Age-related decrease of cholinergic parasympathetic reflex vasodilation in the rat masseter muscle.

Skeletal muscle hemodynamics, including that in jaw muscles, is an important in their functions and is modulated by aging. Marked blood flow increases mediated by parasympathetic vasodilation may be important for blood flow in the masseter muscle (MBF); however, the relationship between parasympathetic vasodilation and aging is unclear. We examined the effect of aging on parasympathetic vasodilation evoked by trigeminal afferent inputs and their mechanisms by investigating the MBF during stimulation of the lingual nerve (LN) in young and old urethane-anesthetized and vago-sympathectomized rats. Electrical stimulation of the central cut end of the LN elicited intensity- and frequency-dependent increases in MBF in young rats, while these increases were significantly reduced in old rats. Increases in the MBF evoked by LN stimulation in the young rats were greatly reduced by hexamethonium and atropine administration. Increases in MBF in young rats were produced by exogenous acetylcholine in a dose-dependent manner, whereas acetylcholine did not influence the MBF in old rats. Significant levels of muscarinic acetylcholine receptor type 1 (MR1) and type 3 (MR3) mRNA were observed in the masseter muscle in young rats, but not in old rats. Our results indicate that cholinergic parasympathetic reflex vasodilation evoked by trigeminal afferent inputs to the masseter muscle is reduced by aging and that this reduction may be mediated by suppression of the expression of MR1 and MR3 in the masseter muscle with age.

The Epidemiologic and Clinical Findings of Patients with Buerger Disease.

BACKGROUND: Buerger disease is a nonatherosclerotic peripheral arterial disease, which is mostly observed in young male smokers. Buerger disease is characterized by the observation of peripheral arterial occlusion by angiography. The condition may be caused by microembolization in the small-sized arteries of the distal extremities. Buerger disease is diagnosed based on the Shionoya's clinical diagnostic criteria, which include: (1) a history of smoking, (2) onset before the age of 50 years, (3) the presence of infrapopliteal arterial occlusions, (4) either upper limb involvement or phlebitis migrans, and (5) the absence of atherosclerotic risk factors other than smoking. Several studies have reported that oral bacterial infections (periodontitis) could activate the onset of Buerger disease. In this study, we report the epidemiologic and clinical manifestations of patients with Buerger disease. METHODS: Fifty-eight patients who were surgically treated between July 1989 and June 2014 at Tokyo Medical and Dental University Hospital were enrolled in this study. All of the patients clinically diagnosed with Buerger disease based on Shionoya's clinical diagnostic criteria. Fifty-five male and 3 female patients were treated. The mean age of the patients was 48 years (range, 21-73 years). RESULTS: All of the patients were either smokers or had a history of smoking. The mean Brinkman index score was 780 (range, 150-1,640). Their mean age at the onset of Buerger disease was 38 years (range, 21-50). The arterial lesions extended to the femoral arteries in 25% of cases, to the iliac arteries in 8% and to the abdominal aorta and/or visceral arteries in 6% of cases. Upper limb involvement, including cyanosis, paleness, and gangrene, was obvious in 84% of patients, and phlebitis migrans was recognized in 34%. The lower extremities symptoms involved intermittent claudication in 23% of the patients, rest pain in 13% of the patients, and ulceration or gangrene in 64% of the patients. Fifteen patients had undergone surgical arterial reconstruction, 4 patients had received endovascular therapy, 33 patients had undergone lumbar sympathectomy and 8 patients had undergone thoracic sympathectomy. Twenty percent of the patients needed minor limb amputations, and 4% required major limb amputations. In the patients who were examined for their oral conditions, periodontitis corresponding to grades B (moderate periodontitis), C (severe periodontitis), and D (edentulous patients) was revealed in 31%, 56%, and 13% of the patients, respectively. CONCLUSIONS: More than half of the Buerger disease patients in this study were suffering from severe periodontitis. It is possible that not only the cessation of smoking, but also the improvement of periodontal care could improve the clinical symptoms related to Buerger disease.

