The role of nitric oxide in orofacial pain

Nitric Oxide 26 (2012) 32–37

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Review

The role of nitric oxide in orofacial pain Wenguo Fan a, Fang Huang b,⇑, Zhi Wu a, Xiao Zhu c, Dongpei Li c, Hongwen He a,⇑ a

Department of Oral Anatomy and Physiology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China Department of Pediatric Dentistry, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China c Key Laboratory of Molecular Diagnosis, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Dongguan, China b

a r t i c l e

i n f o

Article history: Received 31 July 2011 Revised 31 October 2011 Available online 25 November 2011 Keywords: Nitric oxide Orofacial pain Review

a b s t r a c t Nitric oxide (NO) is a free radical gas that has been shown to be produced by nitric oxide synthase (NOS) in different cell types and recognized to act as a neurotransmitter or neuromodulator in the nervous system. NOS isoforms are expressed and/or can be induced in the related structures of trigeminal nerve system, in which the regulation of NOS biosynthesis at different levels of gene expression may allow for a fine control of NO production. Several lines of evidence suggest that NO may play a role through multiple mechanisms in orofacial pain processing. This report will review the latest evidence for the role of NO involved in orofacial pain and the potential cellular mechanisms are also discussed. Ó 2011 Elsevier Inc. All rights reserved.

Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Orofacial pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nociceptive transmission of the orofacial region . . . . . . . . . . . . . . . . Biosynthesis and localization of NO in the trigeminal nerve system. Role of nitric oxide in orofacial pain transmission . . . . . . . . . . . . . . . Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Nitric oxide (NO) is thought to be one of the oldest molecules on earth. Although it is well known that NO is nothing but an air pollutant produced by automobile engines and power plants, NO is discovered as an endogenous gas responsible for the actions of endothelial derived relaxing factor (EDRF) in 1987 [1]. Following this finding, this molecule with very simple structure has been mesmerizing more and more investigators, and research on NO resulted in the publication of no less than 7000 papers annually. Considerable evidence indicates that NO is involved in specific biological actions on different systems, which is regarded as an ⇑ Corresponding authors. Address: Institute of Stomatological Research, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 74 Zhongshan Rd. 2, Guangzhou 510080, China. Fax: +86 20 87330709. E-mail addresses: [email protected] (F. Huang), [email protected] (H. He). 1089-8603/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.niox.2011.11.003

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atypical neural neurotransmitter in the nervous system [2–4]. The increasing amount of evidence has indicated that NO is implicated in spinal pain processing [5,6]. However, much less is studied with respect to orofacial pain transmission. The aim of this review is to give an overview of NO and analyze different lines of evidence for the role of NO in orofacial pain studied to date. Possible cellular mechanisms regarding the connection between NO production and orofacial pain are discussed (see Fig. 1). Orofacial pain Orofacial pain is a term defined by the American Academy of Orofacial Pain (AAOP) as ‘‘pain conditions that are associated with the hard and soft tissues of the head, face, neck, and all the intraoral structures’’ [7]. The term orofacial pain is evolving and the scope of the field is enlarging. At the present time the orofacial pain encompasses: masticatory musculoskeletal pain, cervical

W. Fan et al. / Nitric Oxide 26 (2012) 32–37

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Biosynthesis and localization of NO in the trigeminal nerve system

Fig. 1. Schematic diagram of the NO signal transduction pathway in orofacial nociception.

