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Summary 1. The fibre type distributions, cross-sectional areas (CSA) and succinate dehydrogenase (SDH) activities in the deep (EDLd) and superficial (EDLs) regions of the extensor digitorum longus (EDL) muscle in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were determined after exposure to cigarette smoke at three different dose levels using a smoking machine. 2. Rats were exposed to cigarette smoke at a rate of 15 puffs/min for 20 min/day with 23 cigarettes (low-dose level), 26 cigarettes (medium-dose level) or 30 cigarettes (high-dose level) for 8 weeks. 3. No changes in fibre type distribution, CSA or SDH activity were observed after exposure to cigarette smoke at the low- and medium-dose levels, irrespective of the muscle region or strain. 4. No change in fibre type distribution was observed after exposure to cigarette smoke at the high-dose level, irrespective of the muscle region or strain. A decreased CSA of type IIA and type IIB fibres in EDLd and increased SDH activity of all types of fibres in EDLd and EDLs were observed in WKY rats after exposure to cigarette smoke at the high-dose level. In addition, a decreased CSA of type IIB fibres in EDLd and type IIA and type IIB fibres in EDLs and increased SDH activity of type IIB fibres in EDLd were observed in SHR after exposure to cigarette smoke at the high-dose level. 5. The smaller CSA and higher SDH activity of fibres in EDL observed in WKY rats and SHR after exposure to cigarette smoke at the high-dose level, but not at the low- and medium-dose levels, are adaptive responses, indicating that heavy cigarette smoke affects the morphological and metabolic properties of fibres in skeletal muscle. [ABSTRACT FROM AUTHOR]

Abstract: The activation of cholinergic pathways by nicotine elicits various physiological and pharmacological effects in mammals. For example, the stimulation of nicotinic acetylcholine receptors (nAChRs) leads to an antinociceptive effect. However, it remains to be elucidated which subtypes of nAChR are involved in the antinociceptive effect of nicotine on nerve injury-induced allodynia and the underlying cascades of the nAChR-mediated antiallodynic effect. In this study, we attempted to characterize the actions of nicotine at the spinal level against mechanical allodynia in an animal model of neuropathic pain, tibial nerve transection (TNT) in rats. It was found that the intrathecal injection of nicotine, RJR-2403, a selective α4β2 nAChR agonist, and choline, a selective α7 nAChR agonist, produced an antinociceptive effect on the TNT-induced allodynia. The actions of nicotine were almost completely suppressed by pretreatment with mecamylamine, a non-selective nicotinic antagonist, or dihydro-β-erythroidine, a selective α4β2 nAChR antagonist, and partially reversed by pretreatment with methyllycaconitine, a selective α7 nAChR antagonist. Furthermore, pretreatment with strychnine, a glycine receptor antagonist, blocked the antinociception induced by nicotine, RJR-2403, and choline. On the other hand, the GABAA antagonist bicuculline did not reverse the antiallodynic effect of nicotine. Together, these results indicate that the α4β2 and α7 nAChR system, by enhancing the activities of glycinergic neurons at the spinal level, exerts a suppressive effect on the nociceptive transduction in neuropathic pain. [Copyright &y& Elsevier]

Recent evidence suggested that cyclooxygenase-2 (COX-2) expression in the peripheral nerve early after nerve injury might be involved in the development of neuropathic pain. Although previous investigators have demonstrated that COX-2 is expressed in peripheral nerve at a late phase (2–4 weeks) after nerve injury, COX-2 up-regulation at an early phase after nerve injury has not been determined. Using immunohistochemistry, we observed biphasic increases of COX-2 expression after L5 single spinal nerve injury. The first increment of COX-2 positive cells was noted 1 day after nerve injury and these cells co-expressed the Schwann cell marker S-100. A second increment was noted after 7–14 days and these cells co-expressed the macrophage marker ED-1. These results suggested that the cellular sources of COX-2 expression might be different between the early and late phases after nerve injury. [Copyright &y& Elsevier]

