The Biocompatibility Analysis of Artificial Mucin-Like Glycopolymers.

The ocular surface is covered by a tear film consisting of an aqueous/mucin phase and a superficial lipid layer. Mucins, highly O-glycosylated proteins, are responsible for lubrication and ocular surface protection. Due to contact lens wear or eye disorders, lubrication of the ocular surface can be affected. Artificial glycopolymers which mimic natural mucins could be efficient in ophthalmic therapy. Various neutral, positively, and negatively charged mucin-mimicking glycopolymers were synthesized (n = 11), cultured in different concentrations (1%, 0.1%, and 0.01% w/v) with human corneal epithelial cells (HCE), and analyzed by various cytotoxicity/viability, morphology, and immunohistochemistry (IHC) assays. Six of the eleven glycopolymers were selected for further analysis after cytotoxicity/viability assays. We showed that the six selected glycopolymers had no cytotoxic effect on HCE cells in the 0.01% w/v concentration. They did not negatively affect cell viability and displayed both morphology and characteristic markers as untreated control cells. These polymers could be used in the future as mucin-mimicking semi-synthetic materials for lubrication and protection of the ocular surface.

[Pilot study of the relationship between clinical classification of gallbladder cancer and prognosis: a retrospective multicenter clinical study].

Objectives: To propose a novel clinical classification system of gallbladder cancer, and to investigate the differences of clinicopathological characteristics and prognosis based on patients who underwent radical resection with different types of gallbladder cancer. Methods: The clinical data of 1 059 patients with gallbladder cancer underwent radical resection in 12 institutions in China from January 2013 to December 2017 were retrospectively collected and analyzed.There were 389 males and 670 females, aged (62.0±10.5)years(range:22-88 years).According to the location of tumor and the mode of invasion,the tumors were divided into peritoneal type, hepatic type, hepatic hilum type and mixed type, the surgical procedures were divided into regional radical resection and extended radical resection.The correlation between different types and T stage, N stage, vascular invasion, neural invasion, median survival time and surgical procedures were analyzed.Rates were compared by χ(2) test, survival analysis was carried by Kaplan-Meier and Log-rank test. Results: Regional radical resection was performed in 940 cases,including 81 cases in T1 stage,859 cases in T2-T4 stage,119 cases underwent extended radical resection;R0 resection was achieved in 990 cases(93.5%).The overall median survival time was 28 months.There were 81 patients in Tis-T1 stage and 978 patients in T2-T4 stage.The classification of gallbladder cancer in patients with T2-T4 stage: 345 cases(35.3%)of peritoneal type, 331 cases(33.8%) of hepatic type, 122 cases(12.5%) of hepatic hilum type and 180 cases(18.4%) of mixed type.T stage(χ(2)=288.60,P<0.01),N stage(χ(2)=68.10, P<0.01), vascular invasion(χ(2)=128.70, P<0.01)and neural invasion(χ(2)=54.30, P<0.01)were significantly correlated with the classification.The median survival time of peritoneal type,hepatic type,hepatic hilum type and mixed type was 48 months,21 months,16 months and 11 months,respectively(χ(2)=80.60,P<0.01).There was no significant difference in median survival time between regional radical resection and extended radical resection in the peritoneal type,hepatic type,hepatic hilum type and mixed type(all P>0.05). Conclusion: With application of new clinical classification, different types of gallbladder cancer are proved to be correlated with TNM stage, malignant biological behavior and prognosis, which will facilitate us in preoperative evaluation,surgical planning and prognosis evaluation.

Transcriptome network analysis reveals potential candidate genes for ankylosing spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic, inflammatory arthritis and autoimmune disease. BACKGROUND: The main symptom of AS is inflammatory spinal pain; with time, some patients develop ankylosis and spinal immobility. We aim to find cure available for ankylosing spondylitis. MATERIALS AND METHODS: We used the GSE11886 series to identify potential genes that related to AS to construct a regulation network. RESULTS: In the network, some of TFs and target genes have been proved related with AS in previous study, such as NFKB1, STAT1, STAT4, TNFSF10, IL2RA, and IL2RB. We also found some new TFs (Franscription Factors) and target genes response to AS, such as BXDC5, and EGFR. Further analysis indicated some significant pathways are associated with AS, including antigen processing and presentation and cytokine-cytokine receptor interaction, etc.; although not significant, there was evident that they play an important role in AS progression, such as apoptosis and systemic lupus erythematosus. CONCLUSIONS: Therefore, it is demonstrated that transcriptome network analysis is useful in identification of the candidate genes in AS.

