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Reflex parasympathetic vasodilatation in facial skin
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Pergamon
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Gen. Pharmac.Vol. 26, No. 2, pp. 237-244, 1995 Copyright © 1995 ElsevierScienceLtd Printed in Great Britain. All rights reserved 0306-3623/95 $29.00 + 0.00
REVIEW
Reflex Parasympathetic Vasodilatation in Facial Skin HIROSHI IZUMI Department of Physiology, Tohoku University School Dentistry, Aoba, Sendai 980, Japan [Tel: (022)274 1111; Fax: (022) 263 9867] (Received 25 April 1994)
AMtract--l.The
present report summarizes data from recent studies dealing with parasympathetic innervation of blood vessels in the lower lips (gingiva) of cats. 2. A study using the HRP tracing technique shows that blood vessels in the lower lip are innervated by postganglionic fibres originating in the otic ganglion, but not in the pterygopalatine ganglion. 3. There is a dual innervation of the cat lower lip by two groups of parasympathetic vasodilator fibres; in one case, fibres originating from the facial nerve root are distributed to the lower lip via chorda tympani nerve and in the other, fibres emanating from the glossopharyngeal nerve root project to the lower lip via the otic ganglion. 4. Parasympathetic reflex vasodilatation can be elicited by activation of the trigeminal (somatic), vagus (visceral), chorda tympani (gustatory) and nasal (chemical and mechanical) stimulation in the lower lips of cat. 5. Parasympathetic reflex vasodilatation elicited by somatic stimulation is mediated via the otic ganglion but not via the pterygopalatine ganglion, indicating that parasympathetic neurons, particularly those running as efferents in the glossopharyngeal nerve, are involved in the vasodilatation elicited by somatic, visceral and nasal stimulation.
KeyWords:Parasympathetic,
vasodilatation, facial skin
1. I N T R O D U C T I O N Until recently it was believed that the calibre of the cutaneous vessels of the face was controlled primarily by vasoconstrictor fibres from the cervical sympathetic chain. The general view was that vasodilatation was brought about through an inhibition of sympathetic vasoconstriction tone. However, three other types of neural fibres have been suggested to affect blood flow in the facial skin: (1) sympathetic vasodilator fibres; (2) parasympathetic vasodilator fibres; and (3) trigeminal nociceptive fibres. At present, it is unclear how and when these fibres might be activated under physiological conditions. Indeed, there is very little information available concerning the anatomical or physiological basis of the regulation of cutaneous blood vessels in the face, except that related to sympathetic vasoconstrictor fibres. However, evidence has recently accumulated that there is, at least in the cat, a parasympathetic vasodilator
innervation supplying the oro-facial area (e.g. lower lips, gingiva, tongue and submandibular gland) which originates from the facial and glossopharyngeal nerves and that these fibres are involved in somato-, gustatory- and visceral-parasympathetic reflex vasodilatation in these areas. In this review, the emphasis is placed on four aspects of such parasympathetic innervation of cutaneous blood vessels in the facial area of animals (cats and rats): (I) evidence for the existence of parasympathetic vasodilator fibres; (2) the afferent arm of parasympathetic reflex vasodilatation; (3) efferent pathways involving parasympathetic vasodilator fibres in reflex arcs; and (4) the neurotransmitter(s) of the parasympathetic vasodilator fibres. The properties of facial skin in animals may differ from those of human facial skin because their skin is hairy. So, experimental data obtained from the lower lips (gingiva) of animals are used in the present review. 237
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2. PARASYMPATHETIC FIBRES 2.1 Histological evidence
Montagna (1960) and Montagna et al. (1964) demonstrated the acetylcholinesterase (ACHE) reaction in the cutaneous nerves around arteries and arterioles in the face and scalp of a man and these results may suggest the existence of a cholinergic innervation of the cutaneous blood vessels in the face. However, Kaji et al. (1991) could not find intense AChE activity in the hairy facial skin of the rat and suggested that parasympathetic innervation is sparse or absent in the peripheral vessels of the facial skin in this species. These differences may be due to differences in the richness of the parasympathetic innervation in the facial skin in rat and human. However, an AChE-positive reaction does not necessarily imply a cholinergic function for the fibres concerned, because AChE has also been shown to be distributed widely in non-acetylcholine (ACh)-containing nerves (Cauna and Naik, 1963; Hume and Waterson, 1978; Lehman and Fibigger, 1979, Novikoff et al., 1966). Thus, we cannot, from this evidence alone, conclude that the facial perivascular fibres exhibiting AChE activity belong to the parasympathetic nervous system. Vasoactive intestinal peptide (VIP) has been reported to coexist with ACh (ACHE) in parasympathetic cholinergic fibres (Kaji et al., 1988, 1991). Gibbins et al. (1984) and Gibbins (1990) examined the distribution of nerves containing VIPimmunoreactive material in the cephalic arteries and cranial nerves of cats using an indirect immunofluorescence procedure on whole mounts and found that perivascular VIP-IR nerves have a remarkably widespread distribution within the extracerebral cephalic circulation of the cat. They reported furthermore that a dense perivascular plexus of VIP-IR nerves surrounds both arteries and arterioles supplying most of the muscular structures of the face including the tongue, lips, eyelids, extrinsic eye muscles and some of the jaw muscles. Recent fibre-tracing studies using the horseradish peroxidase (HRP) method have shown that blood vessels in the lower lips in rat and cat are innervated by postganglionic fibres originating in the otic ganglion (Kaji et al., 1988, 1991; Kuchiiwa et al., 1992). HRP-labelled cells in the perivascular nerves showed VIP-IR and removal of the otic ganglion abolished the VIP-IR in rat lower lips (Kaji et al., 1988). In contrast, no notable VIP-immunoreactivity was found in labelled cells either in the superior cervical ganglion or in the trigeminal ganglion;
indeed, no VIP-immunoreactivity at all was detected in these ganglia. From the above histological studies~ it seems likely that lower lip vessels in rat and cat are supplied by parasympathetic otic neurons and that their neurotransmitter is VIP. 2.2 Physiological evidence
Electrical stimulation of the distal cut end of the inferior alveolar nerve (IAN) produces vasodilatation and vasoconstriction in lower gingiva (lip) of cats (Izumi and Karita, 1990; Izumi et al., 1990). The vasodilator response seems to be mediated partly through trigeminal sensory fibres and mast cells; however, other mechanisms are probably involved since antagonists for the trigeminal system such as (o-Pro 2, D-TryT'9)-substance P (a substance P-receptor antagonist) and tripelennamine (a histamine H 1receptor antagonist) caused no more than a 20-30% attenuation of this vasodilatation. On the other hand, the vasoconstrictor response was completely abolished by phentolamine, an ~-adrenoceptor antagonist, indicating that the vasoconstrictor response occurs almost entirely via sympathetic ~-adrenergic receptors. An ipsilateral increase in blood flow was observed in the lower gingiva following electrical stimulation of the trigeminal, facial and glossopharyngeal nerves, both with the cranial nerves intact and after severing them from the brain stem (Izumi and Karita, 1991a, b). It seems reasonable to suppose that the blood flow increase in the lower gingiva was the result of cranial nerve stimulation and was a neurogenic response since there was no concomitant increase in systemic blood pressure when the peripheral end of each cranial nerve was stimulated. These results indicate that the blood circulation in the lower gingiva of the cat is affected by three different cranial nerves, namely, the trigeminal, facial and glossopharyngeal. Pretreatment with hexamethonium, an autonomic ganglionic blocking agent, reduced the increase in blood flow elicited by electrical stimulation of the facial and glossopharyngeal nerves, but had no effect on the increase in blood flow elicited by stimulation of the trigeminal nerve. These results suggest that the autonomic nervous system is responsible for the increase in blood flow elicited by facial and glossopharyngeal nerve stimulation though neither response was affected by pretreatment with atropine, a parasympathetic muscarinic receptor antagonist. Thus, both responses were atropine-resistant but hexamethonium-sensitive. On the other hand, pretreatment with tripelennamine, a histamine H~receptor antagonist, attenuated the trigeminal nervestimulated increase in blood flow but had no effect on
