January-March 1982Ind. J. Physiol. Pharrnac-

the Gairdner Foundationcological Society (1959)Society (1979).

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ANTERIOR CEREBELLUM AS A SITE FOR MORPHINE ANALGESIAAND POST-STIMULATION ANALGESIA

P. K. DEY AND A. K. RAY

Neurophysiology Research Unit,Department of Physiology, Institute of Medical Sciences,

Banaras Hindu University, Varanasi - 221 005

(Received on August 31, 1981)

Summary : The microinjection of 10 ",g Morphine into culmen region of anterior cerebellum producedprofound analgesia in rats. and this was antagonised with intraperitoneal administration of naloxone.On the other hand. the same injection of morphine into lobus simplex and declive region of posteriorcerebellum was without any effect on nociception. Further it was observed that chronic surgicalablation of culmen-centralis region of anterior cerebellum markedly diminished the duration of analgesiaelicited with systemic administration of morphine. though ablation per se had no' influence on nocicep-tion. Also. the focal electrical stimulation of culmen region for a brief period exhibited post-stimulationanalgesia These findings indicate that anterior cerebellum specifically plays some role in the modulationof physiological mechanisms of pain relief.

Key words: morphine analgesia cerebellum post-stimulation analgesia naloxone

INTRODUCTION

There is now considerable evidence that morphine analgesia can be elicited follow-ing its injection into the different loci of the brain: the thalamus (2); the hypo thalamus(4, 7. 19. 20); the periaqueductal gray matter (8, 14, 16); the floor of the fourth ventricle(6) and the ventral surface of the brainstern (3. 15). It has also been demonstrated thatfocal electrical stimulation of some of the aforementioned sites such as, PAG (10). hvpotha-lamus (1) and thalamus (11) can result in the development of anti nociceptive responsein rats. Siegel and Wepsic (17) reported that antinociceptive response can also be elicitedfollowing focal electrical stimulation of anterior cerebellum in monkeys. In the present

/

4 Dey and Ray Januarv-March 1982Ind. J. Phvsio l, Pharrnac,

paper. we now report that the microinjection of morphine in anterior cerebellum producesprofound analgesia in rats. and that the analgesic response of morphine after its systemicadministration is greatly attenuated in chronic anterior cerebellectomised rats. We furtherobserved that focal electrical stimulation of anterior cerebellum in rats produces analgesiaconfirming the observation of Siegel and Wepsic (17) in monkeys.

MATERIALS AND METHODS

The experiments were carried out on male albino rats (200-250 g. CF strain). Thesurgical procedures for implantation of guide cannula or electrodes as well as for partialcerebellectomy were carried out under pentobarbitone-Na (40 mg/kg. ip) anaesthesia inaseptic conditions.

Injection of morphine into cerebellum: A stainless steel guide cannula (22 G) witha stylet inserted into its shaft of 1 mm length was chronically implanted onto the cerebellarsurface under stereotaxic guidance. After a week. the analgesic test (15) was carried outfollowing infusion of morphine solution through the implanted cannula in a volume of 1 p.1by a microinfusion pump which delivered this volume from a 10 ILl Hamilton syringe in 30sec. For such infusion of drug solution. the stylet was removed and a hollow stainlesssteel needle (28 G) was inserted which was already connected with Hamilton Syringe bya length of polythene tubing filled with drug solution to be injected. The infusion needlewas inserted 1 to 2 mm deep from the tip of the guide cannula. For injection of morphineinto the anterior cerebellar region. or into posterior cerebellar cne. the guide cannula wasimplanted in the midline 2.5 to 3.0 mm or 3.0 to 4.0 mm posterior to Lambda respectively.

