0099-2399/90/1602-0067/$02.00/0 JOURNAL OF ENDOOONTICS Copyright 9 1990 by The Amencan Associahon of Endodont=sts
Printed in U.S.A.
VOL. 16, NO. 2, FEBRUARY 1990
Neuropeptides in the Dental Pulp: Distribution, Origins, and Correlation Satoshi Wakisaka, DDS, PhD
It is known that many factors participate in the process of inflammation and pain transmission. Recently, various neuropeptides have been demonstrated in the intrapulpal nerve fibers immunobiohistochemically. These neuropeptides may play some role in the process of inflammation and transmission of pain sensation. In this presentation, the distribution, origins, and correlation of neuropeptides in the dental pulp is reviewed.
assistant role in the synaptic transmitter. These substances are called neuromodulators. The term neuroregulator is used for these substances. Neuropeptide is a protein involved in the nervous system. Recently, several neuropeptides have been demonstrated in both central and peripheral nervous systems by immunohistochemistry and radioimmunoassay. Pharmacological and physiological studies have revealed that some of them act as a neurotransmitter, but many of them act as neuromodulator. SENSORY N E U R O P E P T I D E IN T H E PULP
NEURONAl, P A T H W A Y S TO T i l E P U L P To date, three neuropeptides originating from the trigeminal ganglion have been reported in the dental pulp. These neuropeptides are substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA). SP is the first neuropeptide to be proposed as a neurotransmitter. SP is synthesized in the cell bodies of small diameter primary afferents (unmyelinated fibers), transported by the axonal flow centrally and peripherally, and released from the terminal upon nerve stimulation (4). It is reported that SP interacts with the blood vessel, causing vasodilation and extravasation of plasma (5). SP is the first neuropeptide to be demonstrated in the dental pulp (6). SP-containing nerve fibers enter the pulp in bundles with the large blood vessel through the apical foramen. Not all nerve fibers show SP-like immunoreactivity (SPLI). In the radicular pulp, many SPcontaining nerve fibers are observed around the blood vessel, some of them show a network arrangement at the wall of large blood vessel. Not all blood vessels accompany SPcontaining nerve fibers and not all SP-containing nerve fibers are observed around the blood vessel. Some SP-containing nerve fibers are observed in no obvious relation with the blood vessel. At the subodontoblast layer, single SP-containing nerve fibers branch and run toward the predentin and dentin between the odontoblasts. In the human molar, SPcontaining nerve fibers penetrate into the predentin and show various distribution patterns: some SP-containing nerve fibers in the predentin run straight to the dentin, other run transversely and change lheir directions (7). In rat molar, SPcontaining nerve fibers are observed in the predentin and dentin and can be traced about 20 um from the pulp-dentin surface (8). These SP-containing nerve fibers, disappear completely after inferior alveolar nerve section, but their distribution is not affected by removal of the superior cervical ganglion (8). Thereforc, SP-containing nerve fibers in the dental pulp originate ti'om the trigeminal ganglion.