musculoskeletal pain, neurovascular pain, neuropathic pain, sleep disorders related to orofacial pain, orofacial dystonias and intraoral/intracranial/extracranial and systemic disorders that cause orofacial pain [8]. Ninety percent of orofacial pain arises from the teeth and oral structures. Understanding of the mechanism of orofacial pain is critical for performing successful management of such painful conditions. Nociceptive transmission of the orofacial region Orofacial pain sensation from the intraoral and extraoral structures of the head and face is relayed to the central nervous system (CNS) by trigeminal nerve system. Primary sensory fibers innervating the orofacial region derive from neurons of the trigeminal ganglion (TG) in which central processes enter the pons, where they descend in the brainstem as the spinal trigeminal tract [9–11]. There are two main types of trigeminal afferents: small diameter, slow-conducting, myelinated A-delta fibers and slow-conducting unmyelinated C fibers. Moreover, teeth have a significant A-beta fiber innervation as well as receiving A-delta and C fibers. A variety of peptides associated with nociception are known to be present in the fibers which include calcitonin gene-related peptide (CGRP), substance P, somatostatin, galanin, and enkephalins. In addition, there is an evidence that glutamate is another transmitter in the sensory fibers. The types of fibers and transmitters in orofacial structures are somewhat different which depend on different sites, (e.g., the teeth, tongue, meninges, cornea, conjunctiva, and oral and nasal mucosa) [12]. The spinal trigeminal nucleus (STN) is trigeminal second order nociceptive neurons, which is divided into three subnuclei from caudal to rostral: caudalis (Vc), interpolaris (Vi), and oralis (Vo) [13,14]. The Vc has been regarded as an essential nucleus for orofacial nociception [15,16]. Anatomically, the caudal part of the STN, the Vc, has a laminar structure and is homologous with the dorsal horn of the spinal cord [17]. The Vi relays primarily tactile input to the thalamus, cerebellum, and spinal cord [18], whereas the Vo is also known to be primarily responsible for relaying reflexive orofacial nociceptive information [15,19]. More recently, evidence suggests that the ventral portion of the Vi/Vc transition zone plays an important role in orofacial pain condition associated with deep tissues [20]. A major transmitter in the STN is glutamate and other agents such as substance P, c-aminobutyric acid and enkephalin are also present, which modulate signaling and processing of the orofacial sensory input at central level. From the STN, the information is conveyed to the thalamus and ends at the somatosensory cortex.

NO is synthesized intracellularly directly by nitric oxide synthase (NOS) using L-arginine as substrate. There are three distinct isoforms of NOS, which include neuronal NOS (nNOS, NOS1), inducible NOS (iNOS, NOS2) and endothelial NOS (eNOS, NOS3) [21]. NOS1 is the first to be identified and cloned from neural tissue and it is therefore also called nNOS. NOS3 generates NO in blood vessels and is involved in regulating vascular function. NOS1 and NOS3 are constitutively expressed and dependent on a rise in tissue calcium concentration for activity. NOS2 is an inducible, calcium-independent isoform, and induced under certain conditions (such as inflammation and oxidative stress). These NOS isoforms require nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme to be enzymatically active. Thus, NADPH-diaphorase (NADPH-d) histochemistry is a common marker for all three NOS isoforms and their activity has been shown to parallel NO production [22]. Histochemical and immunohistochemical studies have showed that NADPH-d/NOS is expressed in the trigeminal nerve system. Lohinai et al. report that peripheral axons innervated in the dental pulp and gingival are NADPH-d positive and/or NOS immunoreactive in cats and dogs [23]. Moreover, NADPH-d positive nerve fibers are found in TG [24,25] as well as in the peripheral axons of neurons supplying maxillary and mandibular division of the trigeminal nerve in rabbit [24] and rat [25]. In the TG, most of the intensely NADPH-d/NOS-stained cells are small- or medium-sized neurons and distributed randomly throughout the ganglion in rat [25–28], cat [29], rabbit [24] and the human [30,31]. Another study demonstrates that there are about 50% of the total number of neurons expressed nNOS in the TG and that they are represented mainly as large-sized neurons in human [32]. Small to medium-sized ganglionic cells possess thin unmyelinated C-fibers or fine myelinated A-d-fibers [33]. Since these types of fibers are accepted to mainly mediate nociception, it is likely that these NOS ganglionic cells participate in nociception. Moreover, some investigators find that there are some NOS neurons in the superficial and deep laminae of the STN [28,34–36]. These neurons are not projection neurons and believed to function as interneurons [36–38]. NO is most prominent in interneurons located in Vc and that these interneurons give rise to processes that appose trigeminothalamic neurons [38]. Although the thalamus projecting neurons in the STN do not synthesize NO, they could be modulated by NO diffused from NOS neurons, since the gas NO can diffuse freely into adjacent cells that lie within about 100 lm from their source [39]. The anatomical distribution of NOS in the related structures of trigeminal nerve system indicates that NO/NOS might be involved in the transmission of orofacial nociceptive information. Thus, Yeo proposes that NO might play a seemingly less important role than glutamate in neural transmission [37].