At the end of each experiment. the postmortem examination was made for con-firmation of the position of implanted cannula as well as to note the spread of morphinesolution into the cerebellar tissue. For this purpose. the animal was anaesthetised withpentobarbitone-Na. and Evans blue dye (2%) was infused following the same procedureas that for morphine. After 5 min. the brain was perfused with 100 ml buffered 10%formalin-saline and the whole brain was removed. and the location ot the guide cannulaand spread of dye into the tissue were noted through magnifying lens. following an inci-sion of the cerebellum in sagittal plane below the tip of guide cannula.

Partial cerebellectomy : The head ofthe stereotaxic apparatus. The skull boneincision on the skin. A burr hole was

the anaesthetised animal was fixed inwas exposed by giving a midline

made in the midline on the skull

Volume 26Number 1

either 2.5 mm or 3.5mor posterior cerebellarwhich was connected

After a week. tadministration of mar

At the end of tof the extent of cerebbitone-Na and its hea100 ml buffered 10%carefully and the deptand plotted on aster

Electrical stimulationwas fixed in the sterstatinless steel wirearea at the tip was iand 0.5 to 1 mm deepelectrode and connectaround them and tthe analgesic test wasimpla nted electrode.stimulator (USA).

At the end of tthe brain was perfusposition. Serial frozeThionin for histologi

Morphine infusias small as 10 Jig iin 6 rats (Fig. 1-A)infusion with the pea

Januarv-March 1982Ind. J. Phvsio L Pharrnac.

terior cerebellum producesorphine after its systemictomised rats. We furtherIn rats produces analgesiaeys.

250 g, CF strain). Thedesas well as for partialmg/kg, ip) anaesthesia in

guidecannula (22 G) withlantedonto the cerebellartest (15) was carried outnnula in a volume of 1 p.1"I Hamilton syringe in 30

and a hollow stainlesswith Hamilton Syringe byted. The infusion needleForinjection of morphine

e. the guide cannula wasr to Lambdarespectively.

ation was made for con-te the spread of morphineI was anaesthetised with

wing the same procedureith 100 ml buffered 10%tion of the guide cannulang lens,following an inci-nnula.

animal was fixed inby giving a midlinemidline on the skull

Volume 26Number 1

Cerebellum and Morphine Analgesia 5

either 2.5 mm or 3.5 mm posterior to lambda and then either the anterior cerebellar regionor posterior cerebellar one was partially removed respectively by suction with an aspiratorwhich was connected with a glass capillary tube inserted through the burr hole.

After a week, the analgesic tests were carried out before and after intraperitonealadministration of morphine (10 mg/kg).

At the end of the experiment. the postmortem study was done for the confirmationof the extent of cerebellar area removed. The animal was anaesthetised with pentobar-bitone-Na and its head was fixed in stereotaxic apparatus. The brain was perfused with100 ml buffered 10% formalin-saline solution. After 10 min. the skull bone was removedcarefully and the depth and the extent of the cerebellar area/areas ablated was determinedand plotted on a stereotaxic map of cerebellum.

Electrical stimulation of anterior cerebellum : The animal's head under anaesthesiawas fixed in the stereotaxic instrument. One bipolar electrode made of twistedstatinless steel wire (0.2 mm diameter) teflon coated except for the cross-sectionalarea at the tip was implanted in the midline 2 to 2.5 mm posterior to lamda,and 0.5 to 1 mm deep from the dura so that the tip lay in the culmen area. Theelectrode and connector were secured to the skull by flowing dental acrylic cementaround them and two stainless steel screws threaded into the skull. After a week,the analgesic test was carried out following electrical stimulation of cerebellar tissue throughimplanted electrode. The square wave electrical pulses were delivered from Grass S88stimulator (USA).

At the end of the experiment. the animal was anaesthetised with pentobarbitone andthe bra in was perfused with buffered formal in-saline solution with the electrode in situposition. Serial frozen sections were cut at 40 JAm and alternate sections stained withThionin for histological verification of location of electrode placements.