The role of 5-HT receptor subtypes in the ventrolateral orbital cortex of 5-HT-induced antinociception in the rat.

The present study examined the involvement of 5-HT in the ventrolateral orbital cortex (VLO) on descending antinociception and determined which subtypes of 5-HT receptors mediated this effect. This study focused on the effects of 5-HT microinjection in the VLO of lightly anesthetized male rats on the radiant heat-evoked tail flick (TF) reflex, as well as the influence of 5-HT(1A), 5-HT(2), 5-HT(3), and 5-HT(4) receptor subtype antagonists on the effect of 5-HT. Results showed that 5-HT microinjection (2, 5, 10 microg, in 0.5 microl) into the VLO depressed the TF reflex in a dose-dependent manner. Pretreatment with 5-HT receptor antagonists (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190), cyproheptadine hydrochloride (CPT) and 1-methyl-N-(8-methyl-8-azabicyclo[3.2.3]-oct-3-yl)-1H-indazole-3-carboxamide maleate salt (LY-278,584)), specific for 5-HT(1A), 5-HT(2) and 5-HT(3) receptors, respectively, partially reversed the 5-HT-evoked inhibition. In contrast, the 5-HT(4) receptor antagonist, 1-[2-[(methylsulfonyl)-amino]ethyl]-4-piperidinyl]methyl1-methyl-1H-indole-3-carboxylate (GR 113808), had no effect on the inhibition of 5-HT. Microinjections of NAN-190, CPT and LY-278,584 alone into the VLO had no effect on the TF reflex. These results suggest that 5-HT(1A), 5-HT(2) and 5-HT(3), but not 5-HT(4) receptors, are involved in mediating 5-HT-induced antinociception in the VLO. According to different properties and distribution patterns of the 5-HT receptor subtypes on neurons, the possible mechanism of 5-HT activation of the VLO-periaqueductal gray (PAG) descending antinociceptive pathway is discussed.

Chronic fatigue stress leads to up-regulation of nitric oxide synthase in the rat nucleus accumbens.

In the present study, the effect of chronic fatigue stress on the neuronal nitric oxide synthase (nNOS) in the rat nucleus accumbens (NAc) was assessed in order to explore the neurobiology mechanism of central fatigue stress, especially the role of the NAc in central fatigue. In the experiment, adult male Wistar rats were forced to swim till exhaustion every day for 4 weeks. Immunohistochemistry was used for measurement of the nNOS-positive neurons associated with the image manipulation. Our results showed that a long-time exposure to chronic forced swim stress increased the number of nNOS immunoreactive-positive neurons in the rat NAc (106.7%, P<0.001), distributed area (150.2%, P<0.001) and gray degree value (11.3%, P<0.01). The results indicate that nitric oxide (NO)/nNOS may be involved in the formation of the fatigue stress, and that NO may play a role in the regulation of stress in the NAc. The up-regulation of NO/nNOS during the exposure to long-time swim stress is likely to be one of the results of brain damage and psychiatric disorder induced by NO overproduction.

Roles of different subtypes of opioid receptors in mediating the ventrolateral orbital cortex opioid-induced inhibition of mirror-neuropathic pain in the rat.

Previous studies have demonstrated that opioid receptors in the prefrontal ventrolateral orbital cortex (VLO) are involved in anti-nociception. The aim of this current study was to examine whether opioid receptors in the VLO have effects on the hypersensitivity induced by contralateral L5 and L6 spinal nerve ligation (SNL), termed as mirror neuropathic pain (MNP) in the male rat. Morphine (1.0, 2.5, 5.0 microg) microinjected into the VLO contralateral to the SNL depressed the mechanical paw withdrawal assessed by von Frey filaments and the cold plate (4 degrees C)-induced paw lifting in a dose-dependent manner on the side without SNL. These effects were antagonized by microinjection of the non-selective opioid receptor antagonist naloxone (1.0 mug) into the same VLO site. Microinjection of endomorphin-1 (5.0 microg), a highly selective mu-opioid receptor agonist, and [d-Ala(2), d-Leu(5)]-enkephalin (DADLE, 10 microg), a delta-/mu-receptor agonist, also depressed the MNP. The effects of both drugs were blocked by selective mu-receptor antagonist beta-funaltrexamine (beta-FNA, 3.75 microg), but the effect of the DADLE was not influenced by the selective delta-receptor antagonist naltrindole (5.0 microg). Microinjection of the kappa-opioid receptor agonist spiradoline mesylate salt (U-62066) (100 microg) had no effect on the MNP. These results suggest that the VLO is involved in opioid-induced inhibition of the MNP and the effect is mediated by mu- (but not delta- and kappa-) opioid receptors.

