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Capsaicin-sensitive cutaneous sense organs: Nerve terminals with multiple funcions
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C A P S A I C I N - S E N S I T I V E C U T A N E O U S SENSE ORGANS: N E R V E T E R M I N A L S W I T H M U L T I P L E FUNCIONS. J. S Z O L C S A N Y I ~ R.A. W E S T E R M A N ~ W. M A G E R L 3 AND E. P I N T ~ R 1 1 Dept. 2 Dept. 3 Dept.
Pharmacol. Med. Univ. P@cs, Pf. 99. H-7643, Hungary. Physiol. M o n a s h U n i v e r s i t y , C l a y t o n , Victoria, Australia. Physiol. B i o k y b e r n e t i k Univ. E r l a n g e n BDR.
I n t r o d u c t i o n of a p h a r m a c o l o g i c a l c l a s s i f i c a t i o n for p r i m a r y afferent fibres and n e u r o n e s /i/ by l a b e l l i n g them as c a p s a i d i n - s e n s i t i ve /Szolcs~nyi and Barth6 1978/ has been s u p p o r t e d by single unit r e c o r d i n g s from a f f e r e n t fibres in d i f f e r e n t m a m m a l i a n species. In the skin of adult animals C - a n d A - d e l t a - p o l y m o d a l n o c i c e p t o r s , the few w a r m r e c e p t o r s and m e c h a n i c a l l y i n s e n s i t i v e c h e m o r e c e p t i v e Cfibre units have been shown of being c a p s a i c i n - s e n s i t i v e /2, 3/. The p i v o t a l role of these r e c e p t o r s in t r a n s d u c t i o n of n o x i o u s heat, c h e m o n o c i c e p t i v e and w a r m t h stimuli has been v e r i f i e d by using capsaicin d e s e n s i t i z i n g p r o c e d u r e s w i t h p s y c h o p h y s i c a l and animal beh a v i o u r a l techniques. The c a p s a i c i n - s e n s i t i v e sensory r e c e p t o r s subserve, however, also e f f e r e n t functions/3/. C h a r a c t e r i s t i c s of these p e p t i d e r g i c /tachykinins, CGRP/ e f f e r e n t r e s p o n s e s m e d i a t e d by the sensory nerve t e r m i n a l s were i n v e s t i g a t e d by a n t i d r o m i c s t i m u l a t i o n of the dorsal roots in the rat a n a e s t h e tized w i t h i00 m g / k g t h i o b u t o b a r b i t a l . Plasma e x t r a v a s a t i o n was measured q u a n t i t a t i v e l y w i t h the Evans blue tracer m e t h o d /50 m g / k g i.v./, b l o o d flux changes were r e g i s t e r e d w i t h a P e r i m e d laser d o p p l e r f l o w m e t e r in the p l a n t a r skin /4/. F e w a n t i d r o m i c pulses /1-16, 20V, 0.5ms, 0.025-8Hz/ applied to the p e r i p h e r a l ending of cut dorsal roots e l i c i t e d m a r k e d c u t a n e o u s v a s o d i l a t a t i o n . In m o s t cases /9/11/ a l r e a d y a single pulse e v o k e d the r e s p o n s e lasting for 2.5+1 min /x+ S.D./. Increase in b l o o d flux to few m o r e impulses started a f t e ~ a latency of 5.3+O.2s and lasted for several minutes. The f r e q u e n c y o p t i m u m was e x t r e m e l y low /0.025-O.2Hz/ and 300 pulses at O. iHz induced s u s t a i n e d v a s o d i l a t a t i o n w i t h o u t exhaustion. P e r i n e u r a l p r e t r e a t m e n t of the sciatic nerve w i t h c a p s a i c i n /1%/ a b o l i s h e d or s t r o n g l y i n h i b i t e d the effect of 8-32 pulses. A n t i dromic s t i m u l a t i o n of the l u m b o s a c r a l dorsal roots e v o k e d p l a s m a e x t r a v a s a t i o n not only in the skin, but also in internal organs /urinary bladder, ureter, urethra, uterus, vagina, rectum, anus etc/ p r o v i d i n g in this way a direct e v i d e n c e for an e f f e r e n t funcion of capsaicin-sensitive enteroceptors. It is c o n c l u d e d that s t i m u l a t i o n of p o l y m o d a l n o c i c e p t o r s induces the release of n e u r o p e p t i d e m e d i a t o r s a l r e a d y at low i n t e n s i t i e s w h i c h are i n s u f f i c i e n t to evoke n o c i c e p t i o n or pain sensation. This feature of "antidromic v a s o d i l a t a t i o n " p r o v i d e s the functional basis for the h y p o t h e s i s that this local m e c h a n i s m p a r t i c i p a t e s in the r e g u l a t i o n of c u t a n e o u s m i c r o c i r c u l a t i o n b e s i d e s its important role in i n f l a m m a t o r y processes. i. S z o l c s ~ n y i J. /1982/ in H a n d b o o k of E x p e r i m e n t a l P h a r m a c o l o g y S p r i n g e r V e r l a g , B e r l i n , H e i d d b e r g 60:437-478 2. S z o l c s ~ n y i J. /1987/ J. Physiol. 388:9-23 3. S z o l c s ~ n y i J. /1984/ in Chahl L., S z o l c s ~ n y i J. L e m b e c k F. /eds/ A n t i d r o m i c V a s o d i l a t a t i o n and N e u r o g e n i c Inflammation. A k a d @ m i a i Kiad6, Budapest, pp. 27-55 4. S z o l c s ~ n y i J. /1988/ A g e n t s and A c t i o n s 2_~3: 4-11
C A P S A I C I N - S E N S I T I V E C U T A N E O U S SENSE ORGANS: N E R V E T E R M I N A L S W I T H M U L T I P L E FUNCIONS. J. S Z O L C S A N Y I ~ R.A. W E S T E R M A N ~ W. M A G E R L 3 AND E. P I N T ~ R 1 1 Dept. 2 Dept. 3 Dept.