Role of nitric oxide in orofacial pain transmission NO has been recognized to act as a neurotransmitter or neuromodulator in the nervous system. The increasing amount of evidence has indicated that NO is implicated in spinal pain processing [5]. However, very little is known in the case of orofacial nociception, except for the localization of NOS neurons in the TG and STN we mentioned above. NO, known as EDRF, firstly contributes to vessel homeostasis and causes vasodilation and increasing blood flow. A regional increased level of NO causes excessive vasodilatation. This hyperperfusion is manifested by hyperthermia of the overlying skin [40]. Pain of temporomandibular joint disorders (TMD) is associated

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with skin hyperthermia caused by regional vasodilation, which is induced by NO produced in the extravascular space of the joint [41,42]. Clinical observation confirms this hypothesis. For example, the degree of joint pain is correlated with elevated NO levels in synovial fluid in patients with TMD [43]. Another clinical observation shows that there are elevated levels of NO in the patients diagnosed with chronic orofacial pain (COP) [40] and suggests that NO blood levels may have an association with COP. NO might enhance nociception and aggravate orofacial pain. However, there is a clinical study showing the differences in serum NO concentrations are not statistically significantly different before and after treatment in patients with irreversible pulpitis [44] which can usually produce spontaneous pain, hyperalgesia and allodynia. Inflammatory insults to tooth pulps significantly increased the number of NADPH-d positive neurons in Vc [45]. Our investigation shows that the NADPH-d activity increases in the TG cells and in the Vc in PX-induced chronic pulpal inflammation of rats. Such changes are correlated to changes of c-Fos, a marker for neuronal activity, in the Vc. It suggests that NOS/NO may play an active role in both peripheral and central processing of nociceptive information following chronic tooth inflammation [46]. Moreover, NOS expression in the TG increases in orofacial pain induced by subcutaneous injection of formalin [47]. NOS inhibitor (L-NAME) significantly reduces the hyperalgesia in formalin-induced orofacial pain [48]. Similarly, in the orofacial muscle pain model, the expression of NOS in the Vc is significantly up-regulated after capsaicin stimulation and parallels masseter hypersensitivity. NOS inhibitor significantly attenuates the masseter hypersensitivity. These data show that NOS in the Vc are functionally important for the development of craniofacial muscle hyperalgesia [49]. In the inflammatory pain of orofacial region above, NO may play a pronociceptive role in these pain states. But a more recent study demonstrates that activity of nNOS significantly increases in the chronic-phases of arthritis in the rat temporomandibular joint (TMJ). Meanwhile, head-withdrawal threshold decreases significantly in the chronic arthritis under chronic NOS inhibitor [50]. It indicates that NO/nNOS in the central nociceptive processing plays an anti-nociceptive role. A large body of studies have also indicated a correlation between altered NO production and the generation and/or maintenance of chronic pain associated with nerve injury at spinal level. However, there have been few studies on the role of NO in neuropathic pain in orofacial area. Rodella et al. have found that the number of NADPH-d neurons significantly decrease in the TG in rats with diabetic neuropathy (trigeminal hyperalgesia) evoked by streptozotocin (STZ) administration [51]. Another study demonstrates that the number of nNOS-positive neurons is increased on the ipsilateral side in layers I/II of the Vc by the loose-ligation of inferior alveolar nerves in rats [52]. Law et al. have found that increased intensity of NADPH-d reactivity located in the parainflamed pulp tissue and surrounding endothelial/vascular structures in rat [53]. The expression of iNOS increases in pulpal inflammation induced by the application of lipopolysaccharide (LPS) in rat incisor pulp [54]. By immunohistochemistry, increased numbers of the synovial lining cells with immunoreactivity for iNOS are also seen in the inflamed synovium of TMJ [55]. In the LPS-induced pulpitis, elevated pro-inflammatory cytokines and cyclooxygenase-2 (COX-2) mRNA are drastically decreased by a NOS inhibitor [54]. These results indicate that NO synthesis is related to the initiation of mediator productions, and that its down-regulation should contribute to the prevention of proinflammatory mediator synthesis [54]. These data indicate that NO may mediate these inflammatory response and be implicated in inflammatory pain at nociceptor level. Similarly, Pena-dos-Santos et al. have explained anti-nociceptive effect of the drug 15d-PGJ(2) in the TMJ inflammatory pain