RESULTS

Morphine infusion into cerebellum: The results show that a dose of morphineas small as 10 JAg infused into anterior cerebellar region produced profound analgesiain 6 rats (Fig. 1-A). In all these rats, the analgesia began within 3 mfn of morphineinfusion with the peak analgesia reached around 30 min. The analgesia lasted for more

.Ianuarv-March 1982Ind. J. Phvsio l. Pharrnac.

than 60 min. The postmortem examination in these animals showed that morphinesolution was distributed mainly into the culmen region in 4 rats and partially into dorsallobus centralis in two rats. It has further been observed that the analgesia elicitedfrom the above anterior cerebellar region was antagonised following naloxone administra-tion. The results are shown in Fig. 1-8 Thus in two rats. in which the analgesia beganto develop following morphine injection (10p.g) into culmen of anterior cerebellum.

6 De." and Ray

16 ~

Morphine Micro,njeclion(10jJ9) 1010 CerqbQl!um

8

A

12__ CulmllnG. L. Cerurons,

0---0 L Simpll2x a. Oecuve.

III 40z0uWIII

° 15 30 45 60 75~~ 12,.MORPH 10).l9(Culmcnll.L Centr otrs )

w~ Nolo~onq lmg/k<;j r.p .....J 8 ~

B

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° 15 30 45 60MIN

Fig. l-A : Shows analgesia following microinjection of morphine (10 IAg) into culmen-centralis regionof anterior cerebellum (n-6). Analgesia did not occur following injection into L. simplexand declive region of posterior cerebellum (n=4).

B: Shows that naloxone (1 mg/kg. ip) antagonises analgesia elicited following injectionof 10 ILg morphine into culmen-region (n= 2). Naloxone was administered 15 minafter morphine injection.

the intraperitoneal administration of 1 mg/kg naloxone almost immediately a antagonised

the analgesia (Fig. 1-8).

In four animals. the microinfusion of morphine (10 jJ.g) did r.ot produce analgesia.The postmortem examination showed that in two rats. the cannula was implanted in

Volume 26Number 1

between the inferior collitissue showed inflarnrna

The analgesic rsame dose of morphine'in 4 rats (Fig. 1-A).

Morphine analgesia inThe results in F

ra ts exerted a remarkabh

1nl

f·jg. 2: Shows :heintact con!ablated (nculmen ce

injection of morphine (1(n=5). the analgesia gof analgesia lasted forof morphine in chrani

.Januarv-March 1982Ind. J. Pnvsiot. Pharrnac.

mals showed that morphinerats and partially into dorsaled that the analgesia el icitedlIowing naloxone adrninistra-

n which the analgesia beganmen of anterior cerebellum.

m

•CentrOl,!>Decl.VQ

IIg) into culmen-centralis regionollowinginjection into L. simplex

ia elicitedfollowing injectionne was administered 15 min

st immediately a antagonised

g) did r.ot produce analgesia.cannula was implanted in

Cerebellum and Morphine Analgesia 7Volume 26Number 1

between the inferior colliculus and cerebellum, and in other two rats, the anterior cerebellartissue showed inflammatory reactions around the implanted cannula.

The analgesic response of morphine did not occur following microinfusion ofsame dose of morphine into posterior cerebellar regions such as lobus simplex and declivein 4 rats (Fig. 1-A).

Morphine analgesia in partial cerebellectomized animals:The results in Fig. 2 show 'that removal of anterior cerebellar region in 5

rats exerted a remarkable influence on analgesic response that occurred following i. p.

'ntoct C~~ftumCUlm'ln!l.1.Centrons l·S,mpllZx& Oacl,vlZAbl.:ltlZo Ablated

~ORP'; 10 rrog/kg '!.It

16

o 15 30 45 60 75 90MIN

Shows the analgesic response following i. p. administration of morphine (10 mg/kg) inmtact control (n=5). culmen and centralis ablated (n=5). and lobus simplex and decliveablated (n=5) groups of rats. A marked diminution of duration of analgesia occurred inculmen centralis ablated group.