Parasympathetic reflex vasodilatation the facial and glossopharyngeal nerve-stimulated increase, suggesting a sensory nerve involvement only in the blood flow increase caused by trigeminal nerve stimulation. The findings mentioned above suggest that blood vessels in facial areas such as the lower gingiva and lip might be innervated by two different groups of parasympathetic vasodilator fibres, one originating from each of the facial and glossopharyngeai nerves. However, if the vasodilator nucleus in the brainstem were to extend sufficiently to include the origin of both the facial and glossopharyngeal nerves, then the functional significance of the two groups of vasodilator fibres might be fundamentally the same. However, the observations (Izumi and Karita, 1992c) that the trigeminally mediated reflex vasodilatation in the cat lower lip was abolished by section of the glossopharyngeal nerve root but not of the facial nerve root, suggest that these two groups of parasympathetic vasodilator fibres supplying the lower lip are functionally different. A study using the HRP tracing technique showing that blood vessels in the lower lip are innervated by postganglionic fibres originating in the otic ganglion, but not in the pterygopalatine ganglion (Kuchiiwa et al., 1992) is in agreement with studies on the rat lower lip by Kaji et al. 0988, 1991). Electrical stimulation of the peripheral cut end of the chorda tympani nerve (CTN) elicited a blood flow increase in the ipsilateral lower lip in a stimulus intensity-dependent manner (lzumi and Karita, 1993a). This blood flow increase was also markedly reduced by pretreatment with hexamethonium and abolished by a section of the chorda lingual nerve (CLN), indicating that the CTN is the route taken by preganglionic efferent vasodilator fibres to the cat lower lip. Although the identity of the ganglion associated with parasympathetic vasodilator fibres in the CTN is uncertain at the moment, it seems unlikely that it is the otic ganglion, from the topographical anatomy of the nerves. Previously, Gibbins et al. (1984) have suggested that microganglia which might contain VIP-immunoreactive perikarya are present in the orofacial areas associated with the facial and glossopharyngeal nerves. If this is so, preganglionic fibres from the facial nerve could enter the microganglia via the CTN and the VIP-containing postganglionic fibres terminate in the cat lower lip after running via the inferior alveolar nerve. This might account for our inability to determine the site of the ganglion for the parasympathetic vasodilator fibres originating in the facial (CTN) nerve. Taken together, these results suggest that there is a dual innervation of the cat lower lip by
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two groups of parasympathetic vasodilator fibres; in one case, fibres originating from the facial nerve root are distributed to the lower lip via CTN and in the other, fibres emanating from the glossopharyngeal nerve root project to the lower lip via the otic ganglion. 3, AFFERENT AND EFFERENT PATHWAYS IN REFLEX ARCS 3. I Trigeminal (somatic) stimulation
Stimulation of the trigeminal ganglion or nerve might elicit up to four different vascular responses simultaneously: sympathetic vasoconstriction (Matthews and Robinson, 1980) and parasympathetic (Gonzalez et aL, 1975), antidromic (Couture and Cuello, 1984; Lundblad et aL, 1982; Izumi et aL, 1990) and reflex vasodilatations (Lambert et al., 1984). Therefore, it may be difficult to analyse a given response precisely since the observed change could be a summation of a number of different responses. For this reason, the infra-orbital nerve and maxillary buccal gingiva were electrically stimulated to activate trigeminal sensory fibres and to evoke changes in blood flow bilaterally in the lower lip, which is outside the innervation zone of the infra-orbital nerve and thus to enable elimination of antidromic effects of sensory nerves on the innervated tissues (Izumi and Karita, 1992c). The observation that electrical stimulation of the infra-orbital nerve or maxillary buccal gingiva elicited an increase in ipsilateral lower lip blood flow suggests that there is a reflexly-induced vasodilatation in the cat lip. Three types of fibres might mediate such a reflex vasodilatation: (i) sensory, (ii) sympathetic and (iii) parasympathetic neurons and these will be considered in turn. (i) Axon reflexes were considered because cutaneous sensory fibres from individual dorsal root neurons provide a collateral branch to cutaneous arteriole, and antidromic activation of pure sensory neurons leads to peripheral vascular dilatation (Lewis, 1922; Lewis and Harmer, 1927; Chapman, 1977; Izumi and Karita, 1988, 1991a, b, 1992a, b; Izumi et al., 1988). However, the abolition of the vasodilator responses by acute section of the root of the glossopharyngeal nerve and by pretreatment with an autonomic ganglionic blocker (hexamethonium) indicates that axon reflexes are not responsible for the reflex vasodilatation since the anatomical substrate for axon reflexes was left intact in those experiments (Izumi and Karita, 1992c). (ii) The existence of sympathetic vasodilator fibres has recently been reported in cats and humans (Bell et al., 1985; Blumberg and Wallin, 1987; Lundberg et al., 1989; Nordin, 1990; Izumi and Karita, 1994d).
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However, sympathetic fibres seem unlikely to be involved in the present reflex vasodilatation, since the vasodilatation occurred after ipsilateral section of the sympathetic trunk and disappeared after section of the glossopharyngeal nerve root. (iii) There have been many previous reports of the existence of parasympathetic vasodilator nerve fibres in the lower lip, gingiva, submandibular gland, tongue, nasal mucosa, uvea and pial arteries in various animals (Chorobski and Penfield, 1932; Anggard, 1974; Lundberg et al., 1981a,b, 1982a,b; Nilsson et al., 1985; Izumi and Karita, 1991a, b, 1994a, b, c; Karita and Izurni, 1994b). All of these vasodilator fibres are reported to emerge from the facial nerve and the vasodilator responses have been shown to be mediated via the pterygopalatine ganglion. Thus, the vasodilator pathway to the face and head has been said to pass through the facial nerve and the pterygopalatine ganglion (Chorobski and Penfield, 1932; McNaughton and Feindel, 1977). However, the reflex vasodilator response elicited by stimulation of the infra-orbital nerve of maxillary buccal gingiva was never affected by sectioning the facial nerve root, but was completely abolished by intracranial section of the glossopharyngeal nerve root, suggesting that the reflex vasodilator response was mediated through the glossopharyngeal nerve alone. In addition, the reflex vasodilator response was attenuated by pretreatment with an autonomic ganglionic blocking agent. It seems safe to conclude, therefore, that parasympathetic neurons, particularly those running as efferents in the glossopharyngeal nerve, were involved in the vasodilatation elicited by stimulation of the infra-orbital nerve and the maxillary buccal gingiva. Moreover, the vasodilator response was not affected by lesion of the pterygopalatine ganglion. These results suggest that the reflex vasodilatation and the facial-nerve- and the glossopharyngeal-nerve-stimulated vasodilatations are mediated via the otic ganglion but not via the pterygopalatine ganglion. This is supported by the observation that retrogradely labelled cells have been observed in the ipsilateral otic ganglion following an injection of horseradish peroxidase into the mandibular lip as described before (Kuchiiwa et al., 1992). The lip blood flow increase in response to administration of pentylenetetrazole (a seizure-inducing drug) was found to be completely suppressed by section of the roots of both glossopharyngeal and facial nerves but not by section of the glossopharyngeal nerve root alone (Izumi et al., 1994). These results indicate that parasympathetic vasodilator fibres originating from the facial nerve participate in seizure-induced vasodilatation in the cat lower lip.