Renal sympathetic denervation ameliorates the activated inflammatory response through JAK-STAT pathway in a chronic obstructive sleep apnea animal model.

OBJECTIVES: Obstructive sleep apnea (OSA) is known to increase the risk of cardiovascular disease and inflammation plays a significant role in this process. Renal denervation (RDN) is a novel approach aimed at reducing sympathetic nervous system activity. The role of RDN in the inflammatory response to chronic OSA (COSA) is currently unclear. The main objective was to study inflammatory mechanisms in the rabbit heart with COSA and the effects of RDN. METHODS: Eighteen rabbits were randomized into three groups: sham control, COSA, and COSA-RDN. COSA and COSA-RDN groups received liquid silicone injections, while the sham control group received normal saline. We performed combined surgical and chemical RDN through bilateral retroperitoneal flank incisions in the COSA-RDN group after silicone injections. The inflammatory mechanisms were assessed through immunoblotting, real-time PCR, and ELISA after the experiment. RESULTS: H&E staining showed immune cell infiltration in COSA, which decreased after RDN treatment. The level of α7nAChR was significantly reduced in COSA compared to the sham control but was restored to a similar level in the COSA-RDN group. Furthermore, the expressions of p-JAK2 and p-STAT3 were significantly reduced in COSA but showed an up-regulation following RDN treatment. Similarly, levels of the inflammatory markers IL-6, IL-1ß and TNF-α were markedly increased in COSA but decreased after RDN therapy. We observed NF-κB activation in the COSA rabbit model, which decreased after RDN treatment, as evidenced by decreased NF-κB expression. CONCLUSIONS: Our study suggests that RDN treatment may prevent COSA-associated heart inflammation via the JAK2-STAT3 signaling pathway.

Effects of sympathetic innervation loss on mandibular distraction osteogenesis.

Sympathetic nerve system has been proved to have important regulative effects to bone mass. However, the role of sympathetic nerve system in distraction osteogenesis (DO) is unclear. Here we show that the sympathetic nerve system plays an important role in mandibular DO. Thirty male Sprague-Dawley rats were divided into 2 groups at random. Right-side mandibular DO was performed on the 15 rats in control group (group A). Bilateral transection of cervical sympathetic trunk and right-side mandibular DO were performed on the 15 rats in the experimental group (group B). After operation, quantitative general observations, micro-computed tomography bone morphology analysis, and hematoxylin-eosin staining osseous tissue on new osteotylus in distraction gap were performed at consolidation time of 1, 14, and 28 days. SPSS 12.0 software package was used for statistical analysis. At 1 and 14 days of consolidation time, there was more continuous bone formation in the experimental group than that of the control group as determined by gross observation. Bone formation parameters including bone mineral density, bone volume-total volume ratio, bone trabeculae number as determined by micro-CT, and histological study of the test group were significantly higher than those of the control group (P < 0.05). No significant difference was noted between the 2 groups on consolidation time of 28 days. Our study suggested that the sympathetic innervation loss could improve mandibular DO and new bone formation, and the sympathetic nerve system might negatively regulate the process of DO.

The treatment of palmar hyperhidrosis - a systematic review.

BACKGROUND: Primary palmar hyperhidrosis (PH) can have a significantly negative impact on an individual's quality of life. Currently, there appears to be no review of the effectiveness of the different interventions for its management. METHODS: A systematic review was performed using PRISMA guidelines, the Cochrane Database, and MEDLINE (OVID) to identify relevant studies published from 1997 to 2017. RESULTS: Of the 574 references yielded, six met the inclusion criteria and were analyzed for this review. Two studies evaluated the use of oral oxybutynin as an anticholinergic treatment for PH; this demonstrated high efficacy with over 80% of patients reporting symptom improvement; dry mouth was the most common adverse effect reported. One study looking at the use of iontophoresis reported 81% improvement in patients' symptoms. One randomized, double-blind, trial looked at the use of botulinum toxin A injections for the treatment of PH; it reported 90% of patients experienced an improvement in PH. The remaining two studies evaluated the use of endoscopic thoracic sympathectomy (ETS) in PH, and both reported over 95% patient symptom improvement. CONCLUSION: There are few good quality studies evaluating the treatment of primary PH. Based on the little available evidence, the interventions reviewed significantly improve the symptoms of PH. Anticholinergic medications are considered effective and safe. Both iontophoresis and botulinum toxin provided patients with symptom relief when administered regularly. ETS was reported as successful in the reduction of PH, however, it carries significant adverse effects such as compensatory sweating and the potential of complications associated with surgery.