Hg. 2:

injection of morphine (10 mg/kg). Thus. following morphine injection in control animals(n=5), the analgesia generally reached to its peak response within 15 min and the durationof analgesia lasted for about 75 min. On the other hand. the ip injection of same doseof morphine in chronic anterior cerebellectomised animal produced analgesia but the

8 Dey and Ray .Januarv-March 1982Inc. J. Phvsio l, Pharrnac.

duration of analgesia was greatly shortened. Thus the analgesia remained for not morethan 45 min as compared to about 75 min in control animals.

The postmortem examination in these animals showed that this marked diminutionof analgesic response of morphine was associated with the ablation of culmen or theculmen and dorsal lobule of lobus centralis together. It was interesting to observe thatcerebellar ablation per se did not modify the nociceptive response of the animal.

Such attenuation of morphine analgesia was not observed following ablationof posterior cerebellar region (lobus simplex and declive) in 5 rats. Rather, a tendencyfor prolongation of analgesia was apparent (Fig. 2).

t.a,..A,S~c 160).!A,10 54<;l 1'10).lA,2S~C'S

10

5

, ,311OU(S

~20()J-'~,5 sec l<:IJ}JA, SSIZC

1S

'"0z0 10uLLJ<fl

~ S>uZtuti-' 300)-lA, 10 SIZC

I15

10

5

0 10 20 30 0 ,0 20MINS

Fig 3: Shows post-stimulation analgesia in 5 individual rats following bipolar electrical stimulation (pulse widtho 2 rnsec. 70Hz) of anterior cerebellum. Arrow indicates application of current for particular duration.Top: shows analgesia in one rat witn 1st and 2nd stimulation at an interval of 3 hrs between twostimulations. Electrode was located within the culmen.Middle: shows analgesia in two rats. Electrode was located at the cortical surface of culmen region.Bottom :shows analgesia in two rats with electrode located in lobus centralis but close to culmen region.

,

Volume 26Number 1

Focal electrical stimulati(Following focal E

region for 5 to 10 sec, I

But the current strengthfrom animal to animal,Thus in two rats with ebetween 90 and 110 /lA

was again tested 3 hr astimulation. The resultcurrent of 60 /LA applie

The present resulbears certain physiologimorphine. Thus the deof morphine into culmeduration of morpine antogether, it would apmorphine although occbrain stem. but its corphine on target regionmorphine, following Itsbellar tissue, parri passuof morphine systemicallvalues obtained for oth

That the analgeto be specific becomessimplex or declive reto manifest antinocicethat microinjection ofof centralis, uvula, andlobus simplex, uvula.

It has also beenfrom culmen region ofof naloxone. This ob

.Januarv-March 1982Inc. J. Phvsiol, Pharrnac.

iesia remained for not more

that this marked diminutionablation of culmen or the

s interesting to observe thatonse of the animal.

.bserved following ablation5 rats. Rather, a tendency

I..,...,

\...,....,

larelectrical stimulation (pulse widthtion ef current for particular duration.at an interval of 3 hrs between two

the cortical surface of culmen region.s centralis but close to culmen region.

Cerebellum and Morphine Analgesia 9Volume 26Number 1

Focal electrical stimulation of anterior cerebellum:

Following focal electrical stimulation (0.2 msec pulse-width; 70 Hz) of culmenregion for 5 to 10 sec. in 5 animals. the post-stimulation analgesia developed (Fig. 3).But the current strength and the duration of post-stimulation analgesia showed variationfrom animal to animal, which was found to be related with the location of the electrode.Thus in two rats with electrode located within culmen cortical region. a current strengthbetween 90 and 110 /LA produced analgesia lasting for about 5-15 min. One of the ratswas again tested 3 hr after first stimulation experiment for analgesia with 2nd electricalstimulation. The result is shown in Fig. 3 (top trace). Analgesia occurred again with acurrent of 60 /LA applied for 10 sec.