This is not the same as the path followed by the somato-parasympathetic reflex in cat lower lip reported previously (Izumi and Karita, 1992a, b,c, 1993b, c). This may suggest that the pattern of stimulation of the central parasympathetic nerves is different on seizure as opposed to somatic stimulation (Izumi and Karita, 1994a, b, c, d). Pharmacological analysis showed that this reflex vasodilator response was resistant to blockade by antimuscarinic (atropine), antihistaminergic (tripelennamine) and antiadrenergic agents (phentolamine and propranolol) but sensitive to a ganglionic blocking agent (hexarnethoniurn), suggesting that the reflex vasodilatation is mediated via final neurons that are not cholinergic. These resemble those found in the blood vessels of the submandibular gland and tongue of cats (Anggard, 1974; Lundberg et al., 198la, b, 1982a, b; Nilsson et al., 1985; lzumi and Karita, 1991a, b, 1992b, c, 1994a, c), which mediate the so-called atropine resistant vasodilator response. The existence of nonsympathetic, atropine-resistant vasodilator fibres in the inferior alveolar nerve has previously been suggested by Matthews and Robinson (1980). Similar reflex vasodilator responses have not yet been found in the face and head in humans, although the occurrence of a sornatosympathetic reflex vasodilatation has recently been reported in the human foot (Blumberg and Wallin, 1987). 3.2 Vagus (visceral) stimulation
Recent studies, using a variety of tract-tracing techniques, have shown that trigeminal sensory neurons synapse not only in the trigeminal sensory nuclei of the brain stem as general somatic afferents, but also in the caudal portions of the nucleus of the tractus solitarius (NTS), probably as general visceral afferents (Nornura and Mizuno, 1983; Nomura et al., 1984; Menetrey and Basbaum, 1987; Person, 1989). The two nuclei, according to current doctrine, are functionally different and well defined structures, suggesting that the trigerninal nerve carries not just somatic, but a mixture of somatic and visceral afferent axons. Which afferent fibres in the trigeminal nerves contribute to the autonomic reflex vasodilatation in the cat lower lip remains unclear. The cervical vagus nerves as well as the facial and glossopharyngeal nerves contain a large number of visceral sensory fibres that terminate in the NTS (Torvik, 1956; Menetrey and Basbaurn, 1987; Kawai et al., 1989) and activation of these afferent fibres elicits various kinds of reflex autonomic responses (see reviews by Ranson, 1921; Paintal, 1963, 1973; Koizurni and Brooks, 1972; Sato and Schmidt, 1973; Janig, 1986) and antinociception (Maixner and
Parasympathetic reflex vasodilatation Randich, 1984; Randich et al., 1991; Ren et al., 1991). We have therefore stimulated the central cut end of the cervical vagus nerve and observed the blood flow changes in the cat lower lip in order to investigate the possible role of general visceral afferents in this autonomic reflex vasodilatation (Izumi and Karita, 1993c). We have found that lip vasodilatation is indeed produced by such stimulation, suggesting that vagal visceral afferent activation may influence cutaneous blood flow in the oro-facial areas of cats. Reflex vasodilatation in response to stimulation of the central cut end of the vagus nerve was frequently observed on both sides of the cat lip unlike that induced by trigeminal stimulation (Izumi and Karita, 1992b, c; Karita and Izumi, 1992a, b) which, in most cases, did not occur on the contralateral side unless the stimulus strength to the trigeminal nerve was increased. This may be due to differences in the projection of the trigeminal and vagus nerves to the NTS: the trigeminal nerve projects to NTS ipsilaterally (Nomura et al., 1984) while the vagus nerve projects bilaterally (Torvik, 1956; Anton and Peppel, 1991). Simultaneous stimulation of the central cut ends of both cervical vagus nerves produced an additive vasodilatory effect on both sides of the cat lower lip even when the stimulus intensity applied to each vagus nerve was high enough to cause the maximal response one nerve could produce. These results suggest two possible mechanisms: (1) there is summation within the NTS of ipsilateral and contralateral afferent impulses; and (2) different vasomotor neurons exist in the brain stem which are affected by either ipsilateral or contralateral vagus nerve stimulation. Sympathetic nerves seem not to be involved in this reflex vasodilatation since the experiments described were conducted after bilateral elimination of cervical sympathetic nerves, Ipsilateral section of either the glossopharyngeal nerve root or inferior alveolar nerve abolished the reflex vasodilator response caused by stimulation of the central cut end of the vagus. Thus, these data suggest that the parasympathetic vasodilator fibres emerge from the brain stem with the glossopharyngeal nerve and reach the blood vessels via the inferior alveolar nerve. This reflex parasympathetic efferent pathway is similar to that of the trigeminally elicited vasodilatation described before (Izumi and Karita, 1992b, c). 3.3 Chorda tympani (gustatory) stimulation Electrical stimulation of the central cut end of the CT caused an increase in blood flow in the ipsilateral side of the lower lip (Karita and Izumi, 1993). Capsaicin application to the CT did not elicit a blood flow increase, although capsaicin application to the lingual nerve after cutting the CT evoked a blood GP 2612--B
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flow increase in the ipsilateral lower lips. (Karita and Izumi, 1992a). These results suggest that capsaicininsensitive fibres in the chorda tympani branch of the facial nerve, as well as capsaicin-sensitive ones in the lingual branch of the trigeminal nerve, participate as afferents in the parasympathetic vasodilator reflex in cat lower lip. 3.4 Nasal mucosa stimulation Local application of capsaicin (threshold dose 150pM) or nicotine (threshold dose 15 mM) to the nasal mucosa as well as electrical stimulation (threshold intensity 10 V) of the nasal mucosa elicited dose- or intensity-dependent blood flow increases in the ipsilateral lower lip of the anaesthetized cat (Izumi and Karita, 1993b; Karita and Izumi, 1994a). Pretreatment with 3 mM capsaicin applied locally to the nasal mucosa abolished or reduced the vasodilation in response to capsaicin, nicotine and ammonia vapor but not to light mechanical or electrical stimulation of the nasal mucosa. The blood flow increases elicited by all the above stimuli were greatly reduced by pretreatment with hexamethonium, an autonomic ganglion blocker. These results suggest that stimulation of the nasal mucosa by chemical (capsaicin, nicotine, ammonia), mechanical, or electrical methods elicits an autonomic reflex vasodilatation in the cat lower lip. Furthermore, there seem to be at least two types of afferent fibres in the nasal mucosa of the cat involved in reflex vasodilatation: one type is capsaicin-sensitive while the other is capsaicin-resistant. The efferent pathway of these reflexes is analogous to that of the trigeminally or vagally induced reflex vasodilatation mentioned above (Izumi and Karita, 1992b, c, 1993c). 4, CONCLUSION 4.1 Selective stimulation o f parasympathetic nerves Electrical stimulation of the tongue and proximal cut ends of the lingual nerve to provide a trigeminal input caused a vasodilatation only as a result of a somato-parasympathetic reflex, although sometimes no change in blood flow was observed on electrical stimulation of the tongue (nearly 10% of tests, Izumi and Karita, 1992b). On the other hand, direct electrical stimulation of the glossopharyngeal nerve, which contains the parasympathetic vasodilator fibres, caused either vasodilatation (nearly 77% of tests) or vasoconstriction (nearly 15%) or no change (nearly 8%). These vasodilator responses seem to be attributable largely to parasympathetic nerve activation, since there is no anatomical evidence that the glossopharyngeal nerve contains polymodal nociceptive C-fibres to the lower lips which might cause
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antidromic vasodilatation (Williams and Warwick, 1980) and since pretreatment with hexamethonium markedly reduced the vasodilatation. The observed vasoconstrictor responses suggest that adjacent sympathetic vasoconstrictor fibres may have been costimulated since pretreatment with an ~-adrenergic receptor blocker (phentolamine, 1.0 mg/kg, i.v.) completely abolished the vasoconstrictor response. This is in accordance with previous observations (Thomander et al., 1984; Nilsson et al., 1985; Matthews and Robinson, 1986) that the facial nerve contains sympathetic fibres in the cat. Similarly, stimulation of the distal cut end of the I A N elicited not only vasodilatation, but also vasoconstriction in cat lower lip (Izumi et al., 1990). This vasodilatation cannot be explained as a purely parasympathetic vasodilatation since antidromic vasodilatation occurred as a consequence o f activation of the nociceptive sensory fibres in the IAN. The occurrence of sympathetic vasoconstrictor fibres in the I A N has previously been reported by many investigators (Ogilvie, 1969; Matthews and Robinson, 1980; Izumi et al., 1990). The above finding, that reflex vasodilatation can be exclusively mediated by activation of parasympathetic nerve fibres, suggests that selective excitation of the parasympathetic nerve fibres in the oral area is feasible. This should enable us to clarify the mechanism underlying the vasodilator response elicited via parasympathetic fibres and the physiological function of the vasodilatation in the facial area. Using this reflex parasympathetic activation method, it was possible to differentially evoke salivary and vasodilator responses by direct chorda lingual nerve (parasympathetic nerve fibers) and by reflex parasympathetic stimulation in the cat submandibular gland (Izumi and Karita, 1994b, c). 4.2 Functional implication
Since parasympathetic reflex vasodilatation can be elicited by activation of the trigeminal (somatic), vagus (visceral), chorda tympani (gustatory) and nasal (chemical and mechanical) stimulation, it is unlikely to arise from a specific oral structure (e.g. tooth or tongue). This suggests that these parasympathetic reflex vasodilator responses are not due to excitation of proprioceptors. The physiological function of parasympathetic reflex vasodilatation in the mandibular division of the cats is unknown. However, it has recently been suggested that the trigeminal system may participate in autonomic and behavioral functions such as feeding and drinking (Zeiger and Karten, 1974). Furthermore, Gibbins et al. (1984) and Gibbins (1990) proposed an interesting hypothesis: the perivascular
V I P - I R nerves in orofacial areas might be implicated in vasodilator control and reduce heat stress elicited by a body temperature increase or intense firing in the central nervous system. The data presented here add a new facet to the evidence that the various afferent systems such as somato-, gustatory- and visceral sensory nerves may all link the parasympathetic (autonomic) nervous system in the facial area.