Pharmacol. Med. Univ. P@cs, Pf. 99. H-7643, Hungary. Physiol. M o n a s h U n i v e r s i t y , C l a y t o n , Victoria, Australia. Physiol. B i o k y b e r n e t i k Univ. E r l a n g e n BDR.
I n t r o d u c t i o n of a p h a r m a c o l o g i c a l c l a s s i f i c a t i o n for p r i m a r y afferent fibres and n e u r o n e s /i/ by l a b e l l i n g them as c a p s a i d i n - s e n s i t i ve /Szolcs~nyi and Barth6 1978/ has been s u p p o r t e d by single unit r e c o r d i n g s from a f f e r e n t fibres in d i f f e r e n t m a m m a l i a n species. In the skin of adult animals C - a n d A - d e l t a - p o l y m o d a l n o c i c e p t o r s , the few w a r m r e c e p t o r s and m e c h a n i c a l l y i n s e n s i t i v e c h e m o r e c e p t i v e Cfibre units have been shown of being c a p s a i c i n - s e n s i t i v e /2, 3/. The p i v o t a l role of these r e c e p t o r s in t r a n s d u c t i o n of n o x i o u s heat, c h e m o n o c i c e p t i v e and w a r m t h stimuli has been v e r i f i e d by using capsaicin d e s e n s i t i z i n g p r o c e d u r e s w i t h p s y c h o p h y s i c a l and animal beh a v i o u r a l techniques. The c a p s a i c i n - s e n s i t i v e sensory r e c e p t o r s subserve, however, also e f f e r e n t functions/3/. C h a r a c t e r i s t i c s of these p e p t i d e r g i c /tachykinins, CGRP/ e f f e r e n t r e s p o n s e s m e d i a t e d by the sensory nerve t e r m i n a l s were i n v e s t i g a t e d by a n t i d r o m i c s t i m u l a t i o n of the dorsal roots in the rat a n a e s t h e tized w i t h i00 m g / k g t h i o b u t o b a r b i t a l . Plasma e x t r a v a s a t i o n was measured q u a n t i t a t i v e l y w i t h the Evans blue tracer m e t h o d /50 m g / k g i.v./, b l o o d flux changes were r e g i s t e r e d w i t h a P e r i m e d laser d o p p l e r f l o w m e t e r in the p l a n t a r skin /4/. F e w a n t i d r o m i c pulses /1-16, 20V, 0.5ms, 0.025-8Hz/ applied to the p e r i p h e r a l ending of cut dorsal roots e l i c i t e d m a r k e d c u t a n e o u s v a s o d i l a t a t i o n . In m o s t cases /9/11/ a l r e a d y a single pulse e v o k e d the r e s p o n s e lasting for 2.5+1 min /x+ S.D./. Increase in b l o o d flux to few m o r e impulses started a f t e ~ a latency of 5.3+O.2s and lasted for several minutes. The f r e q u e n c y o p t i m u m was e x t r e m e l y low /0.025-O.2Hz/ and 300 pulses at O. iHz induced s u s t a i n e d v a s o d i l a t a t i o n w i t h o u t exhaustion. P e r i n e u r a l p r e t r e a t m e n t of the sciatic nerve w i t h c a p s a i c i n /1%/ a b o l i s h e d or s t r o n g l y i n h i b i t e d the effect of 8-32 pulses. A n t i dromic s t i m u l a t i o n of the l u m b o s a c r a l dorsal roots e v o k e d p l a s m a e x t r a v a s a t i o n not only in the skin, but also in internal organs /urinary bladder, ureter, urethra, uterus, vagina, rectum, anus etc/ p r o v i d i n g in this way a direct e v i d e n c e for an e f f e r e n t funcion of capsaicin-sensitive enteroceptors. It is c o n c l u d e d that s t i m u l a t i o n of p o l y m o d a l n o c i c e p t o r s induces the release of n e u r o p e p t i d e m e d i a t o r s a l r e a d y at low i n t e n s i t i e s w h i c h are i n s u f f i c i e n t to evoke n o c i c e p t i o n or pain sensation. This feature of "antidromic v a s o d i l a t a t i o n " p r o v i d e s the functional basis for the h y p o t h e s i s that this local m e c h a n i s m p a r t i c i p a t e s in the r e g u l a t i o n of c u t a n e o u s m i c r o c i r c u l a t i o n b e s i d e s its important role in i n f l a m m a t o r y processes. i. S z o l c s ~ n y i J. /1982/ in H a n d b o o k of E x p e r i m e n t a l P h a r m a c o l o g y S p r i n g e r V e r l a g , B e r l i n , H e i d d b e r g 60:437-478 2. S z o l c s ~ n y i J. /1987/ J. Physiol. 388:9-23 3. S z o l c s ~ n y i J. /1984/ in Chahl L., S z o l c s ~ n y i J. L e m b e c k F. /eds/ A n t i d r o m i c V a s o d i l a t a t i o n and N e u r o g e n i c Inflammation. A k a d @ m i a i Kiad6, Budapest, pp. 27-55 4. S z o l c s ~ n y i J. /1988/ A g e n t s and A c t i o n s 2_~3: 4-11