The roles of different subtypes of opioid receptors in mediating the nucleus submedius opioid-evoked antiallodynia in a neuropathic pain model of rats.

Previous studies have indicated that thalamic nucleus submedius is involved in opioid-mediated antinociception in tail flick test and formalin test. The current study examined the effects of opioids microinjected into the thalamic nucleus submedius on the allodynia developed in neuropathic pain model rats, and determined the roles of different subtypes of opioid receptors in the thalamic nucleus submedius opioid-evoked antiallodynia. The allodynic behaviors induced by L5/L6 spinal nerve ligation were assessed by mechanical (von Frey filaments) and cold (4 degrees C plate) stimuli. Morphine (1.0, 2.5, and 5.0 microg) microinjected into the thalamic nucleus submedius contralateral to the nerve injury paw produced a dose-dependent inhibition of the mechanical and cold allodynia, and these effects were reversed by microinjection of the non-selective opioid receptor antagonist naloxone (1.0 microg) into the same site. Microinjection of endomorphin-1 (5.0 microg), a highly selective mu-opioid receptor agonist, and [D-Ala2, D-Leu5]-enkephalin (10 microg), a delta-/mu-opioid receptor agonist, also inhibited the allodynic behaviors, and these effects were blocked by selective mu-opioid receptor antagonist beta-funaltrexamine hydrochloride (3.75 microg). However, the [D-Ala2, D-Leu5]-enkephalin-evoked antiallodynic effects were not influenced by the selective delta-opioid receptor antagonist naltrindole (5.0 microg). Microinjection of the selective kappa-receptor agonist spiradoline mesylate salt (100 microg) into the thalamic nucleus submedius failed to alter the allodynia induced by spinal nerve ligation. These results suggest that the thalamic nucleus submedius is involved in opioid-evoked antiallodynia which is mediated by mu- but not delta- and kappa-opioid receptor in the neuropathic pain model rats.

Thalamic nucleus submedius receives GABAergic projection from thalamic reticular nucleus in the rat.

GABAergic projection from thalamic reticular nucleus to thalamic nucleus submedius in the medial thalamus of the rat was studied by using immunohistochemistry for GABA, retrograde labeling with Fluoro-Gold combined with immunohistochemistry for GABA, and anterograde labeling with biotinylated dextranamine. Immunohistochemistry displayed that only GABA immunoreactive terminals were observed in the thalamic nucleus submedius, while GABA immunoreactive neuronal cell bodies were located in the thalamic reticular nucleus and lateral geniculate nucleus. Injection of Fluoro-Gold into the thalamic nucleus submedius resulted in massive retrogradely labeled neuronal cell bodies in the rostroventral portion of the ipsilateral thalamic reticular nucleus and a few in the contralateral thalamic reticular nucleus, and most of these cell bodies showed GABA immunopositive staining. Many biotinylated dextranamine anterogradely labeled fibers and terminals in the thalamic nucleus submedius were observed after injection of biotinylated dextranamine into the thalamic reticular nucleus. The present results provide a morphological evidence for a hypothesis that a disinhibitory effect on output neurons elicited by opioid or 5-hydroxytryptamine inhibiting a GABAergic terminal in the thalamic nucleus submedius may lead to activation of the descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.

Responses of neurons in the rat thalamic nucleus submedius to cutaneous, muscle and visceral nociceptive stimuli.