The peripheral nervous system is divided into the somatosenspry and autonomic nervous systems. The latter is further subdivided into sympathetic and parasympathetic nervous systems. The somatosensory nerves supplying the pulp originate from the trigeminal ganglion. Upper teeth are innervated by the maxillary nerve, while lower teeth receive nerve supplies from the mandibular nerve. The sympathetic nerves in the dental pulp come from the superior cervical ganglion. There are two sympathetic neuronal pathways to the pulp. The major sympathetic pathway is composed of sympathetic nerves which leave superior cervical ganglion, run encircling around the common and external carotid arteries and then around the maxillary artery and finally enter the pulp with the superior or inferior alveolar artery. Another pathway, recently investigated elecrophysiologically by Matthews and Robinson (1) and neuroanatomically by Marfurt et al. (2), consists of a small number of sympathetic nerve fibers leaving superior cervical ganglion and running toward the trigcminal ganglion and then toward the dental pulp along with sensory nerve fibers. Therefore, the nerve segment running in the mandibular canal consists of both somatosensory and sympathetic nerves. This has been confirmed electrophysiologically by Tonder and Nass (3). N E U R O T R A N S M I ' F I ' E R AND N E U R O P E P T I D E S In the nervous system, some substances are synthesized in the cell body and are transported through the axon. Neurotransmitter is a substance contained in the nerve cells and their cytoplasmic process. Neurotransmission occurs between adjacent cells by the release of this substance from the nerve terminal upon neuronal stimulation. Some substances are very similar to the neurotransmitter in character but play an 67
68
Wakisaka
CGRP is another peptide reported in the pulp (9-11). CGRP-containing nerve fibers entered the pulp in bundles and are distributed throughout the dental pulp. Many CGRPcontaining nerve fibers are observed around the blood vessel, but some of them are apart from the blood vessel. CGRPcontaining nerve fibers are also observed at the subodontoblast layer and penetrate into the predentin and dentin. Sectioning of the inferior alveolar nerve results in complete disappearance of the CGRP-containing nerve fibers, suggesting that CGRP-containing nerve fibers are sensory in nature and originate from the trigeminal ganglion. NKA is the most recent neuropeptide reported in the dental pulp (12). NKA belongs to the tachykinin peptide family, to which SP also belongs. And the percursors of NKA are the same as some precursors of SP. NKA-containing nerve fibers are also observed throughout the dental pulp, and the distribution of NKA-containing nerve fibers is very similar to that of SP-containing nerve fibers. After inferior alveolar nerve sectioning, all NKA-containing nerve fibers disappear completely. But no changes in the distribution and number of NKA-containing nerve fibers are noticed after sympathectomy. Thus, NKA-containing nerve fibers also originate from the trigeminai ganglion. Double immunostaining for C G R P and SP reveal that their distributions are quite similar and that they may be contained in the same nerve fibers (10). The distributions of SP and NKA are also very similar as demonstrated by double immunostaining and these two neuropeptides may also be contained in the same nerve fibers (12). Therefore, it seemed that three sensory neuropeptides, SP, C G R P and NKA, are contained in the same nerve fibers. S Y M P A T H E T I C N E U R O P E P T I D E S IN T I l E P U L P In the sympathetic nerves, catecholamine has been considered to be the neurotransmitter. In the dental pulp, all catecholamine-containing nerve fibers are observed around the blood vessel. Immunohistochemical staining for dopamine flhydroxylase (DBH), one of the catecholamine-synthesizing enzymes, shows that DBH-containing nerve fibers are observed encircling the blood vessel, but not all blood vessels are accompanied by DBH-containing nerve fibers. Recently, neuropeptide Y (NPY) has been demonstrated in the dental pulp by U d d m a n et al. (13). The distribution of NPY-containing nerve fibers is very similar to that of DBH-containing nerve fibers. NPY-containing nerve fibers are observed around the blood vessel and no NPY-containing nerve fibers are found in the odontoblastic layers. Denervation experiments show that NPY-containing nerve fibers completely disappear after removal of the superior cervical ganglion, indicating that NPY-containing nerve fibers are sympathetic in nature and come from the superior cervical ganglion. Uddman et al. (13) reported that NPY coexists with DBH in the intrapulpal nerve. P A R A S Y M P A T H E T I C (?) N E U R O P E P T I D E IN T H E PULP Vasoactive intestinal polypeptide (VIP) is another peptide reported in mammalian dental pulp (14). The distribution of