DISCUSSION

The present results demonstrate that culmen region of anterior cerebellum in ratsbears certain physiological importance in relation to the anti nociceptive response ofmorphine. Thus the development of prolonged analgesia following direct micro-injectionof morphine into culmen or culmen-dorsal centralis, as well as, the marked diminution ofduration of morpine analgesia in rats with chronic ablation of the same area, if consideredtogether, it would appear that antinocieeptive response of systemically administeredmorphine although occurs through its action on well-established analgesic sites in thebrain stem, but its concurrent sustainance appears to be dependent on the action of mor-phine on target regions of anterior cerebellum. In fact it has been shown (13) thatmorphine, following its systemic administration in rats, reaches alse very raoidly into cere-bellar tissue, parri passu with other regions et the brain. Thus about 1 46% of the amourtof morphine systemically injected in rat enters cerebellum which is closely similar tovalues obtained for other anatomical regions of the brain.

That the analgesic action elicited from culmen area of anterior cerebellum appearsto be specific becomes apparent from the findings that injection of morphine into lobussimplex or declive region of posterior cerebellum has been found to be ineffectiveto manifest antinociceptive response. Moreover, Yaksh et al. (21) have earlier shownthat microinjection of morphine into other regions of rat cerebellum, such as, ventral lobuleof centralis, uvula, and into different white matter regions close to lobus centralis, culmen,lobus simplex, uvula, nodulus and lingula failed to elicit analgesia.

It has also been shown in the present experiments, that morphine analgesia el icitedfrom culmen region of anterior cerebellum is completely antagonised by systemic injectionof naloxone. This obviously indicates that analgesic action is mediated through opiate

January-March 1982Ind. J. Phvsiol. Pharmac.

receptors. But the opiate receptor bindings studies in rat brain with 3H-naloxone showedthat cerebellum is the poorest binding site for naloxone as compared to that for otheropiate binding sites of brainstem region (5). This may seem apparently inconsistentwith the present findings of blockade of cerebellar mediated morphine analgesia withnaloxone. However. it is to be noted that receptor binding studies have not been exploredcritically in different anatomical regions of cerebellum. therefore. even thepresence of high affinity opiate receptors in culmen region of anterior cerebellum might havebeen overlooked in such studies. and such argument can also be held true for the reportof the presence of small amount of enkehaplin in cerebellar cortex (9). Recently. Simon(18) has reported that (3H) -etorphine stereospecifically binds in human cerebellarcortex in the range of 0.12-0.07 pmol/mg protein and such bindings are also observedin cow. cat. dog and monkey.

10 Dey and Ray

Since severa I workers (1.10.11) have reported that electrica I stimulation of certainspecific sites in brain stem produces analgesia. and the same sites have already beenshown to be sites in which morphine injection elicits marked analgesia. therefore. a fewexperiments were carried out also to examine analgesia following electrical stimulationof culmen region. The results showed that brief stimulation of culmen for 5 to 10 secwith current varying from 60-300 !LA exhibits development of analgesia which persistsafter withdrawal of stimulus. The duration of post-stimulation analgesia varied between5 and 10 minutes. and in one case. it remained for 20 minutes. The development ofanalgesiC) following electrical stimulation of cerebellum has earlier been reported bySiegel and Wepsic (17). Interestingly. they reported that maximum analgesic response(against noxious electrical shocks in tail) developed in monkeys following elctricalstimulation (0.2 mA) of Intermediate anterior lobe (culmen) as w011 as its physiologicallyrelated rostra I dentate- inter -positus-brach ium conjunctivum reg ion. These observa-tions in conjunction with our present finding indicate in general that culmen area ofanterior cerebellum can serve as important locus whose activation either with narcoticdrug or electrical stimulus can arouse central mechanisms of pain suppression.

