibers are stimulated at 10 to 120 Hz at an intensity evoking a tingling sensation in the painful region. It has been hypothesized that this stimulation closes a "gate" to nociceptive information entering the human spinal cord. 12 It is well known that various afferent nerves may mutually inhibit each other at a presynaptic level.15 It may therefore be that such mechanisms are at least partly responsible for the effects observed; however, the optimal parameters for producing presynaptic and other forms of long-standing inhibition of afferent impulse in man are not well defined. Only subjective reports of what feels "pleasant" or is preferred by small numbers of patients undergoing TENS have been published. 8'14 The reason for the present study was to undertake a systematic investigation in a mammal of the most suitable parameters for conditioning stimulation of a skin nerve to elicit maximal suppression of a C-fiberevoked flexion reflex in a nearby spinal segment. Materials and Methods Eighty-two Wistar rats, weighing 250 to 300 gm each, were used for the present study. The method of preparation has been described elsewhere. 16 Briefly, the rats were anesthetized with 1% to 1.5% halothane in a moist nitrous oxide/oxygen mixture (2:1). A tracheostomy was made, and one external jugular vein and one carotid artery were cannulated. In one hindlimb, the plantar and sural nerves were dissected for stimulation and the common peroneal and sciatic nerves were exposed for flexion reflex and nerve volley recordings, respectively (Fig. 1). During nerve measurements the animals were paralyzed with gallamine and artificially ventilated. The halothane concentration was lowered to 0.4%, still allowing stable anesthesia with constricted pupils and no blood pressure variations. Blood pressure, end-expiratory CO2 concentration, and rectal temperature were monitored continuously and kept at 120 to 140 mm Hg, 3.5% to 4%, and 37* to 38.5"C, respectively. The reflex discharges elicited by stimulation with five shocks at 10-msec intervals were recorded from two poles as 612 J. Neurosurg. / Volume 63/October, 1985

2 Suppression of C-fiber flexion reflex in rats by TENS were monophasic square waves of 150-msec duration. Preparations where the dissected nerves had a threshold of more than 20 uamp were discarded. FIG. 1. Schematic drawing of the experimental preparation used. The neuronal circuitry is only tentative. Rect. and Integr. = rectified and integrated responses. neurograms. They were rectified, integrated (time constant 20 msec), and displayed on a storage oscilloscope for photographic recording. Usually five sweeps were superimposed at a stimulation frequency of 1 Hz. The maximal amplitude in the 100- to 500-msec interval was used as an index of size of C-fiber-evoked activity in the flexor motoneurons. The strength used for stimulation was expressed as multiples of the threshold that just gave a barely visible nerve volley in the sciatic nerve. 3 The stimulation pulses Results As can be seen in Fig. 2A to H, a short-latency flexion reflex can be evoked in the common peroneal nerve by stimulation at twice threshold; that is, at a strength recruiting only A-beta fibers (compare Lloyd9). An additional long-latency discharge is evoked only at a stimulation strength recruiting C-fibers (Fig. 2I to L). This discharge has properties similar to that of a subgroup of Class 2 neurons in the dorsal horn, 13'16 and is very sensitive to morphine in the cat. 7 The relationship between the raw data (lower sweeps) and their integers (upper sweeps) is illustrated in Fig. 2I to L. The results from a typical experiment with conditioning stimulation are illustrated in Fig. 3. The ipsilateral plantar nerve was stimulated at 100 times threshold at the intervals indicated. Between B and C, the ipsilateral sural nerve was stimulated with a frequency of 40 Hz at 10 times threshold for 30 minutes. It can be seen that after this conditioning stimulation there is a transient (C to E) decrease of the C-fiber-evoked discharge, which returned to the control level 75 minutes after the end of the conditioning stimulation. Figure 4 summarizes the results from all the rats at the two stimulation intensities (twice and 10 times threshold) and the seven stimulation frequencies (10, FIG. 2. Reflex discharges on plantar nerve stimulation at strengths given in multiples of threshold (T) in ipsilateral common peroneal nerve (iper.). Int. = rectified and integrated responses. Upper rows (A-D, E-H): at fast sweep speed; lower row (I-L): at slow sweep speed. J. Neurosurg. / Volume 63 / October,