conditions by peripheral opioids receptor, which involves the activation of the intracellular L-arginine/NO pathway [56]. In addition, evidence suggests that intracisternal antidepressants produce antinociception through central NO pathway in the orofacial area [57]. Melatonin can reduce the number of NOS-positive cells in the Vc and produces substantial attenuation of trigeminovascular nociception induced by cortical spreading depression [58]. Ramachandran et al. fully investigate throughout the pain pathways involved in migraine and find that both nNOS and eNOS are highly expression. It indicates that NO/NOS is involved in migraine mechanisms [28]. The onset of migraine headaches is also attributed to NO production [59,60]. Experimental models have demonstrated that NO donors sodium nitroprusside or nitroglycerin (NTG) can induced headache [60–63]. Moreover, pilot trials have shown efficacy of a NOS inhibitor in both migraine attacks and chronic tension-type headache [59,60]. NO production in different tissues and physiologic and pathologic conditions is controlled by NOS biosynthesis. Three NOS isoforms are encoded by three distinct genes and regulated at different levels through complex mechanisms. NO could produce pro- or anti-nociceptive effects in orofacial pain transmission, which remain to be determined.

Mechanisms of action Glutamate, one of the excitatory amino acids (EAAs), is the most abundant excitatory neurotransmitter in the brain and spinal cord, which is stored in vesicles and exerts its action through two types of membrane receptors: ionotropic and metabotropic receptors. Ionotropic glutamate receptors (GluRs) directly gate ion channels and are divided into three major subclasses: N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) and kainate receptor [64]. Metabotropic glutamate receptors belong to the superfamily of G-protein coupled receptors [65]. These receptors are widely located on the pre- and post-synaptic membranes in the CNS, as well as, at extra-synaptic sites where they are involved in the modulation of nociceptive transmission and pain [66,67]. The release of glutamate from primary afferent nerve terminals in the dorsal horn of the spinal cord is a key event in nociceptive signal transduction [68]. Accumulating evidence suggests that activation of NMDA receptors could rapidly augment the conversion of arginine to citrulline and leads to ultimate NO production. Immunocytochemical and in situ hybridization studies show that NMDA/NOS-containing neurons in the STN express more mRNA for NMDA than non-NOScontaining neurons in the STN. It suggests that NMDA activation may lead to NO production in the STN [34]. Similarly, some c-Fos positive neurons in the Vc are colocalized with NOS and various glutamate receptors such as NMDAR1 and GluR2/3 after subcutaneous injection of formalin into face of the rats [69]. Other studies demonstrate that NMDA/NOS/NO pathways may be involved in the development of tactile hypersensitivity evoked by the loose-ligation of inferior alveolar nerves [52,70] and by dental-injury [71] in rats. On the other hand, neuronally generated NO is responsible for S-nitrosylation [72]. Nitrosylation of NMDA receptors decreases their activity. Thus, NO provides a negative regulation to NMDA receptor signaling. The biological effects of NO may be mediated through the activation of soluble guanylate cyclase (sGC) and subsequent production of the intracellular second messenger, cyclic GMP (cGMP). cGMP then activates downstream targets including cGMP-dependent protein kinase, ion channels and receptors [5]. This defined mechanism of NO effects is the most commonly observed. Immunohistochemical study demonstrates that sGC is present in TG on the mRNA and the protein level [73]. Intrathecal administration