It is fairly well-established that there exists a powerful pain suppressive systemin brainstem reticular formation (RF) concentrated specially in periventricular. gray. PAG andreticulogiagantocellularis area. and its activation diminishes responsiveness to noxiousstimuli. atleast in part. through descending spinal pathways which block transmissionof nociceptive stimuli through the spinal cord. Since it is well known that connectionbetween RF and cerebellum are extensive. therefore. it is possible that culmen exhibits

Volume 2:Number 1

its anti nociceptive effecit is interesting to mentoblongata. the surgicalintractable pain). produafter occulusion of th

The authors areNew Delhi. for finanDr. K. S. Rao for his

1. Balagura. S. and T. RalphBrain Res.• 60: 369-3

2. Buxbaum. D.M .. GG. Yaby microir [ections of mo

3. Dey. P.K. and W. Feldbermaeol.. 58 : 383-393. 1

4. Fostor. RS .• D.J Jendemethyl-morphine. J. Ph

5. Garcin. F. Opiate receptNeuropsychopharmacologVol. 2. pp. 1295-1305.

6 Herz. A. K Albus, J. Maction of morphine and

7 Jacouet. Y F and A. Lajthon sue and dose. so

8. Jacquet. Y.F. and A. Lamatter In the rat. Se'

9. Kobayashi. R.• M Palko

10. Uebeskind. J.C. G. Guilqueductal gray matter InBram Res.• 50 : 4 1-4

11. Mavor. D. J • and J.C. Lroenavroral analvsis. Sr

12. Mehler. W.R. Central pon pain). Ed. J.J. Bra I

January-March 1982Ind. J. Phvsiol. Pharmac.

in with 3H-naloxone showedcompared to that for other

seem apparently inconsistentd morphine analgesia with

udieshave not been exploredIIum. therefore. even thenterior cerebellum might haveo be held true for the reportcortex (9). Recently. Simon

binds in human cerebellarbindings are also observed

ectrical stimulation of certainme sites have already beend analgesia. therefore. a few"owing electrical stimulationn of culmen for 5 to 10 secof analgesia which persists

IOnanalgesia varied betweenutes. The development ofs earlier been reported byaximum analgesic responseonkevs following elctrical

as w-311as its physiologicallyregion. These observa-

eneral that culmen area oftivation either with narcoticof pain suppression.

rful pain suppressive systemperiventricular. gray. PAG ands responsiveness to noxious

which block transmissionwell known that connectionssible that culmen exhibits

Volume 26Number 1

CerebelJum and Morphine Analgesia 11

its antinociceptive effect via activation of brainstem pain suppression mechanisms. Lastlyit is interesting to mention the report of Mehler (12) who observed that in medullaoblongata. the surgical lesion of fibres in retro-olivary levels in two cancer patients (havingintractable pain). produced high level of analgesia. but often in some cases. the pain returnsafter occulusion of the posterior inferior cerebellar artery.

ACKNOWLEDGEMENTS

The authors are grateful to the Indian Council ofNew Delhi. for financial assistance of this work.Dr. K. S. Rao for his assistance in this work.

Scientific and Industrial Research.The authors are also thankful to

REFERENCES

1. Balagura. S. and T. Ralph. The analgesic effect of electrical stimulation of the diencephalon and mesencephalon.Brain Res.. 60: 369-379. 1973.

2. Buxbaum. D.M .. G G. Yarbrough and M.E. Carter. Dose-dependent behavioral and analgesic effects producedby microinjections of morphine-sulphate into the anterior thalamic nudei. The Pbermecotoinst, 12 : 210.1970.

3. Dey, P.K. and W. Feldberg. Analgesia produced by morphine when acting from the liquor space. Brit. J. Phar-macol .• 58 : 383-393. 1976.

4. Fostor. R.S.• D.J. Jenden and P.A. Lomax. A comparison of the pharmacological effects of morphine and N-methyl-morphine. J. Pharmac. Expt. Ther., 157 : 185-195. 1967. •.

5. Garcin. F. Opiate receptor binding studies in rat brain during morphine dependence and early abstinence. In:Neuropsychopharmacology. Eds. P. Denikar. G. Radouce-Thomas. A. Villeuve. B. Barnonet LacrOIX. F. Garcin,Vol. 2. pp. 1295-1305, Pargamon Press. New York. 1978.

