Inhibitory effect of stimulation of the anterior pretectal ... - Science Direct

Brain Research, 497 (1989) 325-333

325

Elsevier BRES 14803

Inhibitory effect of stimulation of the anterior pretectal nucleus on the jaw-opening reflex C.Y. Chiang, I.C. Chen, J.O. Dostrovsky and B.J. Sessle Department of Physiology, Faculty of Medicine and Faculty of Dentistry, University of Toronto, Toronto, Ont. (Canada) (Accepted 21 February 1989)

Key words: Anterior pretectal nucleus; Jaw-opening reflex; Descending modulation; Trigeminal; Tooth pulp; Rat

The anterior pretectal nucleus (APT) has been recently implicated in sensorimotor integration and has been shown to have suppresive influences on tail flick behaviour and on nociceptive responses of spinal dorsal horn neurones in rats. The present study tested the effect of stimulation of the APT on the rat's digastric jaw-opening reflex elicited by orofacial stimuli. Either ipsilateral or contralateral electrical stimulation at histologically confirmed sites within and immediately subjacent to the APT produced a suppression of the reflex that had an onset of 20-30 ms, peaked around 50 ms and lasted for 200-300 ms; in some cases, a brief period of reflex facilitation preceded the onset of inhibition and the inhibition was sometimes followed by a facilitatory period. No prolonged period of suppression induced by electrical stimulation was noted in these anaesthetized rats. The injection of monosodium glutamate at comparable sites within and subjacent to APT induced reflex suppression that lasted several minutes. These findings represent the first documentation of APT-induced modulation in the trigeminal sensorimotor system, but support recent evidence suggesting the involvement of APT in sensorimotor integration and modulation.

INTRODUCTION T h e existence of several intrinsic neural systems capable of m o d u l a t i n g s o m a t o s e n s o r y transmission is well d o c u m e n t e d . These include efferent projections arising from the b r a i n s t e m reticular formation, red nucleus, h y p o t h a l a m u s , s e n s o r i m o t o r cerebral cortex, p e r i a q u e d u c t a l gray ( P A G ) , and nucleus raphe magnus ( N R M ) (for review, see refs. 3, 10, 13, 33, 40). Recently, a n o t h e r region which has also been implicated in s o m a t o s e n s o r y m o d u l a t i o n is the anterior pretectal nucleus ( A P T ) . This structure n e a r the junction of the d i e n c e p h a l o n and m e s e n c e p h a l o n receives afferent inputs from ascending somatosensory pathways 6"8"18'2°'39'42 as well as somatosensory cortex 6'41 and its p r o j e c t i o n sites include the intral a m i n a r nuclei of the thalamus, thalamic and mesencephalic reticular formation, and possibly the P A G 5"7"38. Electrical stimulation of A P T is r e p o r t e d

to p r o d u c e a p r o l o n g e d suppression of the tail flick response to noxious heat in u n a n a e s t h e t i z e d rats 27"2s and to inhibit selectively the responses to noxious cutaneous stimuli of nociceptive convergent neurones d e e p in the spinal dorsal horn of anaesthetized rats 27. N o study has yet been directed at the possible influences of A P T on trigeminal (V) s e n s o r i m o t o r behaviour, and so the p r e s e n t study was initiated to d e t e r m i n e if A P T stimulation m o d u l a t e s the digastric j a w - o p e n i n g reflex ( J O R ) e v o k e d by V somatosensory stimuli. Some of these data have been briefly r e p o r t e d in abstract form 9A9, MATERIALS AND METHODS The study was carried out on adult male Wistar rats weighing b e t w e e n 310 and 450 g. E a c h rat was anaesthetized (i.p.) with a mixture of a - c h l o r a l o s e

Correspondence: J.O. Dostrovsky, Dept. of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada M5S 1A8. 0006-8993/89/$03.50 ~ 1989 Elsevier Science Publishers B.V. (Biomedical Division)