First-bite syndrome in oncologic patients.

First-bite syndrome (FBS) is described as a complication of parapharyngeal space surgery and consists of short-term pain in the parotid or mandibular region at the start of each meal, usually on the first bite and improving with subsequently each bite. The pathogenesis is related to a selective sympathetic denervation of the parotid gland and its treatment involves dietary modifications, medical treatment or even surgery, all with poor results. FBS is often undervalued and misdiagnosed, yet it is a pathology that may interfere with the patient's quality of life. We report two patients who underwent major cervical oncologic surgeries. One patient was subject to extended radical neck dissection into the parapharyngeal space and the other patient ligation of the external carotid artery, which post-operatively developed into FBS unresponsive to the medical treatment instituted. During external adjuvant radiotherapy, both had an unexpected FBS improvement, remaining asymptomatic after 7 and 10 months of follow-up. In this study, we discuss why FBS is misdiagnosed in oncologic patients, the possible pathophysiological mechanisms of radiotherapy and its plausibility as a new modality of treatment in selected cases.

Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis.

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.

A medical alternative to the treatment of compensatory sweating.

Compensatory sweating after sympathectomy does not have a satisfactory, free-of-secondary-effects treatment. Glycopyrrolate has been successfully used to treat other types of hyperhidrosis. Compensatory sweating after sympathectomy could respond to the topical application of glycopyrrolate. Ten patients were selected with compensatory sweating after sympathectomy. One milliliter of a 2% water solution of topical glycopyrrolate was applied once a day over the affected area and massaged for 30 seconds. Treatment was maintained for 6 weeks. The results were rated using a scale from 1 to 10 of satisfaction at the end of the study. Eight of the 10 treated patients dramatically improved with the topical application of glycopyrrolate. Two patients quit the treatment due to secondary effects (accommodative failure and dry mouth). The results of the study demonstrated that local application of glycopyrrolate might be the treatment of choice for compensatory hyperhidrosis.

First-bite syndrome after parapharyngeal surgery for cervical schwannoma.

BACKGROUND: First-bite syndrome (FBS) is a rare complication that occurs after patients undergo parapharyngeal space surgery. Characteristically, inadvertent ablation of the parotid gland's sympathetic innervation results in the development of severe parotid gland-area pain at the first bite of food. CASE DESCRIPTION: The authors evaluated a patient who underwent parapharyngeal surgery for cervical schwannoma. This surgery involved the sympathetic chain's superior cervical ganglion (SCG). With destruction of the SCG, the patient developed FBS and Horner syndrome. CONCLUSION AND CLINICAL IMPLICATIONS: Destruction of the SCG or the sympathetic postganglionic supply to the parotid gland causes severe parotid pain when food is first introduced into the mouth. The absence of discomfort during mechanical joint movements helps dentists differentiate this pain from myofascial pain or pain caused by temporomandibular dysfunction. The frequent presence of Horner syndrome also facilitates diagnosis.

Modulation of incisor eruption in rats by sympathetic efferents.