The findings of recent studies have suggested that nucleus submedius (Sm) may be an important thalamic relay for nociceptive information. The aim of the present electrophysiological study was to examine in greater detail the activity and response properties of neurons in the rat Sm in order to further evaluate this hypothesis. Single unit extracellular recordings from neurons histologically verified to be in Sm were obtained in urethane/chloralose-anesthetized rats. Noxious but not innocuous mechanical stimulation elicited responses in 75% of the 204 neurons studied. Most (85%) of these neurons were excited, 10% were inhibited and a few neurons (5%) were excited by stimulation at some sites on the body and inhibited from other sites. The receptive fields were usually very large and bilateral. No marked differences were observed in the incidence, response type, or spontaneous activity of neurons located in dorsal, ventral, rostral or caudal parts of Sm. Most of these neurons (99 of 108, 92%) also responded to noxious heating and had a mean threshold of 47 degrees C. The majority of the neurons (19 of 21, 90%) also responded to subcutaneous, intramuscular or intraperitoneal injections of noxious chemicals (formalin or hypertonic saline). The responses elicited by pinching skin or squeezing muscle were frequently facilitated by the subcutaneous or intramuscular injections of formalin. Single electrical stimuli delivered to the cutaneous receptive field rarely produced responses. However, short trains (15-25 msec trains of 200 Hz, 3 msec pulses at 5-10 mA) delivered repetitively elicited responses in 90% (n = 73) of the neurons. These responses appearing after repetitive stimulation frequently resembled the 'wind-up' pattern observed in spinal cord dorsal horn. The conduction velocities of the primary afferents which elicited the Sm neuronal responses as estimated from the latency differences of responses elicited by stimulation at two points along the tail, were indicative of recruitment of A delta and C fibers. These findings provide further support for the proposed role of Sm in thalamic nociceptive mechanisms.

Inhibitory effects of electrically evoked activation of ventrolateral orbital cortex on the tail-flick reflex are mediated by periaqueductal gray in rats.

The present study found in lightly anesthetized rats that the radiant heat-evoked tail flick (TF) reflex was markedly inhibited by a unilateral electrical stimulation (a 20 ms train of 0.2 ms, 100 Hz, 30-100 microA pulses) of the ventrolateral orbital cortex (VLO), with the tail flick latency (TFL) being increased. The mean threshold of VLO stimulation for producing inhibition of the TF reflex was 39.2 +/- 8.7 microA (n = 26), and this inhibitory effect increased following increasing stimulation intensity from 40 to 70 microA. The inhibition developed and remained during the stimulation and disappeared rapidly after termination of the stimulation. When the VLO was stimulated at an intensity of 100 microA in addition to the inhibition an after-facilitation of the TF reflex (a decrease in TFL) was observed at 5-10 s after termination of the stimulation. Bilateral electrolytic lesions of the lateral or ventrolateral parts of the periaqueductal gray matter (PAG) dramatically reduced or eliminated the VLO-evoked inhibition, and the after-facilitation as well. The difference was significant between the TFL changes produced by VLO stimulation before and after PAG lesion (P < 0.01). The results suggest that the antinociception elicited by VLO stimulation is mediated by PAG, leading to activation of the brainstem descending inhibitory system which depresses the nociceptive transmission at the spinal level. The role played by VLO in pain modulation was discussed in association with the proposed endogenous analgesic system consisting of spinal cord-Sm-VLO-PAG-spinal cord.

Electrically-evoked inhibitory effects of the nucleus submedius on the jaw-opening reflex are mediated by ventrolateral orbital cortex and periaqueductal gray matter in the rat.