326 (50 mg/kg) and urethane (0.9 g/kg), and atropine methylnitrate (0.4 mg/kg) was administered subcutaneously. Continuous recordings were made of % expired CO2, ECG and rectal temperature to ensure that these parameters remained within 3-4%, 360500 bpm and 37-38 °C, respectively. Depth of anaesthesia was checked repeatedly throughout the experiment by pinching the paws or touching the cornea; if a withdrawal or corneal reflex was elicited, respectively, a supplementary dose of the chloralose-urethane mixture was administered. After cannulation of the trachea and left external jugular vein, a pair of Teflon-insulated stainless steel wires (diameter 0.1 mm, exposed tip 2 mm) was inserted into the left (n = 16) and/or right (n = 77) anterior digastric muscle to record the J O R evoked by electrical stimulation of the maxillary upper lip or tooth pulp. Upper lip stimulation (single pulses, 0.2-3 mA, 0.1-0.2 ms, 0.5 Hz) was carried out in 52 rats. In 18 of these animals and an additional 41 rats, the tooth pulps of the mandibular incisor teeth were also stimulated (single pulses, 0.1-1.5 mA, 0.3 ms, 0.5 Hz): a hole of 0.5 mm diameter was carefully drilled 1.5 mm coronal to the labial gingival margin of each tooth and an insulated stainless-steel wire (diameter 0.18 mm, exposed tip 0.4 mm) was inserted into the exposed pulp of each tooth and fixed in place, in a procedure similar to that previously described in the cat 34. For many rats, the threshold for the lip or tooth-evoked J O R was noted. The evoked J O R responses were amplified (filter bandwidth 10 Hz to 1 KHz) and displayed on a storage oscilloscope (Tektronix Model 5113). In order to quantify the J O R amplitude, 16 or 32 successive digastric E M G reflex responses were averaged (Neuroiog NL750; 256 bins, 100 or 200 ~s bin width) and the averaged response stored on a computer (LSI 11/23) and subsequently plotted. To test for the effects of electrical conditioning stimulation of A P T on the JOR, an epoxy-varnished tungsten electrode (exposed tip 50/~m, impedance 0.2-0.5 MI2) was stereotaxically placed 24 within APT: at posterior -4.3 to -5.3, lateral 1.5-2.2, vertical 4.5-6.5. Up to 3 electrode penetrations were made in each animal, and the electrode was then left at the site which had the lowest threshold for producing suppression of the JOR. The effects of APT conditioning stimulation (20 ms train of 0.2 ms

pulses at 400 Hz) was tested on the J O R evoked at 1.5-2 x threshold (T) by test stimulation of the upper lip or tooth pulp. As previously described TM 35,36 the magnitude and latency of the J O R evoked by 16 or 32 test (control) stimuli applied at 0.5 Hz to the tooth or lip were compared with those evoked by a similar number of stimuli in the presence of the conditioning stimulus. In the first few rats (n = 6), the time course of the APT-induced modulation was determined by applying the A P T conditioning stimulus at various conditioning-test intervals between 20 and 600 ms. Since these experiments indicated that the maximal suppression of the J O R occurred at conditioning-test intervals of approximately 50 ms (see Results), the APT stimulus was routinely delivered in subsequent rats at 50 ms prior to the onset of the lip or tooth stimulus, and at 70-100/~A (i.e. at around 2 x inhibition threshold). In addition, in 7 rats, the effect of 15 s of A P T stimulation was tested on the J O R by applying 2 ms pulses at 50 Hz stimulation for 15 s or 20 ms trains (0.2 ms pulses at 400 Hz) at 2-4 Hz for 15 s. The electrode positions were subsequently verified histologically for each rat. The stimulation site was lesioned (20-40 /~A anodal current for 10 s), and the animal perfused with 10% formalin. The brainstem was serially sectioned (60/~m sections) and the sections stained with Cresyl violet. Diagrams of sections containing lesions were drawn with the aid of a camera lucida attachment; brainstem structures were identified according to the atlas of Paxinos and Watson 24. An additional 13 rats were also tested for modulation of the J O R as a result of the microinjection of monosodium glutamate (Sigma; dissolved in distilled water). After the lowest threshold site for inducing inhibition by electrical conditioning stimulation of APT had been determined, the APT stimulating electrode was withdrawn and a Hamilton syringe (1 ~1) reinserted stereotaxically into the same site. Then 0.2-0.6/~1 of a 200 mM glutamate solution was injected slowly over a 20-30 s period. The J O R was tested before, during and after the glutamate injection. The drug injection site was subsequently verified histologically. All data were analyzed for statistical significance (P < 0.05) by the Student's two-tailed t-test, the paired-sample t-test and the Mann-Whitney test 43.