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Parasympathetic reflex vasodilatation Izumi H. and Karita K. (1992c) Somatosensory stimulation causes autonomic vasodilatation in cat lip. J. Physiol. (Lond.) 450, 191-202. Izumi H. and Karita K. (1993a) Innervation of the cat lip by two groups of parasympathetic vasodilator fibres. J. Physiol. (Lond.) 465, 501-512. Izumi H. and Karita K. (1993b) Reflex vasodilatation in the cat lip elicited by stimulation of nasal mucosa by chemical irritants. Am. J. Physiol. 256, (Regulatory Integrative Comp. Physiol. 34), R733-R738. Izumi H. and Karita K. (1993c) Reflex vasodilatation in the cat lip evoked by stimulation of vagal afferents. J. Auton. Nerv. Sys. 42, 215-223. Izumi H. and Karita K. (1994a) The involvement of the parasympathetic vasodilator fibres in the trigeminal portion of the distal lingual nerve in reflex vasodilatation in the cat tongue. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35). Izumi H. and Karita K. (1994b) Low frequency subthreshold sympathetic stimulation augments parasympathetic salivary secretion. Am. J. Physiol. (submitted). Izumi H. and Karita K, (1994c) Parasympathetic-mediated reflex salivation and vasodilatation in the cat submandibular gland. Am. J. PhysioL (in press). Izumi H. and Karita K. (1994d) The vasodilator and secretory effects elicited by sympathetic nerve stimulation in cat submandibular gland. J. Auton. Nerv. Sys. (in press). Izumi H., Kuriwada S. and Karita K. (1988) Axon reflex vasodilatation. Tohoku Igakuzashi (m Japanese) 101, 159-175. Izumi H., Kuriwada S., Karita K., Sasano T. and Sanjo D. (1990) The nervous control of gingival blood flow. Microvasc. Res. 39, 94-104. Izumi H., Takahashi H. and Karita K. (1994) Seizure induced blood flow increase in the lower lip of the cats. Eur. J. Pharmac. (submitted). Janig W. (1986) Spinal cord integration of visceral sensory systems and sympathetic nervous system reflexes. In: Visceral Sensation (Edited by Cetrevero F. and Morrison J. F. B.), pp. 255-277. Elsevier, Amsterdam. Kaji A,, Maeda T. and Watanabe S. (1991) Parasympathetic innervation of cutaneous blood vessels examined by retrograde tracing in the rat lower lip. J. Auton. Nerv. Sys. 32, 153-158. Kaji A., Shigematsu H., Fujita K., Maeda T. and Watanabe S. (1988) Parasympathetic innervation of cutaneous blood vessels by vasoactive intestinal polypeptide-immunoreactive and acetylcholinesterase-positive nerves: histochemical and experimental study on rat lower lip. Neuroscience 25, 353-362. Karita K. and Izumi H. (1992a) Somatosensory afferents in the parasympathetic vasodilator reflex in cat lip. J. Auton. Nerv. Sys. 39, 229-234. Karita K. and Izumi H. (1992b) Innervation areas of afferents and efferents in somato-autonomic vasodilator reflex in the oro-facial areas in the cat. Pain Res. 7, 105-I 14. Karita K. and Izumi H. (1993) Dual afferent pathways of vasodilator reflex induced by lingual stimulation in the cat. J. Auton. Nerv. Sys. 45, 235-240. Karita K. and lzumi H. (1994a) Reflex vasodilatation in cat lower lip elicited by noxious stimulation of the nasal mucosa. Pain Res. 9, 95-98. Karita K. and Izumi H. (1994b) Effect of baseline vascular tone on vasomotor response in cat lip. J. Physiol. (Lond.) (in press). Kawai Y., Mori S. and Takagi H. (1989) Vagal efferents interact with substance P-immunoreactive structures in the nucleus of the tractus solitarius: immunoelectron microscopy combined with an anterograde degeneration study. Neurosci. Lett. 101, 6-10. Koizumi K. and Brooks C. M. (1972) The integration of
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autonomic system reactions: a discussion of autonomic reflexes, their control and their association with somatic reactions. Ergeb. Physiol. 67, 1-68. Kuchiiwa S., Izumi H., Karita K. and Nakagawa S. (1992) Origins of parasympathetic postganglionic vasodilator fibres supplying the lips and gingivae; an WGA-HRP study in the cat. Neurosci. Lett. 142, 237-240. Lambert G. A., Bogduk N., Goadsby P. J., Duckworth J. W. and Lance J. W. (1984) Decreased carotid arterial resistance in cats in response to trigeminal stimulation. J. Neurosurg. 61, 307-315. Lehman J. and Fibigger H. C. (1979) Acetylcholinesterase and the cholinergic neuron. Life Sci. 25, 1939-1947. Lewis T. (1922) Vascular reactions of the skin to injury, Part I. Reaction to stroking; urticaria factitia. Heart 11, 119-140. Lewis T. and Harmer I. M. (1927) Vascular reactions of the skin to injury, Part IX. Further evidence of the release of a histamine-like substance from the injured skin. Heart 14, 19-26. Lundberg J. M., Anggard A. and Fahrenkrug J. (1981a) Complementary role of vasoactive intestinal polypeptide (VIP) acetylcholine for cat submandibular gland blood flow and secretion. I. VIP release. Acta Physiol. Scand. 113, 317-327. Lundberg J. M., Anggard A. and Fahrenkrug J. (1981b) Complementary role of vasoactive intestinal polypeptide (VIP) and acetylcholine for cat submandibular gland blood flow and secretion. II. Effects of cholinergic antagonists and VIP antiserum. Acta Physiol. Scand. 113, 329-336. Lundberg J. M., Anggard A. and Fahrenkrug J. (1982a) Complementary role of vasoactive intestinal polypeptide (VIP) and acetylcholine for cat submandibular gland blood flow and secretion. Acta Physiol. Scand. 114, 329-337. Lundberg J. M., Anggard A. and Fahrenkrug J. (1982b) VIP as a mediator of hexamethonium-sensitive, atropineresistant vasodilation in the cat tongue. Acta Physiol. Scand. 116, 387-392. Lundberg J., Norgren L., Ribbe E., Rosen I., Steen S., Thorne J. and Wallin B. G. (1989) Direct evidence of active sympathetic vasodilatation in the skin of the human foot. J. Physiol. (Lond.) 417, 437-446. Lundblad L., Anggard A. and Lundberg J. M. (1982) Vasodilation in the cat nasal mucosa induced by antidromic trigeminal nerve stimulation. Acta Physiol. Scand. 115, 517-519. Maixner W. and Randich A. (1984) Role of the right vagal nerve trunk in antinociception. Brain Res. 298, 374-377. Matthews B. and Robinson P. P. (1980) The course of post-ganglionic sympathetic fibres distributed with the trigeminal nerve in the cat. J. Physiol. (Lond.) 303, 391-401. Matthews B. and Robinson P. P. (1986) The course of postganglionic sympathetic fibres distributed with the facial nerve in the cat. Brain Res. 382, 55-60. McNaughton F. L. and Feindel W. H. (1977) Innervation of intracranial structures: a reappraisal. In: Physiological Aspects of Clinical Neurology (Edited by Rose F. C.), Vol. 102, pp. 279-293. Blackwell Scientific Publications~ Oxford. Menetrey D. and Basbaum A. I. (1987) Spinal and trigeminal projections to the nucleus of the solitary tract: a possible substrate for somatovisceral and viscerovisceral reflex activation. J. comp. Neurol. 255, 439-450. Montagna W. (1960) Cholinesterase in the cutaneous nerves of man. In Advances of Biology of Skin (Edited by Mantagna W.), Vol. l, pp. 74-78. Pergamon Press, Oxford. Montagna W., Yun J., Ore B., Formisano V. and P. R. (1964) Histology and cytochemistry of human skin XXX.