The behavioral and neurochemical effects of high doses of amphetamine administered to BALB/c mice were examined in the presence and absence of co-administered haloperidol (a D2 antagonist), SCH 23390 (a D1 antagonist) and risperidone (a mixed 5-HT2/D2 antagonist). It was observed that mice displayed a dose-dependent increase in stereotypic behavior, oral dyskinesia, and self-injurious behavior (SIB) in response to amphetamine treatment. Furthermore, agents that blocked the SIB reversed the amphetamine-induced release of serotonin. This effect was unrelated to hyperthermia or non-specific sedation (as assessed by measurement of motor activity). These data are interpreted in the context of the underlying basis of murine SIB involving both dopaminergic and serotonergic activation and demonstrate the efficacy of risperidone in treating these behaviors. [Copyright &y& Elsevier]

To clarify the role of cyclooxygenase in the peripheral nerve on the development of neuropathic pain, we investigated the effects of peri-sciatic administration of indomethacin on the development of allodynia in a model of L5 single spinal nerve injury. Peri-sciatic administration of indomethacin (1 mg/kg) was performed 3, 24, or 72 h after nerve injury (n=6/each). In rats with indomethacin 3 or 24 h after nerve injury, ipsi-lateral paw withdrawal thresholds 7–35 days after nerve injury were significantly higher compared with those in the control group (n=6: without peri-sciatic treatment) (P<0.05). However, such efficacy was no longer apparent when indomethacin was administered 72 h after nerve injury. These results suggest that peri-sciatic administration of indomethacin early (less than 24 h) after nerve injury can attenuate the development of allodynia. [Copyright &y& Elsevier]

We investigated the changes in glutamate release from the ipsi- and contra-lesional medial vestibular nucleus (MVN) following unilateral labyrinthectomy (UL) by in vivo microdialysis study. The concentration of glutamate in the ipsi-lesional MVN was decreased until 4 h. Twelve hours after UL, the concentration of glutamate was restored back to the basal level, after which the release did not show any change between 24 and 48 h post-UL. In contrast, the concentration of glutamate in the contra-lesional MVN, which increased immediately after UL, decreased gradually to the basal level until 3–4 h post-UL, followed by no further change. The difference in the glutamate concentration between ipsi- and contra-lesional MVN increased immediately after UL and gradually decreased accompanied by a reduction in the frequency of nystagmus, although spontaneous nystagmus had not disappeared by the time the imbalance of glutamate release diminished. These results suggest that the imbalance of glutamate release between bilateral nuclei induced the nystagmus, and the change in release is concerned with the rapid development of vestibular compensation. [Copyright &y& Elsevier]

To evaluate the relationship between nicotine and immunological inflammation, we investigated the effects of nicotine on plasma extravasation of the passive skin Arthus reaction, elicitated 4 hr after sensitizing skin with antiserum, and serum corticosterone levels in rats. Pretreatment with a single subcutaneous injection of nicotine (0.4 or 0.8 mg/kg) 30 or 60 min. before antigen challenge attenuated the passive skin Arthus reaction immunological inflammation. Serum corticosterone levels were dose-dependently increased 30 and 60 min. after nicotine administration. Both markers co-varied with a similar dose-response and time course after the nicotine-treatment. In addition, we also examined these nicotine-induced responses after bilateral lesions of the hypothalamic paraventricular nucleus; both the nicotine-induced suppression of immunological inflammation and the increased serum corticosterone levels were attenuated in bilateral paraventricular nucleus-lesioned animals. Moreover, the immunological inflammatory decreasing effects of a single subcutaneous injection of nicotine (0.4 mg/kg) were antagonized by intraperitoneal preinjection with mecamylamine (1.0 mg/kg; blocking the brain nicotinic acetylcholine receptors) as well as by subcutaneous preinjection with mifepristone (30 mg/kg; a glucocorticoid receptor antagonist) but not by intraperitoneal preinjection with hexamethonium (2.0 mg/kg; a peripheral nicotinic acetylcholine receptors antagonist). Finally, intraperitoneal preinjection with cycloheximide (2 mg/kg), a protein synthesis inhibitor, abolished both the inhibitory effect of nicotine (0.4 mg/kg) on the dye leakage and the elevation of blood corticosterone levels. These findings indicate that the nicotine-induced decreasing effect on immunological inflammatory response may be related to serum corticosterone levels elevated by an activation of the paraventricular nucleus through the brain nicotinic acetylcholine receptors. [ABSTRACT FROM AUTHOR]