327 RESULTS

A

Features of JOR

CONTROL

The J O R could be e v o k e d in all animals e x a m i n e d at m e a n ( + S . E . M . ) thresholds of 0.3 + 0.04 m A (n = 20) for u p p e r lip and 0.5 + 0.04 m A (n = 41) for tooth stimulation. Increasing the intensity of the stimulus to the lip o r tooth resulted in an increase in a m p l i t u d e and a small decrease in latency of the J O R (Fig. 1). Fig. 1 also illustrates the frequency distribution of the latencies of the J O R e v o k e d near threshold (1.1T) and at 10T. The m e a n (__. S . E . M . ) latencies of the J O R e v o k e d by u p p e r lip stimulation at 1.1T and 1 0 T w e r e 7.2 + 0.2 ms (n = 50) and 4.9 + 0.1 ms (n = 40), respectively. T h e m e a n latency of the t o o t h - e v o k e d J O R at 1.1T and 1 0 T w a s 7.9 ___ 0.1 ms (n = 50) and 5.6 + 0.1 ms (n = 40), respectively. In 2 rats, a longer latency response (>21 ms) could be e v o k e d with the stimulus p a r a m eters used; because of its instability, this long-latency response could not be utilized in the conditioningtest paradigm.

Effects of electrical stimulation of APT Electrical stimulation of the A P T suppressed the

T

LIP - d O N

TOOTH-JOR

t

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5

10

LATENCY

LATENCY

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10 0

r~l

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3

4

S

6

T

8

9 10 11 (ms)

0

2

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3

4

5

6

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8

9 10 11 ( m l )

Fig. 1. Jaw opening reflex (JOR) recorded in the digastric muscle and evoked by either upper lip (left column) or tooth (right column) stimulation with graded intensities. Each trace represents an average of 16 responses. Bin width = 100 ~ts. T = threshold intensity. The incidence distribution of JOR latencies evoked by stimulation at 1.1T (stippled column; n = 50) and 10T (blank column; n = 40) are illustrated at bottom.

CONTRA-APT

CONTROL

B CONTROL IPSI-APT CONTROL

4

ms

Fig. 2. Bilateral inhibitory effects of APT stimulation on JOR evoked by upper lip stimulation. The conditioning stimulation current to the contralateral (A) or ipsilateral (B) APT was 160 pA, and conditioning-test interval 50 ms. Each trace represents an average of 16 responses. Bin width is 200 ps.

J O R in all animals tested. Both the a m p l i t u d e and latency of the J O R were affected. Fig. 2 shows an example of A P T - i n d u c e d suppression of the J O R , and also d e m o n s t r a t e s that this m o d u l a t o r y influence was bilateral since A P T conditioning stimulation could suppress the J O R e v o k e d ipsilateral o r contralateral to the A P T stimulation site. The threshold for inhibition was a p p r o x i m a t e l y similar for contralateral and ipsilateral A P T stimulation, e.g. the mean thresholds for c o n t r a l a t e r a l and ipsilateral suppression of lip-evoked J O R were 33 + 2 / x A (n = 5) and 36 + 3 p A (n = 13), respectively. The m e a n current to p r o d u c e suppression to a magnitude of the lip-evoked J O R that was 50% of the control was 61 + 4 p A (n = 7). T h e m e a n threshold for A P T - i n d u c e d suppression of the J O R e v o k e d by tooth stimulation was 43 + 7 / x A (n = 8) and the m e a n current to p r o d u c e a 50% reduction was 74 + 7 ~ A (n = 10). T h e r e was no significant difference in these m e a n threshold values b e t w e e n tooth and lip-evoked J O R . Fig. 3 shows an example of A P T - i n d u c e d suppression of a single m o t o r unit r e c o r d e d in the digastric muscle and excited by lip stimulation. N o t e for this unit the decreased excitability and increased latency of its response during A P T conditioning at 1 T; also note the greater decrease in p r o b a b i l i t y of excitation and increased latency when the A P T conditioning stimulus intensity was increased to 10T.