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Cholinesterase-containing nerves in the face. J. Invest. Dermat. 90, 526-529. Nilsson S. F. E., Linder J. and Bill A. (1985) Characteristics of uveal vasodilation produced by facial nerve stimulation in monkeys, cats and rabbits. Exp. Eye Res. 40, 841-852. Nomura S. and Mizuno N. (1983) Central distribution of efferent and afferent components of the cervical branches of the vagus nerve. Anat. Embryol. 166, 1-18. Nomura S., Yasui Y., Takada M. and Mizuno N. (1984) Trigeminal primary afferent neurons projecting directly to the solitary nucleus in the cat: a transganglionic and retrograde horseradish peroxidase study. Neurosci. Lett. 50, 257-262. Nordin M. (1980) Sympathetic discharges in the human supraorbital nerve and their relation to sudo- and vasomotor responses. J. Physiol. (Lond.) 423, 241-255. Novikoff A. B., Quintana N., Vilaverde H. and Furschirm R. (1966) Nucleoside phosphatase and cholinesterase activities in dorsal root ganglia and peripheral nerves. J. Cell Biol. 29, 525-545. Ogilvie R. W. (1969) The vasomotor innervation of the cat's lower right canine tooth pulp. Anat. Rec. 163, 237. Paintal A. S. (1963) Vagal afferent fibres. Ergeb. Physiol. 52, 74-156. Paintal A. S. (1973) Vagal sensory receptors and their reflex effects. Physiol. Rev. 53, 159-227.
Person R. J. (1989) Somatic and vagal afferent convergence on solitary tract neurons in cat: electrophysiological characteristics. Neuroscience 30, 283-295. Randich A., Thurston C. L., Ludwig P. S., Timmerman M. R. and Gebhart G. F. (1991) Antinociception and cardiovascular responses produced by intravenous morphine: the role of vagal afferents. Brain Res. 543, 256-270. Ranson S. W. (1921) Afferent pathways for visceral reflexes. Physiol. Rev. 1, 477-522. Ren K., Randich A. and Gebhart G. F. (1991) Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat. Pain 44, 311 319. Sato A. and Schmidt R. F. (1973) Somatosympathetic reflexes: afferent fibres, central pathways, discharge characteristics. Physiol. Ret,. 53, 916-947. Thomander L., Aldsogius H. and Arvidsson (1984) Evidence for a sympathetic component in motor branches of the facial nerve: a horseradish peroxidase study in the cat. Brain Res. 301, 380-383. Torvik A. (1956) Afferent connections to the sensory trigeminal nuclei, the nucleus of the solitary tract and adjacent structures. J. comp, Neurol. 106, 51-141. Williams P. L. and Warwick R. (1980) Gray's Anatomy, 36th Edition, Churchill-Livingston, Edinburgh. Zeiglr H. P. and Karten H. J. (1974) Central trigeminal structure and the lateral hypothalamic syndrome in the rat. Science 186, 636-638.
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Gen. Pharmac.Vol. 26, No. 2, pp. 237-244, 1995 Copyright © 1995 ElsevierScienceLtd Printed in Great Britain. All rights reserved 0306-3623/95 $29.00 + 0.00
REVIEW
Reflex Parasympathetic Vasodilatation in Facial Skin HIROSHI IZUMI Department of Physiology, Tohoku University School Dentistry, Aoba, Sendai 980, Japan [Tel: (022)274 1111; Fax: (022) 263 9867] (Received 25 April 1994)
AMtract--l.The
present report summarizes data from recent studies dealing with parasympathetic innervation of blood vessels in the lower lips (gingiva) of cats. 2. A study using the HRP tracing technique shows that blood vessels in the lower lip are innervated by postganglionic fibres originating in the otic ganglion, but not in the pterygopalatine ganglion. 3. There is a dual innervation of the cat lower lip by two groups of parasympathetic vasodilator fibres; in one case, fibres originating from the facial nerve root are distributed to the lower lip via chorda tympani nerve and in the other, fibres emanating from the glossopharyngeal nerve root project to the lower lip via the otic ganglion. 4. Parasympathetic reflex vasodilatation can be elicited by activation of the trigeminal (somatic), vagus (visceral), chorda tympani (gustatory) and nasal (chemical and mechanical) stimulation in the lower lips of cat. 5. Parasympathetic reflex vasodilatation elicited by somatic stimulation is mediated via the otic ganglion but not via the pterygopalatine ganglion, indicating that parasympathetic neurons, particularly those running as efferents in the glossopharyngeal nerve, are involved in the vasodilatation elicited by somatic, visceral and nasal stimulation.
KeyWords:Parasympathetic,
vasodilatation, facial skin
1. I N T R O D U C T I O N Until recently it was believed that the calibre of the cutaneous vessels of the face was controlled primarily by vasoconstrictor fibres from the cervical sympathetic chain. The general view was that vasodilatation was brought about through an inhibition of sympathetic vasoconstriction tone. However, three other types of neural fibres have been suggested to affect blood flow in the facial skin: (1) sympathetic vasodilator fibres; (2) parasympathetic vasodilator fibres; and (3) trigeminal nociceptive fibres. At present, it is unclear how and when these fibres might be activated under physiological conditions. Indeed, there is very little information available concerning the anatomical or physiological basis of the regulation of cutaneous blood vessels in the face, except that related to sympathetic vasoconstrictor fibres. However, evidence has recently accumulated that there is, at least in the cat, a parasympathetic vasodilator
innervation supplying the oro-facial area (e.g. lower lips, gingiva, tongue and submandibular gland) which originates from the facial and glossopharyngeal nerves and that these fibres are involved in somato-, gustatory- and visceral-parasympathetic reflex vasodilatation in these areas. In this review, the emphasis is placed on four aspects of such parasympathetic innervation of cutaneous blood vessels in the facial area of animals (cats and rats): (I) evidence for the existence of parasympathetic vasodilator fibres; (2) the afferent arm of parasympathetic reflex vasodilatation; (3) efferent pathways involving parasympathetic vasodilator fibres in reflex arcs; and (4) the neurotransmitter(s) of the parasympathetic vasodilator fibres. The properties of facial skin in animals may differ from those of human facial skin because their skin is hairy. So, experimental data obtained from the lower lips (gingiva) of animals are used in the present review. 237
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2. PARASYMPATHETIC FIBRES 2.1 Histological evidence
Montagna (1960) and Montagna et al. (1964) demonstrated the acetylcholinesterase (ACHE) reaction in the cutaneous nerves around arteries and arterioles in the face and scalp of a man and these results may suggest the existence of a cholinergic innervation of the cutaneous blood vessels in the face. However, Kaji et al. (1991) could not find intense AChE activity in the hairy facial skin of the rat and suggested that parasympathetic innervation is sparse or absent in the peripheral vessels of the facial skin in this species. These differences may be due to differences in the richness of the parasympathetic innervation in the facial skin in rat and human. However, an AChE-positive reaction does not necessarily imply a cholinergic function for the fibres concerned, because AChE has also been shown to be distributed widely in non-acetylcholine (ACh)-containing nerves (Cauna and Naik, 1963; Hume and Waterson, 1978; Lehman and Fibigger, 1979, Novikoff et al., 1966). Thus, we cannot, from this evidence alone, conclude that the facial perivascular fibres exhibiting AChE activity belong to the parasympathetic nervous system. Vasoactive intestinal peptide (VIP) has been reported to coexist with ACh (ACHE) in parasympathetic cholinergic fibres (Kaji et al., 1988, 1991). Gibbins et al. (1984) and Gibbins (1990) examined the distribution of nerves containing VIPimmunoreactive material in the cephalic arteries and cranial nerves of cats using an indirect immunofluorescence procedure on whole mounts and found that perivascular VIP-IR nerves have a remarkably widespread distribution within the extracerebral cephalic circulation of the cat. They reported furthermore that a dense perivascular plexus of VIP-IR nerves surrounds both arteries and arterioles supplying most of the muscular structures of the face including the tongue, lips, eyelids, extrinsic eye muscles and some of the jaw muscles. Recent fibre-tracing studies using the horseradish peroxidase (HRP) method have shown that blood vessels in the lower lips in rat and cat are innervated by postganglionic fibres originating in the otic ganglion (Kaji et al., 1988, 1991; Kuchiiwa et al., 1992). HRP-labelled cells in the perivascular nerves showed VIP-IR and removal of the otic ganglion abolished the VIP-IR in rat lower lips (Kaji et al., 1988). In contrast, no notable VIP-immunoreactivity was found in labelled cells either in the superior cervical ganglion or in the trigeminal ganglion;