The effects of pretreatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on the acute and long-term effects of methamphetamine on striatal dopamine were evaluated in BALB/c mice. Four subcutaneous injections of a non-toxic dose of MPTP (8 mg/kg, at 2 hr intervals) were followed three days later by a toxic regimen of methamphetamine (four injections of 4 mg/kg, at 2 hr intervals) and mice were sacrificed immediately or three days later. Control mice received saline in place of the MPTP or methamphetamine and mice were observed for acute changes in body temperature, self-injurious behaviour, and striatal dopamine metabolites, or long-term changes in striatal dopamine levels, tyrosine hydroxylase immunoreactivity and glial fibrillary acidic protein. It was observed that pretreatment with MPTP protected mice against the acute increase in body temperature caused by the methamphetamine but, at the same time, delayed the occurrence of self-injurious behaviour following the repeated injections of methamphetamine. Likewise, pretreatment with MPTP attenuated the long-term depletion of striatal dopamine induced by the methamphetamine as well as the large increase in glial fibrillary acidic protein and the reduction in tyrosine hydroxylase immunoreactivity. The MPTP-treatment itself did not alter any of these neurotoxic markers. Finally, the acute decrease in 3,4-dihydroxyphenyacetic acid levels and increased ratio of 3-methoxytyramine/dopamine observed 60 min. after a single injection of methamphetamine (4 mg/kg) were also attenuated in MPTP-treated mice. These results are discussed in the context of the hypothesis that the low-dose treatment with MPTP may modify exchange diffusion across the striatal cell membrane thereby altering the acute and long-lasting effects of methamphetamine. [ABSTRACT FROM AUTHOR]

The effects of intracisternal administration of endothelin-1 on blood-brain barrier permeability were examined in dogs and rats. Single doses of endothelin-1 elevated blood-brain barrier permeability about two times compared with control groups in both species. However, repeated dosing with endothelin-1 at a 24 hr intervals caused a highly enhanced disruption of blood-brain barrier permeability in dogs, but not in rats, whereas the repeated administration with a 48 hr interval markedly increased the blood-brain barrier permeability in both species of animals (dogs: 923%, rats: more than 661%). Moreover, this abnormally enhanced permeability of blood-brain barrier in dogs was completely blocked by pretreatment with the endothelin ET-A receptor selective antagonist, S-0139, administered prior to either the first or second dosing with endothelin-1. From these results, we conclude that a repeated attack of endothelin-1 from the adventitial site of brain blood vessels produces a severe disruption of blood-brain barrier permeability through an endothelin ET-A receptor-mediated process. [ABSTRACT FROM AUTHOR]

The function of the 5-hydroxytryptamine (5-HT) system in the medial vestibular nucleus (MVN) was evaluated using KCl-evoked 5-HT release assessed by in vivo microdialysis. The release of 5-HT in the MVN was increased by the local application of KCl (100 mM) in a calcium-dependent manner. Likewise, perfusion of a 5-HT reuptake blocking agent, clomipramine (1 μM), increased extracellular levels of 5-HT in the MVN. Finally, pretreatment with the selective 5-HT1A agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (1 mg/kg, intraperitoneally), attenuated the KCl-evoked 5-HT release. These findings suggest that 5-HT stored in vesicles is released from nerve terminals in the MVN. In addition, its regulation may be mediated by control of somatodendritic 5-HT1A receptor activation. [Copyright &y& Elsevier]