Journal of Endodontics
VIP-containing nerve fibers is somewhat different from that of sensory neuropeptide-containing nerve fibers and also from that of sympathetic neuropeptide containing nerve fibers. VIP-containing nerve fibers are mainly observed around the blood vessel, but some of them are also observed apart from the blood vessel. The number of VIP-containing nerve fibers is greater than that of NPY-containing nerve fibers. The number of the blood-vessel-accompanying VIP-containing nerve fibers is much greater than that of the blood-vesselaccompanying NPY-containing nerve fibers. Except for the abundant number of VIP-containing nerve fibers around the blood vessel, there are no VIP-containing nerve fibers in the odontoblast layer. Double immunostaining for VIP and SP has revealed that some blood vessels are accompanied by both VIP- and SP-containing nerve fibers, but blood vessels associated with SP-containing nerve fibers only are often observed (15). Denervation experiments show that VIP-containing nerve fibers do not disappear after inferior alveolar nerve sectioning. After sympathectomy VIP-containing nerve fibers do not disappear (16). These denervation experiments suggest that VIP-containing nerve fibers originate neither from the trigeminal ganglion nor from superior cervical ganglion. Since VIP has been reported in parasympathetic ganglion and coexists with acethylcholine in other tissues (17), it seems that VIP-containing nerve fibers may originate from a parasympathetic ganglion although the existence of a parasympathetic ganglion sending nerve fibers to the dental pulp has not been demonstrated histologically. FUNCTIONAL ROLE OF NEUROPEPTIDES Recent pharmacological and physiological studies show that SP, CGRP, and VIP have vasodilator functions (18, 19). It has been suggested that SP may participate in the regulation of blood flow in the dental pulp and vasodilatory effects of CGRP in the pulp have also been reported. It seems that some of neuropeptide-containing nerve fibers around the blood vessel may play some role in the regulation of blood flow. However, as shown in our studies, the distribution and origin of tachykinin (SP and NKA) and CGRP are different from those of VIP. Thus. there are at least two different vasodilator mechanisms regulated by neuropeptides in the dental pulp. One is regulated by sensory neuropeptides and another by VIP. Besides the vasodilator effects of neuropeptides, NPY has vasoconstrictive effect. NPY may have some sympathetic function co-acting with catecholamines in the pulp. Our studies also revealed the existence of sensory neuropeptides in the predentin and dentin, where there are very few blood vessels. It is known that various external mechanical, chemical, and thermal stimuli directed to the teeth are recognized as pain. Therefore. sensory neuropeptides in the predentin and dentin may also participate in pain transmission mechanisms. This study was partly supported by grant-in-aidsfrom the Japanese Ministry of Science, Education and Culture (57480335, 59370043. 60771450, 61304053, and 61440078). Dr. Wakisaka is research associate, First Department of Oral Anatomy, Osaka University Faculty of Dentistry, Yamadaoka, Suita, Osaka, Japan.
VoL 16, No. 2, February 1990 References 1 Matthews B, Robinson PP The course of postganglionic sympathetic fibres distributed with the mgeminal nerve of the cat. J Physio11980;303:391401. 2 Marfurt CF, ZaIeski EM, Adans CE, Welther CL. Sympathetic nerve fibers in rat orofacial and cerebral tissues as revealed by me HRP-WGA tracing technique: A light and electron microscopic study. Brain Res 1986;366:373-8. 3. Tonder KH, Nass G Nervous controt of blood flow in the dental pulp in dogs. Acta Physiol Scand 1978;104:13-23 4 Ho~felt T, Kellerth J-O, Nilsson G, Pernow B. Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neuron Brain Res 1975;100:235-52. 5. Leembac_~F, Games R, Juan H Substance P and sensory nerve endings. In: Von Euler US, Pernow B, eds. Substance P. New York; Raven Press, 1977:169-81. 6. Ok:jaR L, Hokfelt T, Nilsson G, Pemow B. Localization of substance Plike immunoreactivity in the nerves of the tooth pulp. Pain 1977;4:153-9. 7. Wakisaka S, Ichikawa H, Nishimoto T, et al. Substance P-like immunoreactivity in the pulp-dentine zone of human molar demonstrated by indirect immunofluoresceflce. Arch Oral Biol 1984;29:73-5. 8 Wakisaka S, Nishikawa S, Ichikawa H, Matsuo S, Takano Y, AkaJ M. The distribution and origin of substance P-like immunoreactivity in rat molar pulp and panodontal tissues. Arch Oral Biol 1985;30:813-5. 9. Uddman R. Grunditz T. Sundler F. CalcJtonin gene-related paptide: a sensory transmitter in dental pulp ?Scand J Dent Res 1986;94:219-24. 10. Wak~saka S, Ichikawa H. Nishikawa S, Matsuo S, Takano Y, Akai M. The distribution and origin of caJcitenin gece-related peptide-containing nerve
Neuropeptide Distribution
69