indeed, no VIP-immunoreactivity at all was detected in these ganglia. From the above histological studies~ it seems likely that lower lip vessels in rat and cat are supplied by parasympathetic otic neurons and that their neurotransmitter is VIP. 2.2 Physiological evidence
Electrical stimulation of the distal cut end of the inferior alveolar nerve (IAN) produces vasodilatation and vasoconstriction in lower gingiva (lip) of cats (Izumi and Karita, 1990; Izumi et al., 1990). The vasodilator response seems to be mediated partly through trigeminal sensory fibres and mast cells; however, other mechanisms are probably involved since antagonists for the trigeminal system such as (o-Pro 2, D-TryT'9)-substance P (a substance P-receptor antagonist) and tripelennamine (a histamine H 1receptor antagonist) caused no more than a 20-30% attenuation of this vasodilatation. On the other hand, the vasoconstrictor response was completely abolished by phentolamine, an ~-adrenoceptor antagonist, indicating that the vasoconstrictor response occurs almost entirely via sympathetic ~-adrenergic receptors. An ipsilateral increase in blood flow was observed in the lower gingiva following electrical stimulation of the trigeminal, facial and glossopharyngeal nerves, both with the cranial nerves intact and after severing them from the brain stem (Izumi and Karita, 1991a, b). It seems reasonable to suppose that the blood flow increase in the lower gingiva was the result of cranial nerve stimulation and was a neurogenic response since there was no concomitant increase in systemic blood pressure when the peripheral end of each cranial nerve was stimulated. These results indicate that the blood circulation in the lower gingiva of the cat is affected by three different cranial nerves, namely, the trigeminal, facial and glossopharyngeal. Pretreatment with hexamethonium, an autonomic ganglionic blocking agent, reduced the increase in blood flow elicited by electrical stimulation of the facial and glossopharyngeal nerves, but had no effect on the increase in blood flow elicited by stimulation of the trigeminal nerve. These results suggest that the autonomic nervous system is responsible for the increase in blood flow elicited by facial and glossopharyngeal nerve stimulation though neither response was affected by pretreatment with atropine, a parasympathetic muscarinic receptor antagonist. Thus, both responses were atropine-resistant but hexamethonium-sensitive. On the other hand, pretreatment with tripelennamine, a histamine H~receptor antagonist, attenuated the trigeminal nervestimulated increase in blood flow but had no effect on
Parasympathetic reflex vasodilatation the facial and glossopharyngeal nerve-stimulated increase, suggesting a sensory nerve involvement only in the blood flow increase caused by trigeminal nerve stimulation. The findings mentioned above suggest that blood vessels in facial areas such as the lower gingiva and lip might be innervated by two different groups of parasympathetic vasodilator fibres, one originating from each of the facial and glossopharyngeai nerves. However, if the vasodilator nucleus in the brainstem were to extend sufficiently to include the origin of both the facial and glossopharyngeal nerves, then the functional significance of the two groups of vasodilator fibres might be fundamentally the same. However, the observations (Izumi and Karita, 1992c) that the trigeminally mediated reflex vasodilatation in the cat lower lip was abolished by section of the glossopharyngeal nerve root but not of the facial nerve root, suggest that these two groups of parasympathetic vasodilator fibres supplying the lower lip are functionally different. A study using the HRP tracing technique showing that blood vessels in the lower lip are innervated by postganglionic fibres originating in the otic ganglion, but not in the pterygopalatine ganglion (Kuchiiwa et al., 1992) is in agreement with studies on the rat lower lip by Kaji et al. 0988, 1991). Electrical stimulation of the peripheral cut end of the chorda tympani nerve (CTN) elicited a blood flow increase in the ipsilateral lower lip in a stimulus intensity-dependent manner (lzumi and Karita, 1993a). This blood flow increase was also markedly reduced by pretreatment with hexamethonium and abolished by a section of the chorda lingual nerve (CLN), indicating that the CTN is the route taken by preganglionic efferent vasodilator fibres to the cat lower lip. Although the identity of the ganglion associated with parasympathetic vasodilator fibres in the CTN is uncertain at the moment, it seems unlikely that it is the otic ganglion, from the topographical anatomy of the nerves. Previously, Gibbins et al. (1984) have suggested that microganglia which might contain VIP-immunoreactive perikarya are present in the orofacial areas associated with the facial and glossopharyngeal nerves. If this is so, preganglionic fibres from the facial nerve could enter the microganglia via the CTN and the VIP-containing postganglionic fibres terminate in the cat lower lip after running via the inferior alveolar nerve. This might account for our inability to determine the site of the ganglion for the parasympathetic vasodilator fibres originating in the facial (CTN) nerve. Taken together, these results suggest that there is a dual innervation of the cat lower lip by
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two groups of parasympathetic vasodilator fibres; in one case, fibres originating from the facial nerve root are distributed to the lower lip via CTN and in the other, fibres emanating from the glossopharyngeal nerve root project to the lower lip via the otic ganglion. 3, AFFERENT AND EFFERENT PATHWAYS IN REFLEX ARCS 3. I Trigeminal (somatic) stimulation
Stimulation of the trigeminal ganglion or nerve might elicit up to four different vascular responses simultaneously: sympathetic vasoconstriction (Matthews and Robinson, 1980) and parasympathetic (Gonzalez et aL, 1975), antidromic (Couture and Cuello, 1984; Lundblad et aL, 1982; Izumi et aL, 1990) and reflex vasodilatations (Lambert et al., 1984). Therefore, it may be difficult to analyse a given response precisely since the observed change could be a summation of a number of different responses. For this reason, the infra-orbital nerve and maxillary buccal gingiva were electrically stimulated to activate trigeminal sensory fibres and to evoke changes in blood flow bilaterally in the lower lip, which is outside the innervation zone of the infra-orbital nerve and thus to enable elimination of antidromic effects of sensory nerves on the innervated tissues (Izumi and Karita, 1992c). The observation that electrical stimulation of the infra-orbital nerve or maxillary buccal gingiva elicited an increase in ipsilateral lower lip blood flow suggests that there is a reflexly-induced vasodilatation in the cat lip. Three types of fibres might mediate such a reflex vasodilatation: (i) sensory, (ii) sympathetic and (iii) parasympathetic neurons and these will be considered in turn. (i) Axon reflexes were considered because cutaneous sensory fibres from individual dorsal root neurons provide a collateral branch to cutaneous arteriole, and antidromic activation of pure sensory neurons leads to peripheral vascular dilatation (Lewis, 1922; Lewis and Harmer, 1927; Chapman, 1977; Izumi and Karita, 1988, 1991a, b, 1992a, b; Izumi et al., 1988). However, the abolition of the vasodilator responses by acute section of the root of the glossopharyngeal nerve and by pretreatment with an autonomic ganglionic blocker (hexamethonium) indicates that axon reflexes are not responsible for the reflex vasodilatation since the anatomical substrate for axon reflexes was left intact in those experiments (Izumi and Karita, 1992c). (ii) The existence of sympathetic vasodilator fibres has recently been reported in cats and humans (Bell et al., 1985; Blumberg and Wallin, 1987; Lundberg et al., 1989; Nordin, 1990; Izumi and Karita, 1994d).