328 125 JOR

CONTROL

II' ~ -

APT

COND. 15JJA

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APT CONDITIONING

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UOR CONTROL

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U~ J M , A

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o

5 ms

Fig. 3. APT-induced inhibition of a single motor unit in the digastric muscle. The unit's threshold response (control) to ipsilateral upper lip stimulation could be depressed by conditioning stimulation of contralateral APT at 15 ~A (i.e. 1T) and at 150/tA (10T). The conditioning-test interval was 50 ms. Each trace represents 5 superimposed responses to 5 successive lip stimuli.

The time course of the APT conditioning effect on the lip or tooth-elicited JOR was examined in 6 animals (see Materials and Methods). No significant difference was noted between ipsilateral and contralateral stimulation. The onset of inhibition occurred at conditioning-test intervals of 20-30 ms, reached its peak at approximately 50 ms, and lasted for 200-300 ms. The average time course for the APT-induced inhibition of the JOR in the 6 animals is shown in Fig. 4. In 4 of the 6 animals, the onset of inhibition was preceded by a short period of facilitation (mean 163 + 14% of control level of JOR). In 3 animals, a late facilitation (mean 119 +

t

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, . ~ J 0 . 5 mV I 0

Sl I 10

I 20

I 30

I 40 TIME

I so

I 60

I 70

I 80

(rain)

Fig. 5. Effects of several different parameters of ipsilateral APT conditioning stimulation (S1-4) on tooth-evoked JOR that was monitored over a 80 min period. SI: 0.2 ms, 400 Hz, 20 ms train, 50 ms conditioning-test interval; $2:2 ms, 50 Hz continuous stimulation for 15 s; $3:4 Hz train stimulation for 15 s, 0.2 ms, 400 Hz, 20 ms; $4:2 Hz train stimulation for 15 s, 0.2 ms, 400 Hz, 20 ms. The intensity of the APT stimulation was the same for S1-4 (70/~A).

3%) with an onset around 200 ms and duration of approximately 200 ms was noted.

-4.8

APT CONDITIONING

150

-5.3 m m Z O U

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loo n=6

50

O

I

I

I

100

200

300

CONDITIONING-TEST

-

INTERVAL

I

.J

400

500

(ms)

Fig. 4. Time course of APT-induced inhibition of JOR. Each point represents the mean (S.E.M. indicated by vertical bar) change in the JOR induced by ipsilateral or contralateral APT conditioning stimulation in 6 animals.

Fig. 6. Reconstruction of stimulation sites in and adjacent to APT at 4 coronal planes along the rostral-caudal axis. The effectiveness of 35 /~A at each site in inhibiting the JOR is represented according to the symbols defined at lower right and was expressed as a percentage of the control level of the JOR. PF, parafascicular nucleus; PO, posterior thalamic nucleus; ML, medial lemniscus; APT, anterior pretectal nucleus; CG, central grey; MG, medial geniculate body; RN, red nucleus.