In previous studies we have shown that electrical stimulation of the nucleus submedius inhibits the rat radiant heat-induced tail flick reflex, and that this antinociceptive effect is mediated by the ventrolateral orbital cortex and periaqueductal gray. The aim of the present study was to examine whether electrical stimulation of the nucleus submedius could inhibit the rat jaw-opening reflex, and to determine whether electrolytic lesions of the ventrolateral orbital cortex or the periaqueductal gray could attenuate the nucleus submedius-evoked inhibition. Experiments were performed on pentobarbital-anesthetized rats. The jaw-opening reflex elicited by electrical stimulation of the tooth pulp or the facial skin was monitored by recording the evoked digastric electromyogram. Conditioning stimulation was delivered unilaterally to the nucleus submedius 90 ms prior to each test stimulus to the tooth pulp. After that, electrolytic lesions were made in ventrolateral orbital cortex or periaqueductal gray, and the effect of nucleus submedius stimulation on the jaw-opening reflex was re-examined. Unilateral electrical stimulation of nucleus submedius was found to significantly depress the jaw-opening reflex (mean threshold of 28.0+/-1.4 microA, n = 48), and the magnitude of inhibition increased linearly when the stimulus intensity was increased from 20 to 70 microA, resulting in depression of the digastric electromyogram amplitude from 18.4+/-5.4% to 74.0+/-4.9% of the control (P < 0.01, n = 37). The onset of inhibition occured 60 ms after the beginning of nucleus submedius stimulation and lasted about 100 ms, as determined by varying the conditioning-test time interval. Furthermore, ipsilateral lesions of the ventrolateral orbital cortex or bilateral lesions of the lateral or ventrolateral parts of periaqueductal gray eliminated the nucleus submedius-evoked inhibition of the jaw-opening reflex. These data suggest that the nucleus submedius plays an important role in modulation of orofacial nociception, and provide further support for a hypothesis that the antinociceptive effect of nucleus submedius stimulation is mediated by ventrolateral orbital cortex and activation of a descending inhibitory system in the periaqueductal gray.

Mu but not delta and kappa opioid receptor involvement in ventrolateral orbital cortex opioid-evoked antinociception in formalin test rats.

The present study was designed to investigate the roles of different subtypes of opioid receptors in ventrolateral orbital cortex (VLO) opioid-evoked antinociception in formalin test by using an automatic detection system for recording the nociceptive behavior (agitation) and a manual method for detecting the duration of licking the injected paw in the conscious rat. Formalin (5%, 50 microl) s.c. injected into the hindpaw produced a biphasic agitation response or lengthening duration of licking. Morphine (5 microg) microinjected unilaterally into VLO significantly inhibited the agitation response and the licking time, and these effects were blocked by pre-administration of the non-selective opioid receptor antagonist naloxone (1.0 microg) into the same site. Microinjection of endomorphin-1 (5 microg), a selective micro-receptor agonist, and [D-Ala2, D-Leu5]-enkephalin (DADLE, 10 microg), a delta-/micro-receptor agonist also inhibited the nociceptive behaviors, and both the effects were blocked by selective mu-receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA; 3.75 microg), but the DADLE-evoked inhibition was not influenced by the selective delta-receptor antagonist naltrindole (5 microg). Microinjection of selective kappa-receptor agonist (+/-)-trans-U-50488 methanesulfonate salt (1.5 microg) failed to alter the nociceptive behaviors induced by formalin injection. The beta-FNA and naloxone applied into VLO and morphine into the adjacent regions ventral and dorsal to VLO had no effect on the formalin-evoked nociceptive behaviors. These results suggest that mu- but not delta- or kappa-opioid receptor is involved in the VLO opioid-evoked antinociception in formalin test rat.

Liver resection for hepatocellular carcinoma in octogenarians.

BACKGROUND: Liver resection is risky in patients aged > or = 80 years. Because of short life expectancies and improved nonoperative modalities, the role of liver resection in octogenarians with hepatocellular carcinoma (HCC) is unclear. METHODS: A retrospective review of the operative results of 260 patients with HCC between 1991 and 1997 was performed. According to the age at the time of operation, these patients were divided into 2 groups. Group 1 comprised 21 patients aged > or = 80 years, and group 2 comprised the other 239 younger patients. The backgrounds, pathologic features of the tumor, and operative results of the patients were compared. RESULTS: Octogenarians had a higher incidence of associated medical diseases, a higher incidence of negative serum hepatitis B surface antigen, a lower alpha-fetoprotein level, and a higher indocyanine green retention rate. Although octogenarians had a longer postoperative hospital stay, there were no significant differences between the 2 groups regarding operative morbidity and mortality. The 5-year disease-free and actuarial survival rates for octogenarians and younger patients were 50.6% and 35.3% (P = .15) and 40.9% and 59.3% (P = .46), respectively. CONCLUSION: Under meticulous preoperative assessments and postoperative care, liver resection for HCC is justified in selected octogenarians, with short- and long-term results comparable to those of younger patients.