INTRODUCTION: Intact neural supply is necessary for tooth eruption. Sympathetic denervation accelerates or decelerates the eruption rate depending on the tooth condition (intact or injured). The aim of this study is to reexamine the role of the sympathetic innervation, through the observation of the effects of pre or post ganglionic chemical sympathectomy on the eruption of intact rat incisors. MATERIALS AND METHODS: Different groups of rats were subjected to either ganglionic or peripheral chemical sympathectomy and the observed effects on incisor eruption were compared to those made on intact/sham groups or on rats subjected to inferior alveolar nerve (IAN) lesion. RESULTS: The total amount of eruption in control/naïve rats, measured over a total period of 144 h, was 3 ±â€¯0.15 mm and decreased to 2.57 ±â€¯0.06 mm (n = 8; p < 0.01) or 2.8 ±â€¯0.10 mm (n = 8; p < 0.05) following treatment with guanethidine and hexamethonium, respectively. This amount decreased to 1.8 ±â€¯0.14 mm (p < 0.001 vs. control, n = 7; or p < 0.01 vs. sham, n = 5) in rats subjected to IAN lesion. CONCLUSION: Sympathectomy delayed tooth eruption. Blocking the sympathetic effectors with guanethidine exerted more potent effects than ganglionic block with hexamethonium. Intact sympathetic supply is required for tooth growth under normal conditions.

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages.

Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.

Modulation of dental inflammation by the sympathetic nervous system.

Recent findings have indicated that immune responses are subjected to modulation by the sympathetic nervous system (SNS). Moreover, the findings show that the SNS inhibits the production of pro-inflammatory cytokines, while stimulating the production of anti-inflammatory cytokines. The present review is an attempt to summarize the current results on how the SNS affects inflammation in dental tissues. In dental tissues, it has been found that the SNS is significant for recruitment of inflammatory cells such as CD 43+ granulocytes. Sympathetic nerves appear to have an inhibitory effect on osteoclasts, odontoclasts, and on IL-1alpha production. The SNS stimulates reparative dentin production, since reparative dentin formation was reduced after sympathectomy. Sprouting of sympathetic nerve fibers occurs in chronically inflamed dental pulp, and neural imbalance caused by unilateral sympathectomy recruits immunoglobulin-producing cells to the dental pulp. In conclusion, this article presents evidence in support of interactions between the sympathetic nervous system and dental inflammation.

Immunoglobulin producing cells in the rat dental pulp after unilateral sympathectomy.

Recent studies show that sympathetic nerves participate in immunomodulation. We investigated the effects of unilateral sympathectomy on recruitment of cells expressing kappa and lambda (kappa and lambda) light chains in the rat dental pulp. Superior cervical ganglion was removed in experimental rats (n=10) while control rats (n=8) received sham surgery. Following perfusion 18 days later, mandibular jaws were processed for immunohistochemistry and electron microscopy. Sympathectomy results in recruitment of cells expressing kappa and lambda light chains into the dental pulp (P=0.005). Electron microscopy revealed these cells to be mainly plasma cells and Mott cells. We conclude that neural imbalance caused by unilateral sympathectomy recruits immunoglobulin producing cells in the dental pulp. Our results are in agreement with a model of immune regulation in which the sympathetic nervous system exerts a tonic regulatory effect over lymphocyte proliferation and migration.

Sympathetic decentralization abolishes increased secretion of immunoglobulin A evoked by parasympathetic stimulation of rat submandibular glands.

Salivary secretion of immunoglobulin A (IgA) in response to electrical stimulation of the parasympathetic nerve supply was assessed bilaterally in the submandibular glands of anaesthetized rats 1 week following unilateral pre-ganglionic sympathectomy (decentralization). Nerve-mediated stimulation on the non-denervated side increased IgA secretion several fold above an unstimulated rate of secretion whereas sympathetic decentralization reduced the parasympathetically stimulated secretion of IgA without affecting the basal rate. Glandular levels of IgA were increased following decentralization compared to the control glands. Salivary levels of free secretory component (FSC), the cleaved polymeric immunoglobulin receptor (plgR), were increased by parasympathetic stimulation and reduced by sympathectomy, though not as much as IgA. The decreased secretion of FSC suggests a reduced production of plgR and may account in part, for reduced IgA secretion following long-term removal of sympathetic nerve impulses.

Effects of sympathectomy on experimentally induced pulpal inflammation and periapical lesions in rats.