fibres in feline dental pulp: relationship with substance P-containing nerve fibres. Histochemistry 1987;86:585-9. 11. Sdverman JD. Kruger L. An interpretation of dental innervat~on based upon the pattern of calc~ton~n gene-related (CGRPHmmunoreactive thin sensory axons. Somatosens Res 1987;5:157-75 12. Wakisaka S, Ichikawa H, Nishikawa S, Matsuo S, Takano Y, Akai M Neurokinin A-liKe immunoreactivity in feline dental pulp: its distribution, origin and coexistence with substance P-like immunoreactivity. Cell Tissue Res 1988;251:565-9 13. Uddman R, Grundltz J, Sundler F. Neuropeptide Y: occurrence and distribution in dentaJ pulp. Acta OdontoJ ScarEI 1983;42:361-5. 14. Uddman R, Bjorlin S, Moiler B. Sundler F. Occurrence of VIP nerves in mammalian dental pulps. Acta Odontol Scand 1980;38:325-8. 15. Wakisaka S, Ich~kawa H, Nish=kawa S, Matsuo S, Takano Y, Akai M. Immunohistochem=cal observation o~ tt~ correlation between substance Pand vasoactive intestinal p~ypeptide-like immunor in the feline dental pulp. Arch Oral Bio11987;32:449-53. 16. Wakisaka S, IchJkawa H. Akai M The distributions and ongins of peptide- and catect~olamine~ontaining nerve fibres and effects of cavity weparat~on on these nerve fibres J Osaka Univ Dent SCh 1986:26:17-28. 17. Lundberg JM, Hokfelt T. Coexistence of peptides and classical neurotransmitter. Trends Neurosc~ 1983;6:325-33. 18. Burcher E, Attedlog J-H. Pemow B, Rossel S. Cardiovascular effect of substance P: effects on the heart and regional blood flow in the dog. In: Yon Euler US, Pemow B, eds. Substance P. New York: Raven Press, 1977:261-8. 19. Fahrenkrug J. VIP as a neurotransmitter in peripheral nervous system. In: Said SI, ed. Vasoactive ~ntestinal polypeptide. New York: Raven Press, 1982:361-72.
Printed in U.S.A.
VOL. 16, NO. 2, FEBRUARY 1990
Neuropeptides in the Dental Pulp: Distribution, Origins, and Correlation Satoshi Wakisaka, DDS, PhD
It is known that many factors participate in the process of inflammation and pain transmission. Recently, various neuropeptides have been demonstrated in the intrapulpal nerve fibers immunobiohistochemically. These neuropeptides may play some role in the process of inflammation and transmission of pain sensation. In this presentation, the distribution, origins, and correlation of neuropeptides in the dental pulp is reviewed.
assistant role in the synaptic transmitter. These substances are called neuromodulators. The term neuroregulator is used for these substances. Neuropeptide is a protein involved in the nervous system. Recently, several neuropeptides have been demonstrated in both central and peripheral nervous systems by immunohistochemistry and radioimmunoassay. Pharmacological and physiological studies have revealed that some of them act as a neurotransmitter, but many of them act as neuromodulator. SENSORY N E U R O P E P T I D E IN T H E PULP
NEURONAl, P A T H W A Y S TO T i l E P U L P To date, three neuropeptides originating from the trigeminal ganglion have been reported in the dental pulp. These neuropeptides are substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA). SP is the first neuropeptide to be proposed as a neurotransmitter. SP is synthesized in the cell bodies of small diameter primary afferents (unmyelinated fibers), transported by the axonal flow centrally and peripherally, and released from the terminal upon nerve stimulation (4). It is reported that SP interacts with the blood vessel, causing vasodilation and extravasation of plasma (5). SP is the first neuropeptide to be demonstrated in the dental pulp (6). SP-containing nerve fibers enter the pulp in bundles with the large blood vessel through the apical foramen. Not all nerve fibers show SP-like immunoreactivity (SPLI). In the radicular pulp, many SPcontaining nerve fibers are observed around the blood vessel, some of them show a network arrangement at the wall of large blood vessel. Not all blood vessels accompany SPcontaining nerve fibers and not all SP-containing nerve fibers are observed around the blood vessel. Some SP-containing nerve fibers are observed in no obvious relation with the blood vessel. At the subodontoblast layer, single SP-containing nerve fibers branch and run toward the predentin and dentin between the odontoblasts. In the human molar, SPcontaining nerve fibers penetrate into the predentin and show various distribution patterns: some SP-containing nerve fibers in the predentin run straight to the dentin, other run transversely and change lheir directions (7). In rat molar, SPcontaining nerve fibers are observed in the predentin and dentin and can be traced about 20 um from the pulp-dentin surface (8). These SP-containing nerve fibers, disappear completely after inferior alveolar nerve section, but their distribution is not affected by removal of the superior cervical ganglion (8). Thereforc, SP-containing nerve fibers in the dental pulp originate ti'om the trigeminal ganglion.