Effects of thalamic nucleus submedius lesions on the tail flick reflex inhibition evoked by hindlimb electrical stimulation in the rat.

Bilateral electrolytic lesions of the thalamic nucleus submedius (Sm) facilitated the TF reflex and attenuated the antinociception evoked by hindlimb electrical stimulation with high intensities in lightly anaesthetized rats. However, the antinociception produced by low intensity hindlimb stimulation was unchanged, except that the after-effect was reduced. The results show that the Sm is probably involved in pain modulation and plays an important role in mediation of the antinociception elicited by high intensity peripheral stimulation.

Prediction and limitation of hepatic tumor resection without blood transfusion in cirrhotic patients.

BACKGROUND: The need for blood transfusion in cirrhotic liver resection is difficult to determine because of inaccurate estimation of operative blood loss. Moreover, blood transfusion is detrimental to cirrhotic patients. OBJECTIVE: To investigate the predictors and limitations of hepatectomy without blood transfusion for cirrhotic patients. DESIGN: Retrospective study. SETTING: University hospital, a tertiary referral center. PATIENTS: A consecutive 163 cirrhotic patients underwent resection for liver tumor(s) under a policy of restrictive blood transfusion. INTERVENTIONS: Estimated blood losses and clinicopathological features of patients who received and those who did not receive a blood transfusion were compared. MAIN OUTCOME MEASURES: Estimated operative blood losses, preoperative assessments, and operative procedures. RESULTS: There were 48 patients in the group who received a blood transfusion, with 1275 +/- 650 mL (mean +/- SE) of blood transfused, and 115 patients in the group who did not receive a blood transfusion. From discriminant analysis, the cutoff value of estimated blood loss for blood transfusion was 1685 mL. Tumor size and site of hepatectomy were found to be independent variables influencing blood transfusion under logistic regression analysis. CONCLUSIONS: Most cirrhotic patients tolerate hepatectomy without blood transfusion when the estimated operative blood loss is less than 1600 mL. Hepatectomy can be performed in cirrhotic patients without blood transfusion if the tumor is small (<5 cm), and/or the resection area is confined to Couinaud segments II, III, and VI. In this study, the largest amount of estimated blood loss in cirrhotic liver resection without blood transfusion was 2350 mL, but the uppermost limit remains to be determined.

Inhibitory effects of electrical stimulation of thalamic nucleus submedius on the nociceptive responses of spinal dorsal horn neurons in the rat.

The aim of the present study is to examine whether stimulation of the thalamic nucleus submedius (Sm) exerts an inhibitory influence on the long latency responses (C-responses) of the spinal cord dorsal horn neurons evoked by noxious cutaneous electrical stimulation, in an attempt to provide electrophysiological evidence for involvement of the Sm in modulation of nociception. Single unit extracellular recordings from the dorsal horn neurons were obtained with glass micropipettes in pentobarbital-anesthetized rats. A total of 71 nociceptive neurons, including 61 wide dynamic range (WDR) and 10 nociceptive specific (NS) neurons, were studied in 29 rats. Electrical stimulation of either ipsilateral or contralateral Sm markedly suppressed the C-responses in most (75%, 53/71) of these neurons, and facilitated the responses in only a few neurons. In general, the inhibitory effect was dependent on both the stimulus intensity and the length of stimulus train, and the stimulus threshold for the inhibition to be elicited was about 50 microA when a 300-ms train of 0.2-ms pulses at 200 Hz was used. The inhibitory effect outlasted the Sm stimulation about 500 ms. Inhibition of C-responses could also be produced by stimulation of the dorsal hypothalamic area (DA). On the other hand, stimulation of the structures in the medial thalamus surrounding Sm had no obvious influences on the C-responses of the dorsal horn neurons. The findings of this study provided further support for the hypothesis that Sm may be implicated in the descending modulation of nociception.

Inhibitory effects of electrical stimulation of ventrolateral orbital cortex on the rat jaw-opening reflex.