3 B. H. Sj61und FIG. 3. Results of a typical experiment with ipsilateral plantar nerve stimulation 100 times threshold (iplant. 100T), and a conditioning stimulation of ipsilateral sural nerve at 40 Hz (10 times threshold) for 30 minutes between B and C (arrow). Numbers denote time from start (control) in minutes. Recordings are from the ipsilateral common peroneal nerve (iper.). Int. = rectified and integrated responses. 40, 60, 80, 100, 120, and 160 Hz) tested. Each combination was tested in at least five rats and, after normalization to 100% of reflex control values (stable and measured at least twice with an interval of 15 minutes), the mean amplitude of the integrated reflex response is given at the times indicated. It can be seen that, with a weak intensity (twice threshold, A-D and I-K), 10, 40, 60, and 160 Hz caused no significant depression of the reflex discharge. On the other hand, stimulation at 80 and 100 Hz resulted in marked long-lasting depressions of the C-fiber-evoked reflex. With higher stimulus intensity (10 times threshold, E-H and L-N), only stimulation at 10 Hz caused no significant depression, whereas the other frequencies depressed the reflex discharges to a varying extent. Stimulation at 40 to 80 Hz, however, had a more marked effect than the other frequencies tested. Discussion The results in this study show that a C-fiber-evoked flexion reflex in the rat ~6 is susceptible to a 30-minute conditioning stimulation of afferent fibers in an ipsilateral cutaneous nerve adjacent to that used for eliciting the reflex. ~'2.~7 The reflex depression elicited has a time course similar to the pain relief seen after TENS in man, 4,t~ and indicates a temporary decrease of the transmission from nociceptive C-fibers to second-order neurons in the spinal cord of this mammal. The corresponding flexion reflex in the spinal cord-transected cat has previously been shown to be sensitive to morphine 7 and to low-frequency conditioning stimulation of Group II and III afferent muscle fibers. 17 This study also indicates that a higher stimulus intensity (at 10 times threshold), recruiting A-delta fibers in addition to the A-beta fibers, gives a more efficient suppression of the transmission of nociceptive stimuli than does stimulation at a lower intensity (twice threshold), which activates only A-beta fibers. Moreover, a weak stimulus intensity seems to make the choice of stimulus frequency more critical in that only 80- to 100-Hz stimulation caused a marked reflex depression with this intensity. With higher stimulus intensity, on the other hand, stimulus frequencies in the range of 40 to 160 Hz all gave a significant depression of the reflex discharge. The depression of the C-fiber-evoked flexion reflex in this mammal by long-lasting conditioning stimulation of skin afferent fibers in a nerve adjacent to that used to elicit the reflex may well have a relationship to the pain relief enjoyed by man after TENS. If so, these results speak against a peripheral fatigue phenomenon as the sole cause of such pain relief; instead they stress the importance of selection of proper stimulus parameters for TENS in man. Thus, the highest tolerable stimulus intensity should be used, since marked A-delta fiber stimulation causes an unpleasant pinprick sensation, ~9 and the stimulation frequency should not be less than 40 Hz. If a weaker stimulation is used, the frequency may ideally be around 80 Hz, since there is nothing to indicate a markedly different time course of inhibitory phenomena in the spinal cord from mammal to mammal. A double-blind study in patients with chronic facial pain 5 is in progress in an effort to confirm the application of these findings to man. Acknowledgment The expert technical assistance by Ms. Ulla Ekstrrm is gratefully acknowledged. References 1. Cervero F, Schouenborg J, Sjrlund BH: Effects of conditioning stimulation of somatic and visceral afferent fibres on viscero-somatic and somato-somatic reflexes. J Physiol (Lond) 317:84P, 1981 (Abstract) 2. Chung JM, Fang ZR, Cargill CL, et al: Prolonged, naloxone-reversible inhibition of the flexion reflex in the cat. Pain 15:35-53, Eccles RM, Lundberg A: Synaptic actions in motoneurones by afferents which may evoke the flexion reflex. Arch Ital Bio197: , Eriksson M, Sjrlund B: Acupunturelike electroanalgesia in TNS-resistant chronic pain, in Zotterman Y (ed): Sensory Functions of the Skin. Oxford: Pergamon Press, 1976, pp J. Neurosurg. / Volume 63/October, 1985