The peripheral nervous system is divided into the somatosenspry and autonomic nervous systems. The latter is further subdivided into sympathetic and parasympathetic nervous systems. The somatosensory nerves supplying the pulp originate from the trigeminal ganglion. Upper teeth are innervated by the maxillary nerve, while lower teeth receive nerve supplies from the mandibular nerve. The sympathetic nerves in the dental pulp come from the superior cervical ganglion. There are two sympathetic neuronal pathways to the pulp. The major sympathetic pathway is composed of sympathetic nerves which leave superior cervical ganglion, run encircling around the common and external carotid arteries and then around the maxillary artery and finally enter the pulp with the superior or inferior alveolar artery. Another pathway, recently investigated elecrophysiologically by Matthews and Robinson (1) and neuroanatomically by Marfurt et al. (2), consists of a small number of sympathetic nerve fibers leaving superior cervical ganglion and running toward the trigcminal ganglion and then toward the dental pulp along with sensory nerve fibers. Therefore, the nerve segment running in the mandibular canal consists of both somatosensory and sympathetic nerves. This has been confirmed electrophysiologically by Tonder and Nass (3). N E U R O T R A N S M I ' F I ' E R AND N E U R O P E P T I D E S In the nervous system, some substances are synthesized in the cell body and are transported through the axon. Neurotransmitter is a substance contained in the nerve cells and their cytoplasmic process. Neurotransmission occurs between adjacent cells by the release of this substance from the nerve terminal upon neuronal stimulation. Some substances are very similar to the neurotransmitter in character but play an 67
68
Wakisaka
CGRP is another peptide reported in the pulp (9-11). CGRP-containing nerve fibers entered the pulp in bundles and are distributed throughout the dental pulp. Many CGRPcontaining nerve fibers are observed around the blood vessel, but some of them are apart from the blood vessel. CGRPcontaining nerve fibers are also observed at the subodontoblast layer and penetrate into the predentin and dentin. Sectioning of the inferior alveolar nerve results in complete disappearance of the CGRP-containing nerve fibers, suggesting that CGRP-containing nerve fibers are sensory in nature and originate from the trigeminal ganglion. NKA is the most recent neuropeptide reported in the dental pulp (12). NKA belongs to the tachykinin peptide family, to which SP also belongs. And the percursors of NKA are the same as some precursors of SP. NKA-containing nerve fibers are also observed throughout the dental pulp, and the distribution of NKA-containing nerve fibers is very similar to that of SP-containing nerve fibers. After inferior alveolar nerve sectioning, all NKA-containing nerve fibers disappear completely. But no changes in the distribution and number of NKA-containing nerve fibers are noticed after sympathectomy. Thus, NKA-containing nerve fibers also originate from the trigeminai ganglion. Double immunostaining for C G R P and SP reveal that their distributions are quite similar and that they may be contained in the same nerve fibers (10). The distributions of SP and NKA are also very similar as demonstrated by double immunostaining and these two neuropeptides may also be contained in the same nerve fibers (12). Therefore, it seemed that three sensory neuropeptides, SP, C G R P and NKA, are contained in the same nerve fibers. S Y M P A T H E T I C N E U R O P E P T I D E S IN T I l E P U L P In the sympathetic nerves, catecholamine has been considered to be the neurotransmitter. In the dental pulp, all catecholamine-containing nerve fibers are observed around the blood vessel. Immunohistochemical staining for dopamine flhydroxylase (DBH), one of the catecholamine-synthesizing enzymes, shows that DBH-containing nerve fibers are observed encircling the blood vessel, but not all blood vessels are accompanied by DBH-containing nerve fibers. Recently, neuropeptide