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of sGC inhibitors blocks the capsaicin-induced reduction of mechanical threshold to noxious stimulation of the masseter, which indicates that the NO-sGC pathway in the Vc is involved in mediating orofacial muscle hypersensitivity under acute inflammatory conditions [74]. Several groups have suggested that the activity of NO/cGMP pathway decreases TMJ kappa-mediated [75] and electroacupuncture (EA) at acupoint St36-induced [76] antinociception. In addition, the most recent study has been shown that estradiol decreases TMJ nociception in female rats through a peripheral non-genomic activation of the NO/cGMP signaling pathway [77]. The mechanisms responsible for hyperalgesia in chronic pain state may involve not only NO itself, but also peroxynitrite (ONOO ), the product of its reaction with superoxide. Heat-evoked hyperalgesia is inhibited by preventing the formation of peroxynitrite in rats with an experimental painful peripheral neuropathy [78]. Moreover, intracerebroventricular (i.c.v.) injection of peroxynitrite scavenger results in an anti-nociceptive effect in carrageenan induced facial pain but no effect on normal tactile sensation. This indicates that peroxynitrite plays an important role on CNS in nociception [79]. The increasing amount of evidence indicates that glial cells play a critical role in the genesis or maintenance of persistent pain [80– 82]. Masseter inflammation activates glial cells and upregulates inflammatory cytokine in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input, which is blocked by a NOS inhibitor [83]. It suggests that a role for NO in neuronal-glial signaling in the trigeminal model of inflammatory hyperalgesia. NO might mediate inflammation and pain in the TMJ through several signaling pathways which includes extracellular signalregulated kinase (ERK), p38 and mitogen kinase phosphatases (MKPs) [84]. These data are obtained in the experiment of rat in vivo, which are determined in TG neurons and satellite glial cells, and indicate that they are involved in peripheral sensitization as well as control of inflammatory and nociceptive responses [84]. Another study in vitro shows that CGRP binding to its receptor can stimulate iNOS gene expression via activation of mitogen-activated protein kinase (MAPK) signaling pathways in trigeminal satellite glial cells [85]. The molecular mechanisms of migraine have not yet been clarified. Vasodilation and neurogenic inflammation of the meningeal blood vessels have been suggested as causative factors [59,86]. CGRP released from trigeminal sensory neurons can provoke the vasodilatation and vessels’ inflammation, which have been believed as a key mediator in migraine [86–89]. Some authors demonstrate that NO can increase the release or production of CGRP in TG in vitro [90,91], through which CGRP or CGRP-receptor expression might be changed [91]. Nitroglycerin (NTG, a NO donor) provokes a hyperalgesic state in animals, which probably activates the second-order neurons in the Vc [92]. In this process CGRP seems to be regulated by NO at the Vc level [92]. On the other hand, activation of CGRP1 receptors regulates glial iNOS and NO release. Li et al. demonstrate that following trigeminal nerve activation, CGRP secretion from neuronal cell bodies activates satellite glial cells that release NO and initiate inflammatory events in the ganglia that contribute to peripheral sensitization in migraine [88]. Interaction of NO/NOS and CGRP might be one of the most important molecular mechanisms in the migraine.

Conclusions In summary, NO might play a seemingly less important role than glutamate in orofacial pain transmission [37], which is confirmed by some studies. On the one hand, NO could produce pro-