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However, sympathetic fibres seem unlikely to be involved in the present reflex vasodilatation, since the vasodilatation occurred after ipsilateral section of the sympathetic trunk and disappeared after section of the glossopharyngeal nerve root. (iii) There have been many previous reports of the existence of parasympathetic vasodilator nerve fibres in the lower lip, gingiva, submandibular gland, tongue, nasal mucosa, uvea and pial arteries in various animals (Chorobski and Penfield, 1932; Anggard, 1974; Lundberg et al., 1981a,b, 1982a,b; Nilsson et al., 1985; Izumi and Karita, 1991a, b, 1994a, b, c; Karita and Izurni, 1994b). All of these vasodilator fibres are reported to emerge from the facial nerve and the vasodilator responses have been shown to be mediated via the pterygopalatine ganglion. Thus, the vasodilator pathway to the face and head has been said to pass through the facial nerve and the pterygopalatine ganglion (Chorobski and Penfield, 1932; McNaughton and Feindel, 1977). However, the reflex vasodilator response elicited by stimulation of the infra-orbital nerve of maxillary buccal gingiva was never affected by sectioning the facial nerve root, but was completely abolished by intracranial section of the glossopharyngeal nerve root, suggesting that the reflex vasodilator response was mediated through the glossopharyngeal nerve alone. In addition, the reflex vasodilator response was attenuated by pretreatment with an autonomic ganglionic blocking agent. It seems safe to conclude, therefore, that parasympathetic neurons, particularly those running as efferents in the glossopharyngeal nerve, were involved in the vasodilatation elicited by stimulation of the infra-orbital nerve and the maxillary buccal gingiva. Moreover, the vasodilator response was not affected by lesion of the pterygopalatine ganglion. These results suggest that the reflex vasodilatation and the facial-nerve- and the glossopharyngeal-nerve-stimulated vasodilatations are mediated via the otic ganglion but not via the pterygopalatine ganglion. This is supported by the observation that retrogradely labelled cells have been observed in the ipsilateral otic ganglion following an injection of horseradish peroxidase into the mandibular lip as described before (Kuchiiwa et al., 1992). The lip blood flow increase in response to administration of pentylenetetrazole (a seizure-inducing drug) was found to be completely suppressed by section of the roots of both glossopharyngeal and facial nerves but not by section of the glossopharyngeal nerve root alone (Izumi et al., 1994). These results indicate that parasympathetic vasodilator fibres originating from the facial nerve participate in seizure-induced vasodilatation in the cat lower lip.
This is not the same as the path followed by the somato-parasympathetic reflex in cat lower lip reported previously (Izumi and Karita, 1992a, b,c, 1993b, c). This may suggest that the pattern of stimulation of the central parasympathetic nerves is different on seizure as opposed to somatic stimulation (Izumi and Karita, 1994a, b, c, d). Pharmacological analysis showed that this reflex vasodilator response was resistant to blockade by antimuscarinic (atropine), antihistaminergic (tripelennamine) and antiadrenergic agents (phentolamine and propranolol) but sensitive to a ganglionic blocking agent (hexarnethoniurn), suggesting that the reflex vasodilatation is mediated via final neurons that are not cholinergic. These resemble those found in the blood vessels of the submandibular gland and tongue of cats (Anggard, 1974; Lundberg et al., 198la, b, 1982a, b; Nilsson et al., 1985; lzumi and Karita, 1991a, b, 1992b, c, 1994a, c), which mediate the so-called atropine resistant vasodilator response. The existence of nonsympathetic, atropine-resistant vasodilator fibres in the inferior alveolar nerve has previously been suggested by Matthews and Robinson (1980). Similar reflex vasodilator responses have not yet been found in the face and head in humans, although the occurrence of a sornatosympathetic reflex vasodilatation has recently been reported in the human foot (Blumberg and Wallin, 1987). 3.2 Vagus (visceral) stimulation
Recent studies, using a variety of tract-tracing techniques, have shown that trigeminal sensory neurons synapse not only in the trigeminal sensory nuclei of the brain stem as general somatic afferents, but also in the caudal portions of the nucleus of the tractus solitarius (NTS), probably as general visceral afferents (Nornura and Mizuno, 1983; Nomura et al., 1984; Menetrey and Basbaum, 1987; Person, 1989). The two nuclei, according to current doctrine, are functionally different and well defined structures, suggesting that the trigerninal nerve carries not just somatic, but a mixture of somatic and visceral afferent axons. Which afferent fibres in the trigeminal nerves contribute to the autonomic reflex vasodilatation in the cat lower lip remains unclear. The cervical vagus nerves as well as the facial and glossopharyngeal nerves contain a large number of visceral sensory fibres that terminate in the NTS (Torvik, 1956; Menetrey and Basbaurn, 1987; Kawai et al., 1989) and activation of these afferent fibres elicits various kinds of reflex autonomic responses (see reviews by Ranson, 1921; Paintal, 1963, 1973; Koizurni and Brooks, 1972; Sato and Schmidt, 1973; Janig, 1986) and antinociception (Maixner and
Parasympathetic reflex vasodilatation Randich, 1984; Randich et al., 1991; Ren et al., 1991). We have therefore stimulated the central cut end of the cervical vagus nerve and observed the blood flow changes in the cat lower lip in order to investigate the possible role of general visceral afferents in this autonomic reflex vasodilatation (Izumi and Karita, 1993c). We have found that lip vasodilatation is indeed produced by such stimulation, suggesting that vagal visceral afferent activation may influence cutaneous blood flow in the oro-facial areas of cats. Reflex vasodilatation in response to stimulation of the central cut end of the vagus nerve was frequently observed on both sides of the cat lip unlike that induced by trigeminal stimulation (Izumi and Karita, 1992b, c; Karita and Izumi, 1992a, b) which, in most cases, did not occur on the contralateral side unless the stimulus strength to the trigeminal nerve was increased. This may be due to differences in the projection of the trigeminal and vagus nerves to the NTS: the trigeminal nerve projects to NTS ipsilaterally (Nomura et al., 1984) while the vagus nerve projects bilaterally (Torvik, 1956; Anton and Peppel, 1991). Simultaneous stimulation of the central cut ends of both cervical vagus nerves produced an additive vasodilatory effect on both sides of the cat lower lip even when the stimulus intensity applied to each vagus nerve was high enough to cause the maximal response one nerve could produce. These results suggest two possible mechanisms: (1) there is summation within the NTS of ipsilateral and contralateral afferent impulses; and (2) different vasomotor neurons exist in the brain stem which are affected by either ipsilateral or contralateral vagus nerve stimulation. Sympathetic nerves seem not to be involved in this reflex vasodilatation since the experiments described were conducted after bilateral elimination of cervical sympathetic nerves, Ipsilateral section of either the glossopharyngeal nerve root or inferior alveolar nerve abolished the reflex vasodilator response caused by stimulation of the central cut end of the vagus. Thus, these data suggest that the parasympathetic vasodilator fibres emerge from the brain stem with the glossopharyngeal nerve and reach the blood vessels via the inferior alveolar nerve. This reflex parasympathetic efferent pathway is similar to that of the trigeminally elicited vasodilatation described before (Izumi and Karita, 1992b, c). 3.3 Chorda tympani (gustatory) stimulation Electrical stimulation of the central cut end of the CT caused an increase in blood flow in the ipsilateral side of the lower lip (Karita and Izumi, 1993). Capsaicin application to the CT did not elicit a blood flow increase, although capsaicin application to the lingual nerve after cutting the CT evoked a blood GP 2612--B