Y (NPY) has been demonstrated in the dental pulp by U d d m a n et al. (13). The distribution of NPY-containing nerve fibers is very similar to that of DBH-containing nerve fibers. NPY-containing nerve fibers are observed around the blood vessel and no NPY-containing nerve fibers are found in the odontoblastic layers. Denervation experiments show that NPY-containing nerve fibers completely disappear after removal of the superior cervical ganglion, indicating that NPY-containing nerve fibers are sympathetic in nature and come from the superior cervical ganglion. Uddman et al. (13) reported that NPY coexists with DBH in the intrapulpal nerve. P A R A S Y M P A T H E T I C (?) N E U R O P E P T I D E IN T H E PULP Vasoactive intestinal polypeptide (VIP) is another peptide reported in mammalian dental pulp (14). The distribution of
Journal of Endodontics
VIP-containing nerve fibers is somewhat different from that of sensory neuropeptide-containing nerve fibers and also from that of sympathetic neuropeptide containing nerve fibers. VIP-containing nerve fibers are mainly observed around the blood vessel, but some of them are also observed apart from the blood vessel. The number of VIP-containing nerve fibers is greater than that of NPY-containing nerve fibers. The number of the blood-vessel-accompanying VIP-containing nerve fibers is much greater than that of the blood-vesselaccompanying NPY-containing nerve fibers. Except for the abundant number of VIP-containing nerve fibers around the blood vessel, there are no VIP-containing nerve fibers in the odontoblast layer. Double immunostaining for VIP and SP has revealed that some blood vessels are accompanied by both VIP- and SP-containing nerve fibers, but blood vessels associated with SP-containing nerve fibers only are often observed (15). Denervation experiments show that VIP-containing nerve fibers do not disappear after inferior alveolar nerve sectioning. After sympathectomy VIP-containing nerve fibers do not disappear (16). These denervation experiments suggest that VIP-containing nerve fibers originate neither from the trigeminal ganglion nor from superior cervical ganglion. Since VIP has been reported in parasympathetic ganglion and coexists with acethylcholine in other tissues (17), it seems that VIP-containing nerve fibers may originate from a parasympathetic ganglion although the existence of a parasympathetic ganglion sending nerve fibers to the dental pulp has not been demonstrated histologically. FUNCTIONAL ROLE OF NEUROPEPTIDES Recent pharmacological and physiological studies show that SP, CGRP, and VIP have vasodilator functions (18, 19). It has been suggested that SP may participate in the regulation of blood flow in the dental pulp and vasodilatory effects of CGRP in the pulp have also been reported. It seems that some of neuropeptide-containing nerve fibers around the blood vessel may play some role in the regulation of blood flow. However, as shown in our studies, the distribution and origin of tachykinin (SP and NKA) and CGRP are different from those of VIP. Thus. there are at least two different vasodilator mechanisms regulated by neuropeptides in the dental pulp. One is regulated by sensory neuropeptides and another by VIP. Besides the vasodilator effects of neuropeptides, NPY has vasoconstrictive effect. NPY may have some sympathetic function co-acting with catecholamines in the pulp. Our studies also revealed the existence of sensory neuropeptides in the predentin and dentin, where there are very few blood vessels. It is known that various external mechanical, chemical, and thermal stimuli directed to the teeth are recognized as pain. Therefore. sensory neuropeptides in the predentin and dentin may also participate in pain transmission mechanisms. This study was partly supported by grant-in-aidsfrom the Japanese Ministry of Science, Education and Culture (57480335, 59370043. 60771450, 61304053, and 61440078). Dr. Wakisaka is research associate, First Department of Oral Anatomy, Osaka University Faculty of Dentistry, Yamadaoka, Suita, Osaka, Japan.