6. Herz. A.. K. Albus. J. Metys. P. Schubert and H. Teschemacher. On the central sites for the antinocrceonveaction of morphine and fentanyl. Neuropharmacology. 9 : 539. 1975. .

7. Jecquet. Y.F and A. Lajtha. Morphine action at centra' nervous system In rat: Analqesia or hyperalgesia deoendinqon site and dose. SCience. 182 : 490-492. 1973.

8. Jacquet. Y.F. and A. Lajtha Paradox-a! effects after micro-injection of morphine In the penaqueductal graymatter In the rat. Science. 185 : 1055-1057. 1974.

9. Kobayashi. R.• M Palkovits. R. MlJer. K.J. Chang and P Cuatrecasas. Lite SCI.. 22 : 527-530. 1977.

10. Uebesklnd. J.C., G. Guilbaud. J.M. Besson and J.L. Clivers. .A.nalgesiafrom electrical stimulation of the peria-queductal gray matter In the cat. Behavioral observation and inhibitory effects on spinal cord interneurones.Brain Res.• 50 : 441-446, 1973.

11. Mavor. 0 ..1, and J.C. Liebeskind. Pain reduction by focal electrical stimulation of the brain: An anatomical a-idbehavioral analysis. Brain Res.• 68 : 73-93. 1974.

12. Mehler. W.R. Central pain and the spinothalamic tract. I'): Advances In Neuroloov (InternatIOnal Symposiumon pain) Ed. J.J. Bromcs. Vol. 4. pp. 127-146. Raven Press, New York. 1974.

J anuary- March 1981.nd. J. Physiol. Pharmac

13. Oldendrcf. W.H. Factors affecting passage of opiates throuqf the blood-brain barrier. In: Factors affecting theaction of narcotics. Eds. M.l. Adler. l. Manara. and R. Sarnarun. pp. 221. Raven Press. New York. 1978.

12 Dey and Ray

14. Pert. A. and T. Yaksh. Sites of morphine induced analgesia in the primate brain: Relation to pain pathways.Brain Res.• 80 : 135-140. 1974.

15. Ray. A.K. and P.K. Dey. Morphine analgesia following its infusion into different liquor spaces in rat brain. Arch.tnt. Pharmacodyn.. 246 : 108-117. 1980.

16. Sharpe, l.C .• J.E. Garnett and T.N.Cicere. Analgesia and hyperactivity produced by intracranial microinjectionsof morphine into the periaqueductal gray matter of the rat. Behav. Bioi .• 11 : 303-313. 1974.

17. Siegel. P. and J.G. Wepsic. Alteration of nociception by stimulation of cerebellar structures in the monkey.Physiol. Behav .• 13 : 189-194. 1974.

18. Simon. E.J. The opiate receptors. In: Receptors in Pharmacology Eds. J.R. Smythies and R. J. Bradlev. p. 257.Marcel Dekker Inc. New York. 1978.

19. Tsou. K. and C.S. Jang. Analgesic effect of intraventricular or intracerebral microinjection of morphine. ActaPhysiologica Sinice, 25 : 119-128. 1962.

20. Tsou. K. and C.S. Jang. Studies on the site of analgesic action of morphine by intracerebral micro-injectionSei. Sinica. 1099-1109. 1964.

21. Yaksh. T.l.. J.C. Yeung and T.,A. Rudv. Systematic examination in the rat of brain sites sensitive to the directapplication of morphine: observation of differential etfscts within the periaqueductal gray. Brain Res ..114 : 83-103, 1976.

MOTOR AND SEUNANAESTHETIZEr:

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Summary : Motor 'nervlthetized streptozotocin dnormal and ischemic con

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Abnormal preseto occur in diabetic suopatients with diabetesthan did normal subjectconduction velOCity (M• Contribution No. 660 from t

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