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or anti-nociceptive effects in different stimulus or pathologic condition. The role of NO in nociception may be more complicated than one has expected. On the other hand, studies on NO involved in orofacial nociception (trigeminal sensory system) are much less than it is in the spinal system. The precise mechanisms of NO in orofacial nociception so far have not been clear, especially in dental pain, TMD, neuropathic pain and magrine. Thus, a significant number of studies must be performed in the trigeminal sensory system not only in different pain models but in clinical experiments. A better understanding of orofacial pain will help to find potential therapeutic targets and develop new analgesics for the prevention and/ or treatment of different pain states of human. Acknowledgments This work is supported in part by the National Natural Science Foundation of China(No: 30070952; 30472248) and Natural Science Foundation of Guangdong Province (No: 10451008901006145) References [1] R.M. Palmer, A.G. Ferrige, S. Moncada, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor, Nature 327 (1987) 524–526. [2] D.E. Baranano, C.D. Ferris, S.H. Snyder, Atypical neural messengers, Trends Neurosci. 24 (2001) 99–106. [3] D. Boehning, S.H. Snyder, Novel neural modulators, Annu. Rev. Neurosci. 26 (2003) 105–131. [4] A. Dhir, S.K. Kulkarni, Nitric oxide and major depression, Nitric Oxide 24 (2011) 125–131. [5] Z.D. Luo, D. Cizkova, The role of nitric oxide in nociception, Curr. Rev. Pain 4 (2000) 459–466. [6] Y. Cury, G. Picolo, V.P. Gutierrez, S.H. Ferreira, Pain and analgesia: the dual effect of nitric oxide in the nociceptive system, Nitric Oxide 25 (2011) 243– 254. [7] American Board of Orofacial Pain. . [8] J.P. OKESON, Orofacial Pain-Guidelines for Assessment, Diagnosis, and Management, Quintessence Books, Chicago, 1996, pp. 1–3. [9] N.E. Lazarov, The mesencephalic trigeminal nucleus in the cat, Adv. Anat. Embryol. Cell Biol. 153 (2000) iii–xiv. 1–103. [10] E. Marani, K.G. Usunoff, The trigeminal motonucleus in man, Arch. Physiol. Biochem. 106 (1998) 346–354. [11] N.E. Lazarov, Comparative analysis of the chemical neuroanatomy of the mammalian trigeminal ganglion and mesencephalic trigeminal nucleus, Prog. Neurobiol. 66 (2002) 19–59. [12] D.A. Bereiter, K.M. Hargreaves, J.W. Hu, Trigeminal mechanisms of nociception: peripheral and brainstem organization, in: A. Basbaum, M.C. Bushnell (Eds.), Science of Pain, vol. 5, Elsevier, New York City, 2009, pp. 435– 460. [13] B.J. Sessle, Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates, Crit. Rev. Oral Biol. Med. 11 (2000) 57–91. [14] J. Olszewski, On the anatomical and functional organization of the spinal trigeminal nucleus, J. Comp. Neurol. 92 (1950) 401–413. [15] J.W. Hu, B.J. Sessle, Comparison of responses of cutaneous nociceptive and nonnociceptive brain stem neurons in trigeminal subnucleus caudalis (medullary dorsal horn) and subnucleus oralis to natural and electrical stimulation of tooth pulp, J. Neurophysiol. 52 (1984) 39–53. [16] J.G. Broton, J.W. Hu, B.J. Sessle, Effects of temporomandibular joint stimulation on nociceptive and nonnociceptive neurons of the cat’s trigeminal subnucleus caudalis (medullary dorsal horn), J. Neurophysiol. 59 (1988) 1575–1589. [17] S. Gobel, Golgi studies in the substantia gelatinosa neurons in the spinal trigeminal nucleus, J. Comp. Neurol. 162 (1975) 397–415. [18] K.D. Phelan, W.M. Falls, An analysis of the cyto- and myeloarchitectonic organization of trigeminal nucleus interpolaris in the rat, Somatosens. Mot. Res. 6 (1989) 333–366. [19] W.M. Falls, B.J. Moore, M.T. Schneider, Fine structural characteristics and synaptic connections of trigeminocerebellar projection neurons in rat trigeminal nucleus oralis, Somatosens. Mot. Res. 7 (1990) 1–18. [20] H. Wang, F. Wei, R. Dubner, K. Ren, Selective distribution and function of primary afferent nociceptive inputs from deep muscle tissue to the brainstem trigeminal transition zone, J. Comp. Neurol. 498 (2006) 390–402. [21] C. Nathan, Q.W. Xie, Nitric oxide synthases: roles, tolls, and controls, Cell 78 (1994) 915–918. [22] D.S. Bredt, S.H. Snyder, Nitric oxide a novel neuronal messenger, Neuron 8 (1992) 3–11. [23] Z. Lohinai, A.D. Szekely, P. Benedek, A. Csillag, Nitric oxide synthase containing nerves in the cat and dog dental pulp and gingiva, Neurosci. Lett. 227 (1997) 91–94.

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