VoL 16, No. 2, February 1990 References 1 Matthews B, Robinson PP The course of postganglionic sympathetic fibres distributed with the mgeminal nerve of the cat. J Physio11980;303:391401. 2 Marfurt CF, ZaIeski EM, Adans CE, Welther CL. Sympathetic nerve fibers in rat orofacial and cerebral tissues as revealed by me HRP-WGA tracing technique: A light and electron microscopic study. Brain Res 1986;366:373-8. 3. Tonder KH, Nass G Nervous controt of blood flow in the dental pulp in dogs. Acta Physiol Scand 1978;104:13-23 4 Ho~felt T, Kellerth J-O, Nilsson G, Pernow B. Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neuron Brain Res 1975;100:235-52. 5. Leembac_~F, Games R, Juan H Substance P and sensory nerve endings. In: Von Euler US, Pernow B, eds. Substance P. New York; Raven Press, 1977:169-81. 6. Ok:jaR L, Hokfelt T, Nilsson G, Pemow B. Localization of substance Plike immunoreactivity in the nerves of the tooth pulp. Pain 1977;4:153-9. 7. Wakisaka S, Ichikawa H, Nishimoto T, et al. Substance P-like immunoreactivity in the pulp-dentine zone of human molar demonstrated by indirect immunofluoresceflce. Arch Oral Biol 1984;29:73-5. 8 Wakisaka S, Nishikawa S, Ichikawa H, Matsuo S, Takano Y, AkaJ M. The distribution and origin of substance P-like immunoreactivity in rat molar pulp and panodontal tissues. Arch Oral Biol 1985;30:813-5. 9. Uddman R. Grunditz T. Sundler F. CalcJtonin gene-related paptide: a sensory transmitter in dental pulp ?Scand J Dent Res 1986;94:219-24. 10. Wak~saka S, Ichikawa H. Nishikawa S, Matsuo S, Takano Y, Akai M. The distribution and origin of caJcitenin gece-related peptide-containing nerve
Neuropeptide Distribution
69
fibres in feline dental pulp: relationship with substance P-containing nerve fibres. Histochemistry 1987;86:585-9. 11. Sdverman JD. Kruger L. An interpretation of dental innervat~on based upon the pattern of calc~ton~n gene-related (CGRPHmmunoreactive thin sensory axons. Somatosens Res 1987;5:157-75 12. Wakisaka S, Ichikawa H, Nishikawa S, Matsuo S, Takano Y, Akai M Neurokinin A-liKe immunoreactivity in feline dental pulp: its distribution, origin and coexistence with substance P-like immunoreactivity. Cell Tissue Res 1988;251:565-9 13. Uddman R, Grundltz J, Sundler F. Neuropeptide Y: occurrence and distribution in dentaJ pulp. Acta OdontoJ ScarEI 1983;42:361-5. 14. Uddman R, Bjorlin S, Moiler B. Sundler F. Occurrence of VIP nerves in mammalian dental pulps. Acta Odontol Scand 1980;38:325-8. 15. Wakisaka S, Ich~kawa H, Nish=kawa S, Matsuo S, Takano Y, Akai M. Immunohistochem=cal observation o~ tt~ correlation between substance Pand vasoactive intestinal p~ypeptide-like immunor in the feline dental pulp. Arch Oral Bio11987;32:449-53. 16. Wakisaka S, IchJkawa H. Akai M The distributions and ongins of peptide- and catect~olamine~ontaining nerve fibres and effects of cavity weparat~on on these nerve fibres J Osaka Univ Dent SCh 1986:26:17-28. 17. Lundberg JM, Hokfelt T. Coexistence of peptides and classical neurotransmitter. Trends Neurosc~ 1983;6:325-33. 18. Burcher E, Attedlog J-H. Pemow B, Rossel S. Cardiovascular effect of substance P: effects on the heart and regional blood flow in the dog. In: Yon Euler US, Pemow B, eds. Substance P. New York: Raven Press, 1977:261-8. 19. Fahrenkrug J. VIP as a neurotransmitter in peripheral nervous system. In: Said SI, ed. Vasoactive ~ntestinal polypeptide. New York: Raven Press, 1982:361-72.