329

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INHIBITIO-o -10% O - 25% 25 - 50% • > 50%

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CONDITIONING STIMULUS INTENSITY (alA) Fig. 7. Inhibitory effects on JOR of graded-intensity conditioning stimulation of different regions of the ipsilateral APT. The control level of the JOR is represented as 100% (ordinate). Note that conditioning stimulation of the ventral (V) part of the middle (mid) portion of APT was more effective in inducing inhibition than stimulation of the dorsal (d) part or stimulation of rostral (rost) portion of APT.

In a n o t h e r 7 animals the effect of a 15 s period of A P T stimulation was tested on the excitability of the J O R . Fig. 5 shows a typical example of data from

200

.•150 t,-

"~ 100 L E

~

so

0

GLU I

0

I

2

I

I

4 6 TIME (rain)

I

8

I

10

Fig. 8. Time course of glutamate-induced inhibition of the tooth-evoked JOR. 0.4 ~1 of 200 mM monosodium glutamate injected in the ipsilateral APT produced a statistically significant (**P < 0.01) reduction in JOR amplitude at 0.5, 2 and 5 min. Each vertical bar represents S.E.M. obtained from 7 rats.

Fig. 9. Reconstruction of effective sites, in and adjacent to APT, where glutamate injection induced inhibition of JOR. Glutamate doses were the same as noted in Fig. 8, and inhibition was plotted as for Fig. 6, at 3 coronal planes along the rostral-caudal axis. one of these animals. Note that despite the use of several p a r a m e t e r s of A P T stimulation for the 15 s period, no long-term decrease in J O R excitability was apparent. The most effective sites for inducing suppression of the lip-evoked J O R or t o o t h - e v o k e d J O R were examined in 13 and 19 animals, respectively. Fig. 6 shows at 4 rostrocaudal planes the sites that were effective in producing a > 50%, 2 5 - 5 0 % , or 1 0 - 2 5 % reduction (from control level) in the J O R as well as the ineffective ( < 10% reduction) sites. Note that the most effective sites were c o n c e n t r a t e d in the ventral part of the middle and caudal planes of A P T as well as in the region i m m e d i a t e l y ventral to APT. O t h e r than these ventral loci, few of the o t h e r sites tested outside A P T were effective sites for inducing J O R suppression, A P T was also systematically m a p p e d in 5 animals by making 2 or 3 electrode penetrations ( s e p a r a t e d by 0.3 m m mediolaterally) at rostral, middle and (in some animals) caudal planes of A P T in each animal; 4 - 5 sites ( s e p a r a t e d vertically by 0.5 mm) p e r p e n e t r a t i o n were tested with graded intensities of conditioning stimulation of APT. A g a i n it was evident that the ventral and middle part of A P T was significantly ( M a n n - W h i t ney test; P < 0.01) the most effective in inducing suppression of the J O R (Fig. 7).

330

Effects of glutamate injection into APT When 0.2/~l of monosodium glutamate (200 mM) was injected into APT, a mild inhibition of the JOR was noted in the 6 animals tested; the JOR was reduced to 70 _+ 13% of control values. The injection of 0.4 pl of glutamate had a somewhat more profound effect, and a reduction to 62 + 5% (n = 7) from control was noted. The magnitude and time course of the effect are shown in Fig. 8. Note that the inhibitory effect reached its peak within 20 s after the injection of glutamate into APT, and that the JOR had returned to control values by around 10 min. The histological reconstructions of the glutamate injection sites and their effectiveness are illustrated in Fig. 9, and reveal that the distribution of effective sites is comparable to that noted for sites at which electrical stimulation had been used (Fig. 6). The most effective sites for reflex suppression were concentrated in and immediately subjacent to the ventral part of the middle and caudal regions of APT. DISCUSSION This study has demonstrated that stimulation of the APT evokes a suppression of the JOR evoked by stimulation of either the upper lip or tooth. This finding is in general consistent with observations that APT stimulation suppresses the tail flick response and the nociceptive responses of spinal dorsal horn neurones 27'28. However, while our data have provided the first evidence for the involvement of the APT in descending modulation of V sensorimotor function, we consider that it is premature to relate the observed effects to one directed exclusively or even selectively at nociceptive transmission. The paradigm tested was the JOR elicited by stimulation of the tooth or the upper lip. We have no direct evidence in this study on the receptors and afferents activated by these stimuli, and it is presently unclear from the literature whether the short-latency JOR that we evoked from stimulation of these two sites is a reflection of activation of nociceptive pathways or whether indeed our tooth pulp stimulus may also have activated periodontal receptors (for review, see refs. 21, 22, 25, 31, 32). The latency of the tooth-evoked JOR was similar to that of the JOR