4 Suppression of C-fiber flexion reflex in rats by TENS A. % reflex size *-SEM. B. C. D= +,,, 2T, 80 Hz for 30 min. 1804,,,,2T,10 Hz for 30 mi~ 140,,,,2T,40 Hz for 30 min.,,,2t,60 Hz for 30 rain. n ~ / time min. O~'"l;". & b =",,,,~,,~ ~ ~,/,,,. ij E. % reflex size -+SEM. F. G. H. 180I.... lot, 10 HZ for 30 rain. I... 10T,40 Hz for 30 rain.,,,10t,60 Hz for 30 m~.,,,,10t,80 Hz for 30 n=11 60 z _ ---, C"r ~i,,,(,,,/,,,,,'.... " I. 6 reflex size +SEM T,100 Hz for 30 min. m5 140 looi J. K.... 2T,120 Hz for 30 mi~,,,,2t,160 Hz for 30 rain. rp oi C '~";'~'"a () time rnin. *45 +~ '"~"~",,,' L, % reflex size-+sem. M. i 1801,,,,10T,100 Hz for 30 n ~,-10T,120 Hz for 30 mitt n:5 N.,,,,10T,160 Hz for 30 rain. n=7 Student's t-tesl o~ - 20C,~,~e / ~ time min. +15 *3'0 +4~5 +60 ee 9 9 eee p< o,ooos.. eee ~ o,oos ee ~.o,o~s 9 p< 0,05 FIG. 4. Summary of all experiments. Controls in each rat normalized to 100%. Each dot is the mean amplitude (_ standard error of the mean (SEM)) of the number of rats given (n). C = control; A = after conditioning stimulation (interrupted bar); T = threshold. J. Neurosurg. / Volume 63/October,

5 B. H. Sj61und 5. Eriksson M, Sj61und BH, Sundb~rg G: Pain relief from peripheral conditioning stimulation in patients with chronic facial pain. J Neurosurg 61: , Ignelzi R J, Nyquist JK: Direct effect of electrical stimulation on peripheral nerve evoked activity: implications in pain relief. J Neurosurg 45: , Koll W, Haase J, Block G, et al: The predilective action of small doses of morphine on nociceptive spinal reflexes on low spinal cats. lnt J Pharmaeol 2:57-65, Linzer M, Long DM: Transcutaneous neural stimulation for relief of pain. IEEE Trans Biomed Eng 23: , Lloyd DPC: Reflex action in relation to pattern and peripheral source of afferent stimulation. J Neurophysiol 6: , Loeser JD, Black RG, Christman A: Relief of pain by transcutaneous stimulation. J Neurosurg 42: , Long DM: Cutaneous afferent stimulation for relief of pain. Prog Neurol Surg 7:35-51, Melzack R, Wall PD: Pain mechanisms: a new theory. A gate control system modulates sensory input from the skin before it evokes pain perception and response. Science 150: , Men6trey D, Giesler GJ Jr, Besson JM: An analysis of response properties of spinal cord dorsal horn neurones to nonnoxious and noxious stimuli in the spinal rat. Exp Brain Res 27:15-33, Picaza JA, Cannon BW, Hunter SE, et al: Pain suppression by peripheral nerve stimulation. Part I. Observations with transcutaneous stimuli. Surg Neurol 4: , Schmidt RF: Presynaptic inhibition in the vertebrate central nervous system. Ergebn Physiol 63:20-101, Schouenborg J, Sj61und BH: Activity evoked by A- and C-afferent fibers in rat dorsal horn neurons and its relation to a flexion reflex. J Neurnphysiol 50: , Sj61und BH, Eriksson MBE: Naloxone-reversible depression of C-fiber evoked flexion reflex in low spinal cats after conditioning electrical stimulation of primary afterents. Nenrosci 1.ell Snppl 3:264, 1979 (Abstract) 18. Sj61und BH, Eriksson MBE: Stimulation techniques in the management of pain, in Kosterlitz HW, Terenius LY (eds): Pain and Society. Weinheim: Verlag Chemie, 1980, pp Trouche E, Massion J: Parameters of cutaneous nerve stimulation provoking a defensive reaction in the cat. Arch Ital Biol 118:33-50, Wall PD, Sweet WH: Temporary abolition of pain in man. Science 155: , 1967 Manuscript received January 11, This study was supported by grants from Medtronic Inc., Minneapolis, Minnesota, and from the Swedish Medical Research Council (No ). Address reprint requests to: Bengt H. Sj61und, M.D., Ph.D., Science Branch, Medical Board of the Armed Forces, Karolinen, S Karlstad, Sweden. 616 J. Neurosurg. / Volume 63 / October, 1985