The role of sympathetic nerves in bone physiology is largely unknown. Recent studies have shown a correlation between sympathectomy and bone remodeling. The present experiments were aimed to study the effects of unilateral sympathectomy on bilateral experimentally induced pulpitis and periapical lesions in the rat maxilla and mandible. Adult male Sprague-Dawley rats were used. Experimental rats (n=11) had the right superior cervical ganglion surgically removed (SCGx) and control rats (n=5) had sham surgery. Pulpal inflammation and periapical bone lesions in the maxilla and mandible were created 14 days later in both experimental and control rats by exposing the dental pulp in the first and second molars and leaving them open to the oral microflora. The rats were perfused 20 days thereafter and the jaws processed for immunohistochemistry with neuropeptide Y (NPY) and ED1 as primary antibodies. Sympathectomy resulted in an almost complete loss of NPY-immunoreactive (IR) fibers in the right SCGx jaws. In the non-sympathectomized (non-SCGx) left side and in the control rats, sprouting of NPY-IR fiber was observed in the inflamed pulp tissue adjacent to reparative dentin formation and in the apical periodontal ligament of the partially necrotic first molars. Significantly more ED1-IR osteoclasts were found in the resorptive lacunae lining the periphery of the periapical lesions on the SCGx side compared with the non-SCGx side (P<0.04) and the controls (P<0.03). The size of the periapical lesions were larger on the SCGx side compared with the non-SCGx side (P<0.03) in the mandible, but not in the maxilla. We conclude that inflammation causes sprouting of NPY-IR nerve fibers and that unilateral removal of the SCG increases both the area of the periapical lesions and the number of osteoclasts in the inflamed region.

Effects of cyclic AMP-affecting agents on contractile reactivity of isolated mesenteric and renal resistance arteries of the rat.

1. Effects of adenosine 3':5'-cyclic monophosphate (cyclic AMP)-affecting agents were compared in mesenteric and renal resistance arteries that had been isolated from 20 week old Wistar-Kyoto rats, chemically sympathectomized, stretched to their optimal diameter for mechanical performance and made to contract in response to 30 mM potassium. 2. In mesenteric resistance arteries, isoprenaline, dopamine, NaF, forskolin, isobutyl-methylxanthine, milrinone and dibutyryl-cyclic AMP induced relaxation. Clonidine induced further increases in tension that could be reduced by pertussis toxin and prazosin but not by yohimbine. Clonidine also reduced relaxant responses to isoprenaline. 3. In renal resistance arteries, isoprenaline and dopamine failed to induce relaxation. Compared to mesenteric resistance arteries, renal vessels were less sensitive to the relaxant effect of NaF, forskolin and isobutyl-methylxanthine. Relaxant responses to dibutyryl-cyclic AMP did not differ between the two resistance arteries. 4. Indirect evidence thus suggests that in mesenteric resistance arteries, adenylate cyclase is susceptible to pharmacological activation and inhibition and is functionally coupled to relaxation. The refractory nature of renal resistance arteries to the relaxant effects of isoprenaline and dopamine could be due primarily to absence of appropriate receptors and to a relatively low activity of adenylate cyclase.

Dissimilar metals in a rib spreader a surgical electrical hazard.

A case is presented and electrochemical theory is discussed in a situation in which a battery was produced between two dissimilar metals in a Finochietto rib spreader. The problem developed in the thorax of a patient undergoing transthoracic cervical sympathectomy and resection of the first rib. Caution is advised in the use of dissimilar metals in patients undergoing surgery.

A review of one hundred forty-seven popliteal aneurysms with long-term follow-up.