evoked by upper lip stimulation and consistent with that reported previously for the rat's JOR elicited by cutaneous or dental afferents 14'22'25. The stimulus currents effective in evoking the JOR and the latency of the JOR are not inconsistent with the activation of relatively large-diameter, fast-conducting afferents that may not be nociceptive in character (e.g. refs. 14-16, 21, 22, 25, 31). The possibility that the modulatory influence demonstrated from the APT may be directed at nonnociceptive transmission is further reinforced by our recent preliminary findings 9 (Chiang et al. unpublished observations) in the V brainstem sensory nuclear complex that non-nociceptive low-threshold mechanoreceptive neurones recorded in V subnuclei oralis and caudalis as well as caudalis nociceptive neurones can be suppressed by APT conditioning stimulation. The effect of APT stimulation on low-threshold mechanoreceptive neurones in the ascending spinal somatosensory system does not yet appear to have been tested. Recent findings implicating APT as a possible modulatory source in nociceptive processing27'28 are reminiscent of the initial emphasis in analgesia studies given to the demonstration of the modulatory effects of PAG and NRM on somatosensory transmission; subsequent studies have demonstrated that these modulatory influences are directed at non-nociceptive responses as well as nociceptive responses in both the spinal and V somatosensory systems (for review, see refs. 10, 32, 33, 40). When we used a conditioning-test paradigm to determine the time course of the APT-induced suppression of the lip or tooth-evoked JOR, we documented that the inhibition had an onset at 20-30 ms, peaked at 50 ms and lasted for 200-300 ms. While inhibition was always the dominant effect of APT conditioning stimulation, in some instances a brief period of facilitation of the JOR prior to the onset of inhibition and a late facilitation were also seen. This time course of inhibition, and the occurrence sometimes of facilitation, are not inconsistent with the effect and time course of the demonstrated modulatory influences of the sensorimotor cortex on the JOR 23'3°, but the inhibitory effect may be less substantial than that documented with similar stimulation parameters in PAG and NRM x1"35"36. The use of a 15 s period of APT stimulation produced no

331 evidence of a long-term inhibition analogous to that demonstrated for tail flick in unanaesthetized rats 28. This difference might be explained by differences in the sensorimotor systems studied, animal preparations, stimulation parameters, or the use of anasthesia in our investigation. However, the latter two possible explanations are unlikely since we used a variety of stimulation parameters, including ones similar to t h o s e used to demonstrate tail flick suppression 28, and a profound suppression of nociceptive responses in spinal dorsal horn neurones by APT stimulation that lasted several minutes has been reported in anaesthetized rats 27. Our results provide no direct information as to the site(s) of action of the modulatory influence from the APT, i.e. peripheral afferent input, interneurones, or motoneurones. Since we have demonstrated in preliminary observations (see above) that neurones in the V brainstem complex implicated in orofacial reflex interneuronai systems (e.g. refs. 14, 37) can be suppressed by APT conditioning stimulation it is possible that the effect of APT is mediated, at least in part, by an action on excitatory interneurones for the JOR. This view is also consistent with the findings of Rees and Roberts 27"28 that APT stimulation has little effect on spinal motoneurones and motor behaviour but suppresses dorsal horn neurones that may be involved in spinal reflex behaviour. Moreover, no direct projection from APT to the V motor nucleus has been documented 7'29"38 although such an input to the V brainstem somatosensory complex has also not been found; the effects of A P T stimulation on the V system appear to involve relays in other structures such as the PAG (see below). The most effective sites for inducing J O R suppression were in the ventral part of the mid and/or caudal region of APT and the region immediately ventral to APT. Rees and Roberts 27"2s also illustrate sites within and just ventral to APT that were effective in suppressing the tail flick and spinal dorsal horn neurones. The effectiveness of sites ventral to A P T may conceivably be due to the activation of A P T efferent axons since the descending output from APT predominantly involves a ventral trajectory 7"38. Except for the sites just ventral to APT, it is unlikely that the inhibitory effects