In previous studies, we have shown that electrically or chemically evoked activation of the ventrolateral orbital cortex (VLO) depresses the rat tail-flick (TF) reflex, and this antinociceptive effect is mediated by the periaqueductal gray (PAG). The aim of the present study was to examine whether electrical stimulation of the VLO could inhibit the rat jaw-opening reflex (JOR), and to determine whether electrolytic lesions of the PAG could attenuate this VLO-evoked inhibition. Unilateral electrical stimulation of the VLO significantly depressed the JOR elicited by tooth pulp or facial skin stimuli, with a mean threshold of 30.5+/-2.3 microA (n=22). Increasing stimulation intensities from 30 to 80 microA resulted in greater reduction of the dEMG amplitude from 22.9+/-5.0% to 69.7+/-3.7% of the baseline value (P<0.01, n=22). The inhibitory effect appeared 50 ms after the beginning of VLO stimulation and lasted about 150 ms, as determined by varying the conditioning-test (C-T) time interval. Unilateral lateral or ventrolateral lesions of the PAG produced only a small attenuation of the VLO-evoked inhibition of the JOR, but bilateral lesions eliminated this inhibition. These findings suggest that the VLO plays an important role in modulation of orofacial nociceptive inputs, and provide further support for the hypothesis that the antinociceptive effect of VLO is mediated by PAG leading to activation of a brainstem descending inhibitory system and depression of nociceptive inputs at the trigeminal level. The role played by VLO in pain modulation is discussed in association with the proposed endogenous analgesic system consisting of medullary cord-Sm-VLO-PAG-medullary cord.

Electrophysiological identification of spinally projecting neurons in the lateral reticular nucleus of the rat.

Eighty-four neurons in the caudal ventrolateral medullary reticular formation were antidromically activated by the stimulation of the dorsolateral funiculus in 49 urethane-anesthetized rats. Of 76 neurons, 37 had no spontaneous discharge. Of the neurons that had spontaneous discharges, 80% had firing rates between 0.1 and 15 Hz. The average conduction velocity, determined among 70 neurons, was 15.20 +/- 1.23 m/s, and 87% had conduction velocities within the range of 2-30 m/s. This study further confirms the existence of spinally-projecting neurons in the lateral reticular nucleus (LRN) of the caudal medulla, and some of them are probably responsible for the descending controls of nociception from the LRN.

Inhibitory effects of electrical stimulation of thalamic nucleus submedius area on the rat tail flick reflex.

This study in lightly anesthetized rats found that unilateral electrical stimulation delivered to the ventral part of the thalamic nucleus submedius (Sm), the thalamic reuniens nucleus (Re) and the hypothalamic dorsal area (DA) markedly depressed the TF reflex, and this inhibitory effect increased following increasing stimulation intensity. Stimulation in the dorsal part of Sm did not produce any or only slight depression of the TF reflex. Furthermore, an ipsilateral electrolytic lesion of the ventrolateral orbital cortex (VLO) eliminated the unilateral Sm-evoked inhibition, but not the inhibition elicited by Re and DA and contralateral Sm stimulation. Finally, after bilateral electrolytic lesions of the ventrolateral periaqueductal gray (PAG) the DA and Re and contralateral Sm-evoked inhibitions were also eliminated. The results suggest that the Sm plays an important role in modulation of nociceptive inputs, and this role of Sm is mediated by the VLO and leads to activation of the PAG descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.

Involvement of the frontal ventrolateral orbital cortex in descending inhibition of nociception mediated by the periaqueductal gray in rats.

Our previous findings which indicated that electrical stimulation of ventrolateral orbital cortex (VLO) can depress the rat tail flick (TF) reflex and that the VLO-evoked inhibitory effect is blocked by electrolytic lesions of periaqueductal gray (PAG) suggest a role of the VLO in the modulation of nociception. To further investigate the involvement of VLO in this nociceptive modulatory pathway, we tested the effects of microinjections of glutamate (200 mM, 0.7 microliter) into the VLO on the TF reflex. An unilateral microinjection of glutamate into the VLO significantly depressed the TF reflex; and this effect was repeatable. Furthermore, bilateral microinjections of gamma-aminobutyric acid (GABA: 100 mM, 0.5 microliter on each side) into the ventrolateral parts of PAG could eliminate this VLO-evoked inhibition of the TF reflex. These results, along with our previous findings provide further support for a hypothesis that VLO, as a higher center in the frontal cortex, plays an important role in modulation of nociception, and this role is mediated by PAG leading to activation of the brainstem descending inhibitory system which depresses the nociceptive information at the spinal level.