A 20-year experience with a collected series of 147 popliteal aneurysm in 87 patients is reviewed; there were 84 male patients. Ages ranged from 42 to 90 years with a median age of 60.2. Bilateral aneurysms were found in 60 patients (68%). Ninety-eight extremities presented with symptoms, whereas 94 aneurysms had one or more preoperative complications. Sixty-six (45%) were thrombosed, 34 (23%) had embolized, and four (3%) had ruptured. Associated aneurysms were found in 55% of the total group and in 68% of those with bilateral popliteal aneurysms. Forty percent of all patients had abdominal aortic aneurysms, whereas 34% had femoral aneurysms and 25% had iliac aneurysms. Therapy included bypass grafting (99), observations (26), primary amputation (12), sympathectomy (3), and exploration only (7). In 32 limbs, grafts became occluded during the follow-up period. All except one of the occluded grafts were in patients with preoperative symptoms related to the aneurysm, and all but one primary form of therapy and 22 as a secondary procedure. All were associated with preoperative vascular ischemia or a complicated aneurysm. Complete, detailed, long-term follow-up of 1 to 14 years is reported for 65 patients. The overall follow-up averaged 44 months. Death rates were shown by life-table analysis to be significantly greater than rates among the general population. Complications of aneurysms were very common (64%) and when the occurred, 36% ended in amputation. Therefore, elective replacement of the aneurysm at the time of diagnosis is recommended.

Progression of popliteal aneurysmal disease following popliteal aneurysm resection with graft: a twenty year experience.

Multifocal occurrence of peripheral atherosclerotic aneurysm is well known. However, little attention has been directed to subsequent progressive aneurysmal development adjacent to sites of previously resected and grafted popliteal aneurysms. During a 20 year follow-up study of 79 patients with 115 popliteal aneurysms, we have observed the development of six atherosclerotic femoropopliteal aneurysms adjacent to the original aneurysm site in four patients, occurring 5 months to 10 years (average, 5 1/2 years) after the initial operation. Operative repaire was accomplished successfully of five of the six aneurysms; one popliteal aneurysm has not been operlateral popliteal aneurysm (46 percent). Fifty-seven patients (72 percent) presented with complications of the aneurysm, including 35 with thrombosis. As initial therapy, 69 grafting procedures were performed on 58 patients; nine extremities had sympathectomy only; four aneurysms were ligated or resected without grafting; and four extremities required amputation as the only procedure. Among patients with grafts, nine subsequent amputations were necessary in the early postoperative period, all occurring in patients presenting with thrombosed aneurysms. No patient who developed pedal pulses in the period immediately after operation required amputation. In addition, two patients developed aneurysmal degeneration in popliteal homografts. These data demonstrate the progressive nature of popliteal aneurysmal disease and emphasize the need for regular and life-long follow-up.

Neuropeptide Y-like immunoreactive primary afferents in the periodontal tissues following dental injury in the rat.

The distribution of neuropeptide Y (NPY)-like immunoreactive (-IR) nerve fibers in the periodontal tissues following dental injury to the rat maxillary first molar was examined with a combination of dental injury and surgical sympathectomy of the superior cervical ganglion (SCGx). In normal animals, NPY-IR nerve fibers were observed around the blood vessels of the trigeminal ganglion, dental pulp and periodontal tissues. These nerve fibers completely disappeared following SCGx. Fourteen days following dental injury of the maxillary first molar combined with SCGx, a small number NPY-IR cells was observed in the dorsal to middle portion of the maxillary division of the trigeminal ganglion. These were mostly medium- to large-sized cells with a mean +/- SD cross-sectional area of 541.4 +/- 239.3 microns 2. Approx. 50% of these cells had the cross-sectional areas between 400-600 micron 2. In the periodontal tissues of injured first molar, thick NPY-IR nerve fibers showing an irregular appearance were detected in the apical region. Immunoelectron microscopy showed that most NPY-IR nerve fibers near the lower half of the injured periodontal ligament had an axonal diameter of approx. 7-8 microns, and lacked apparent myelin sheaths. Near NPY-IR nerve fibers, many macrophages with phagosomes containing debris of the myelin sheaths were observed. At the oral epithelium covering the injured roots of the maxillary first molar, thick NPY-IR nerve fibers were recognizable and some penetrated the epithelium. No NPY-IR nerve fibers were observed in the dental pulp or periodontal tissues in second and third molars, and ultrastructural views of nerve fibers were almost intact following combined SCGx and dental injury to the first molar. The present results indicate that NPY-IR primary afferents appeared in the periodontal tissues following dental injury, and that NPY may be closely associated with the regeneration process of injured primary afferents.