observed were due to activation of neural elements outside APT. With the currents used, it is likely that the effective current spread was less than 1 mm 2"11'26 and we documented many examples where sites 1-2 mm dorsal, lateral or medial to effective sites in A P T in the same animals were ineffective in inducing J O R suppression. Furthermore, the distribution of effective sites was very similar for both electrical stimulation and glutamate injection sites. Since glutamate excitation is limited to cell body activation 4, this observation is further supportive of the view that the induced J O R suppression results from activation of neurones within and immediately subjacent to APT. Our data that stimulation of the APT suppresses the J O R evoked by orofacial somatosensory stimuli are consistent with recent findings implicating the APT in somatosensory processing and sensorimotor integration 6'8A7"18'2°'27'28"39'41'42. Further studies are needed on the functional significance of these actions and the pathways involved. The lack of a demonstrated A P T input directly to the spinal or V ascending somatosensory system or motoneurones 7" 17.29.38 suggests an indirect pathway. The bilateral effectiveness of APT stimulation, which has been documented for the first time in the present study, is consistent with anatomical descriptions of reciprocal connections between the left and right A P T 7"38. Other possible projection sites of the APT include the mesencephalic reticular formation and P A G 5' 7,38, sites which have been shown to be effective in inhibiting the J O R 12'32. We have recently demonstrated that local anaesthesia of caudal P A G interferes with APT-induced suppression of the J O R 19. Other effective sites for suppressing the J O R include the NRM (for review, see ref. 32). However, the NRM does not receive a direct APT input 1 and lesions of the NRM or use of antagonists of 5-HT which is implicated in NRM actions are reported not to affect APT-induced modulation (M.H.T. Roberts, personal communication). While these recent data raise possible routes by which the APT modulation of V and spinal sensorimotor function may be effected, the action of APT per se may also be related to forebrain function. In particular, in addition to receiving ascending somatosensory information 6"18"2°'39"42, APT also receives direct input from somatosensory cortex 6"18"41.

332 T h u s it is r e a s o n a b l e to s p e c u l a t e that s o m a t o s e n s o r y

ACKNOWLEDGEMENTS

c o r t i c o f u g a i m o d u l a t i o n of V and spinal s e n s o r i m o We gratefully a c k n o w l e d g e t h e critical c o m m e n t s

tor f u n c t i o n (for r e v i e w , see refs. 14, 32, 40) m a y This possibility is

given by Dr. J.W. H u on an e a r l i e r draft of this

s u p p o r t e d by o u r r e c e n t findings of the similarity in

m a n u s c r i p t , and the technical assistance of Mrs. M.

i n v o l v e a relay via the A P T .

the t i m e c o u r s e of A P T - i n d u c e d suppression of the

Teofilo and K. M a c L e o d . W e are also grateful for

J O R with that p r e v i o u s l y r e p o r t e d for corticofugal

the secretarial assistance of Ms. E Y u e n , and the

inhibition of the reflex (see a b o v e ) and that lesioning

p h o t o g r a p h i c assistance of Mrs. R. B a u e r and Mr. S.

of the A P T i n t e r f e r e s with this corticofugal effect 19.

Burany.

The

study

Medical Research

was s u p p o r t e d Grant

by C a n a d i a n

M T - 4 9 1 8 to B . J . S .

and

U . S . N a t i o n a l Institutes of H e a l t h G r a n t D E 5 4 0 4 to J.O.D.

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