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Small molecular G-protein plays a key role in several diseases. This study was designed to reveal the role of RhoA signaling in the pathophysiology of neuropathic pain in mice. Partial sciatic nerve injury caused thermal hyperalgesia, mechanical allodynia, and increased plasma membrane translocation of RhoA in the lumber spinal cord. GFAP-immunoreactivity (ir), Iba-1-ir, and Rho kinase 2 (ROCK2-ir) was also increased in the ipsilateral spinal dorsal horn of nerve-ligated mice. Moreover, partial nerve ligation increased the expression of phosphorylated myristoylated alanine-rich protein kinase C substrate (MARCKS)-ir in the ipsilateral spinal dorsal horn. Daily intrathecal administration of simvastatin, beginning 3 days before nerve injury, completely blocked all these changes in nerve-ligated mice. Pharmacological inhibition of ROCK also attenuated the increased expression of GFAP-ir and phosphorylated MARCKS-ir. Together, it is suggested that astrogliosis initiated by the activation of RhoA/ROCK signaling results in MARCKS phosphorylation in nerve terminals, which leads to hyperalgesia in neuropathic pain. Furthermore, simvastatin exerts antihyperalgesic and antiallodynic effects through the inhibition of spinal RhoA activation. [ABSTRACT FROM AUTHOR]

Abstract: Renal ischemia produces sympathoexcitation, which is responsible for the development of ischemic acute kidney injury. Stimulation of central opioid receptors activates the renal sympathetic nerve. The present study examined the effect of an opioid receptor antagonist naloxone on the ischemia/reperfusion-induced renal dysfunction in mice. Blood urea nitrogen (BUN) and plasma creatinine increased 24 h after the renal ischemia/reperfusion. Intraperitoneal or intracerebroventricular, but not intrathecal, pretreatment with naloxone suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine. This effect of naloxone was reversed by subcutaneous pretreatment with morphine. Selective MOP receptor antagonist β-funaltrexamine (FNA) also suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine. Moreover, tyrosine hydroxylase expression in the renal tissue increased 24 h after renal ischemia/reperfusion, which was abolished by intraperitoneal or intracerebroventricular pretreatment with naloxone and FNA. Immunohistochemical experiments revealed a significant increase in the number of the Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) positive cells in the paraventricular nucleus of hypothalamus and supraoptic nucleus 24 h after the renal ischemia/reperfusion. Intracerebroventricular pretreatment with naloxone attenuated the renal ischemia/reperfusion-induced increase in the number of the Fos family proteins positive cells in these areas. Finally, we observed that i.c.v. pretreatment with antiserum against β-endorphin also suppressed the increased blood urea and plasma creatinine. These results suggest that the blockade of central opioid receptors can attenuate the ischemic acute kidney injury through the inhibition of renal sympathoexcitation. The central opioid receptors may thus be a new target for the treatment of ischemic organ failures. [Copyright &y& Elsevier]

Rationale: The traditional antihistamine chlorpheniramine ameliorates panic attacks, phobias, and lowered mood, and this therapeutic effect is independent of the blockade of histamine H receptors. Since chlorpheniramine inhibits the reuptake of serotonin (5-HT), the anxiolytic-like effect of chlorpheniramine may be produced by an increase in serotonergic function. Objective: To elucidate the mechanisms underlying the anxiolytic-like effects of chlorpheniramine in mice, we examined the involvement of 5-HT systems in the prefrontal cortex that is a crucial region in the regulation of emotional function. Results: Chlorpheniramine (0.05-5 mg/kg, i.p.) dose-dependently and significantly decreased the duration of freezing behavior in both the elevated open-platform and conditioned fear tests. The anti-freezing effects of chlorpheniramine (5 mg/kg, i.p.) in these tests were inhibited by pretreatment with the non-selective antagonist at 5-HT receptors, methiothepin (0.01 mg/kg, s.c.). In addition, the local injection of chlorpheniramine (10-100 ng/mouse) and 5-HT (1-10 μg/mouse) into the medial part of the prefrontal cortex (mPFC) dose-dependently and significantly decreased the duration of freezing behavior in the elevated open-platform test. In a microdialysis study, chlorpheniramine (0.5 and 5 mg/kg, i.p.) dose-dependently and significantly increased the extracellular 5-HT level in the mPFC. In addition, the local perfusion of chlorpheniramine (10 and 30 μM), but not of the selective H1 receptor antagonist, cetirizine, into the mPFC markedly increased the extracellular 5-HT level in the mPFC. Conclusion: The anxiolytic-like effect of chlorpheniramine is produced, at least in part, by the facilitation of serotonergic neurotransmission in the PFC. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the relation between bronchoconstriction and cough induced by methacholine (Mch) inhalation and to elucidate the role of C-fibers and rapidly adapting irritant receptors (RARs) in these reactions in conscious guinea pigs. The authors measured enhanced pause (Penh) as an index of bronchoconstriction and also measured the number of coughs induced by Mch inhalation in conscious guinea pigs. The authors also examined the effects of pretreatment with procaterol, capsaicin desensitization and moguisteine on these responses. There was a significant positive correlation between the increase in Penh and the number of coughs induced by Mch inhalation. Procaterol (0.1 mg/kg, intraperitoneal [i.p.]) completely abolished both the Mch-induced increase in Penh and cough. Capsaicin desensitization had no effect on Penh or the number of coughs. Moguisteine (0.02, 0.2, or 2 mg/kg, i.p.) dose-dependently inhibited the number of coughs but not the increase in Penh induced by Mch inhalation. Bronchoconstriction causes cough via RARs, but not C-fibers. Neither RARs nor C-fibers are involved in Mch-induced bronchoconstriction itself. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathy accompanied by abnormal sensory perception is the most common complication in insulin-dependent and -independent diabetes mellitus. Since there are very few effective therapeutic regimens for sensory abnormalities in diabetes, we examined the effect of cytidine 5′-diphosphocholine (CDP)-choline on the thermal nociceptive threshold in streptozotocin-induced diabetic mice using the tail-flick test. Diabetic mice showed a shorter tail-flick latency at 1–4 weeks after streptozotocin treatment and a longer tail-flick latency after 8–12 weeks. This hyper- and hypoalgesia in diabetic mice was almost completely inhibited by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning on the day of streptozotocin treatment. Daily treatment with CDP-choline beginning 5 weeks after streptozotocin treatment attenuated the development of hypoalgesia. Diabetic mice showed a significant increase in Na+-K+-ATPase activity at 3 weeks after streptozotocin treatment, whereas Na+-K+-ATPase activity was decreased at 12 weeks after treatment. These alterations were normalized by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning the day of streptozotocin treatment. These results provide evidence to support the therapeutic potency of CDP-choline on the development of thermal hyper- and hypoalgesia and the progression of thermal hypoalgesia in diabetic mice. Moreover, these effects of CDP-choline may result from the normalization of Na+-K+-ATPase activity. [Copyright &y& Elsevier]