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flow increase in the ipsilateral lower lips. (Karita and Izumi, 1992a). These results suggest that capsaicininsensitive fibres in the chorda tympani branch of the facial nerve, as well as capsaicin-sensitive ones in the lingual branch of the trigeminal nerve, participate as afferents in the parasympathetic vasodilator reflex in cat lower lip. 3.4 Nasal mucosa stimulation Local application of capsaicin (threshold dose 150pM) or nicotine (threshold dose 15 mM) to the nasal mucosa as well as electrical stimulation (threshold intensity 10 V) of the nasal mucosa elicited dose- or intensity-dependent blood flow increases in the ipsilateral lower lip of the anaesthetized cat (Izumi and Karita, 1993b; Karita and Izumi, 1994a). Pretreatment with 3 mM capsaicin applied locally to the nasal mucosa abolished or reduced the vasodilation in response to capsaicin, nicotine and ammonia vapor but not to light mechanical or electrical stimulation of the nasal mucosa. The blood flow increases elicited by all the above stimuli were greatly reduced by pretreatment with hexamethonium, an autonomic ganglion blocker. These results suggest that stimulation of the nasal mucosa by chemical (capsaicin, nicotine, ammonia), mechanical, or electrical methods elicits an autonomic reflex vasodilatation in the cat lower lip. Furthermore, there seem to be at least two types of afferent fibres in the nasal mucosa of the cat involved in reflex vasodilatation: one type is capsaicin-sensitive while the other is capsaicin-resistant. The efferent pathway of these reflexes is analogous to that of the trigeminally or vagally induced reflex vasodilatation mentioned above (Izumi and Karita, 1992b, c, 1993c). 4, CONCLUSION 4.1 Selective stimulation o f parasympathetic nerves Electrical stimulation of the tongue and proximal cut ends of the lingual nerve to provide a trigeminal input caused a vasodilatation only as a result of a somato-parasympathetic reflex, although sometimes no change in blood flow was observed on electrical stimulation of the tongue (nearly 10% of tests, Izumi and Karita, 1992b). On the other hand, direct electrical stimulation of the glossopharyngeal nerve, which contains the parasympathetic vasodilator fibres, caused either vasodilatation (nearly 77% of tests) or vasoconstriction (nearly 15%) or no change (nearly 8%). These vasodilator responses seem to be attributable largely to parasympathetic nerve activation, since there is no anatomical evidence that the glossopharyngeal nerve contains polymodal nociceptive C-fibres to the lower lips which might cause
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antidromic vasodilatation (Williams and Warwick, 1980) and since pretreatment with hexamethonium markedly reduced the vasodilatation. The observed vasoconstrictor responses suggest that adjacent sympathetic vasoconstrictor fibres may have been costimulated since pretreatment with an ~-adrenergic receptor blocker (phentolamine, 1.0 mg/kg, i.v.) completely abolished the vasoconstrictor response. This is in accordance with previous observations (Thomander et al., 1984; Nilsson et al., 1985; Matthews and Robinson, 1986) that the facial nerve contains sympathetic fibres in the cat. Similarly, stimulation of the distal cut end of the I A N elicited not only vasodilatation, but also vasoconstriction in cat lower lip (Izumi et al., 1990). This vasodilatation cannot be explained as a purely parasympathetic vasodilatation since antidromic vasodilatation occurred as a consequence o f activation of the nociceptive sensory fibres in the IAN. The occurrence of sympathetic vasoconstrictor fibres in the I A N has previously been reported by many investigators (Ogilvie, 1969; Matthews and Robinson, 1980; Izumi et al., 1990). The above finding, that reflex vasodilatation can be exclusively mediated by activation of parasympathetic nerve fibres, suggests that selective excitation of the parasympathetic nerve fibres in the oral area is feasible. This should enable us to clarify the mechanism underlying the vasodilator response elicited via parasympathetic fibres and the physiological function of the vasodilatation in the facial area. Using this reflex parasympathetic activation method, it was possible to differentially evoke salivary and vasodilator responses by direct chorda lingual nerve (parasympathetic nerve fibers) and by reflex parasympathetic stimulation in the cat submandibular gland (Izumi and Karita, 1994b, c). 4.2 Functional implication
Since parasympathetic reflex vasodilatation can be elicited by activation of the trigeminal (somatic), vagus (visceral), chorda tympani (gustatory) and nasal (chemical and mechanical) stimulation, it is unlikely to arise from a specific oral structure (e.g. tooth or tongue). This suggests that these parasympathetic reflex vasodilator responses are not due to excitation of proprioceptors. The physiological function of parasympathetic reflex vasodilatation in the mandibular division of the cats is unknown. However, it has recently been suggested that the trigeminal system may participate in autonomic and behavioral functions such as feeding and drinking (Zeiger and Karten, 1974). Furthermore, Gibbins et al. (1984) and Gibbins (1990) proposed an interesting hypothesis: the perivascular
V I P - I R nerves in orofacial areas might be implicated in vasodilator control and reduce heat stress elicited by a body temperature increase or intense firing in the central nervous system. The data presented here add a new facet to the evidence that the various afferent systems such as somato-, gustatory- and visceral sensory nerves may all link the parasympathetic (autonomic) nervous system in the facial area.
REFERENCES Anggard A. (1974) Capillary and shunt blood flow in the nasal mucosa of the cat. Acta Otol. 78, 418-422. Anton F. and Peppel P. (1991) Central projections of trigeminal primary afferents innervating the nasal mucosa: a horseradish peroxidase study in the rat. Neuroscience 41, 617-628. Bell C., Janig W., Kummel H. and Xu H. (1985) Differentiation of vasodilator and sudomotor responses in the cat paw pad to preganglionic sympathetic stimulation. J. Physiol. (Lond.) 364, 93-104. Blumberg H. and WaUin B. G. (1987) Direct evidence of neurally mediated vasodilatation in hairy skin of the human foot. J. Physiol. (Lond.) 382, 105-121. Cauna N. and Naik N. T, (1963) The distribution of cholinesterase in the sensory ganglia of man or some animals. J. Histochem. Cytochem. 11, 129-138. Chapman L. F. (1977) Mechanisms of the flare reaction in human skin. J. Invest. Dermat. 69, 88-97. Chorobski J. and Penfield W. (1932) Cerebral vasodilator nerves and their pathway from the medulla oblongata: with observations on the pial and intracerebral vascular plexus. Arch. Neurol. Psych. 28, 1257 1289. Couture R. and Cuello A. C. (1984) Studies on the trigeminal antidromic vasodilatation and plasma extravasation in the rat. 3. Physiol. (Lond.) 346, 273--285. Gibbins I. L. (1990) Target-related patterns of co-existence of neuropeptides Y, vasoactive intestinal peptide, enkephalin and substance P in cranial parasympathetic neurons innervating the facial skin and exocrine glands of guinea-pigs. Neuroscience 38, 541-560. Gibbins I. L., Brayden J. E. and Bevan J. A. (1984) Perivascular nerves with immunoreactivity to vasoactive intestinal polypeptide in cephalic arteries of the cat: distribution, possible origins and functional implications. Neuroscience 13, 1327-1346. Gonzalez G., Onofrio B. M. and Kerr F. W. (1975) Vasodilator system for the face. J. Neurosurg. 42, 696-703. Hume W. R. and Waterson J. G. (1978) The innervation of the rabbit ear artery. Blood Vessels 15, 348 364. Izumi H. and Karita K. (1988) Investigation of mechanisms of the flare and wheal reactions in human skin by band method. Brain Res. 449, 328-331. Izumi H. and Karita K. (1990) The effects of capsaicin applied topically to inferior alveolar nerve on antidromic vasodilatation. Neurosci. Lett. 112, 65-69. Izumi H. and Karita K. (1991a) Axon reflex vasodilatation in human skin by laser Doppler measurement, Jpn. J. Physiol. 41, 693-702. Izumi H. and Karita K. (1991b) Vasodilator responses following intracranial stimulation of the trigeminal, facial and glossopharyngeal nerves in cat gingiva. Brain Res. 560, 71-75. Izumi H. and Karita K. (1992a) Axon reflex flare evoked by nicotine in human skin. Jpn J. Physiol. 42, 721-730. Izumi H. and Karita K. (1992b) Selective excitation of parasympathetic nerve fibres to elicit the vasodilatation in cat lip. J. Auton. Nerv. Sys. 37, 99-108.
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