Antinociceptive effect of chronic lithium on visceral hypersensitivity in a rat model of diarrhea-predominant irritable bowel syndrome: The role of nitric oxide pathway.

BACKGROUND AND AIM: Lithium, a widely used drug in bipolar-affective disorders, plays gastro-protective roles. The effects of lithium on several tissues are mediated through nitric oxide (NO), which regulates gastrointestinal motility and mucosal integrity. The aim of this study was to investigate the protective effect of chronic lithium administration on visceral hypersensitivity and to investigate the role of NO as a potential mechanism of lithium in a rat model of irritable bowel syndrome. METHODS: Colitis was induced by the intracolonic administration of acetic acid. After subsidence of inflammation on the seventh experimental day, nociception and defecation parameters were measured. A subgroup of animals had been pretreated with lithium carbonate (600 mg/L) for 35 days. Thereafter, either a non-selective NO synthase (NOS) inhibitor (N-nitro-L-arginine methyl ester [L-NAME], 10 mg/kg), a selective NOS inhibitor (aminoguanidine, 100 mg/kg), or saline were administered intraperitoneally 1 h before measurements. RESULTS: Chronic lithium attenuated the visceral hypersensitivity, increased the nociceptive threshold, and decreased stool frequency. L-NAME and aminoguanidine decreased the nociceptive threshold and reduced the protective effects of lithium on visceral hypersensitivity. Stool frequency was increased in both the lithium-treated and water-treated groups by L-NAME administration, but not aminoguanidine. The form of defecation in the lithium-treated rats shifted toward hard stools rather than being soft and formless, but NOS inhibitors did not change the stool consistency pattern. CONCLUSION: The results indicate the antinociceptive property of chronic lithium on visceral hypersensitivity. As this effect was lowered by NOS inhibitors, NO might play a role in the protective effect of lithium to some extent.

Study of morphine-induced dependence in gonadectomized male and female mice.

In this study we evaluated the effects of sex difference and also sex hormones on the naloxone-precipitated morphine withdrawal in both orchidectomized (ORC) male and ovariectomized (OVX) female mice. Morphine (50, 50 and 75 mg/kg/day for 4 days, s.c.) was administered to animals and at 5th day naloxone (4 mg/kg, i.p.)-precipitated morphine withdrawal signs, jumpings and the percentage of weight loss, were measured. There was no significant alteration in withdrawal jumpings between male and female mice, though weight loss was significantly higher in male ones. Jumpings was significantly lower in both OVX and ORC mice and percentage of weight loss was significantly higher in OVX mice than corresponding non-operated or sham animals. In OVX mice, E(2)V (10 mg/kg, s.c.) increased number of jumpings and decreased percentage of weight loss. Progesterone (25 mg/kg, s.c.) had no effect on jumpings, whereas it decreased weight loss in OVX mice. Testosterone (2.5 mg/kg, s.c.) increased jumpings in ORC mice while it had no effect on percentage of weight loss. Our results demonstrated that sex hormones could play a role in the morphine withdrawal syndrome in both ORC male and OVX female mice.

Modulation by female sex hormones of the cannabinoid-induced catalepsy and analgesia in ovariectomized mice.

Cannabinoids are psychoactive compounds with many pharmacological properties such as analgesia, sedation and catalepsy most of which are mediated by cannabinoid CB1 receptors. In the present study, we evaluated whether the ovarian sex hormones are involved in the cannabinoid-induced catalepsy and analgesia in ovariectomized female mice. Female NMRI mice (weighing 25-30 g) were divided into 3 main groups: unoperated, sham-operated and ovariectomized. Both the catalepsy and analgesia induced by different doses of the synthetic cannabinoid WIN 55,212-2 (2 and 4 mg/kg, i.p.) were examined in the groups in the presence or absence of the cannabinoid CB1 antagonist AM251 (0.5 mg/kg). We also evaluated effects of estradiol valerate (10 mg/kg) and progesterone (25 mg/kg) on catalepsy and analgesia induced by WIN 55,212-2 in ovariectomized mice. The antinociceptive effect of WIN 55,212-2 was significantly (P<0.01) enhanced in ovariectomized mice, which was prevented by pretreatment with estradiol but not by progesterone. There was no significant difference in the cannabinoid-induced catalepsy between control and ovariectomized mice. However, pretreatment with progesterone but not estradiol potentiated the cataleptic effect of low dose of WIN 55,212-2 (2 mg/kg) in ovariectomized mice (P<0.01). The present data demonstrated for the first time that ovarian sex steroids could modulate both cannabinoid-induced catalepsy and analgesia in female ovariectomized mice.

Effects of diltiazem or verapamil on calcium uptake and release from chicken skeletal muscle sarcoplasmic reticulum.

The purpose of this study was to determine the effects of 2 Ca2+ channel blockers, verapamil and diltiazem, on calcium loading (active Ca2+ uptake) and the following Ca2+ release induced by silver ion (Ag+) and Ca2+ from the membrane of heavy sarcoplasmic reticulum (SR) of chicken skeletal muscle. A fluorescent probe technique was employed to determine the calcium movement through the SR. Pretreatment of the medium with diltiazem and verapamil resulted in a significant decrease in the active Ca2+ uptake, with IC50 of about 290 micromol/L for verapamil and 260 micromol/L for diltiazem. Inhibition of Ca2+ uptake was not due to the development of a substantial drug-dependent leak of Ca2+ from the SR. It might, in part, have been mediated by a direct inhibitory effect of these drugs on the Ca2+ ATPase activity of the SR Ca2+ pump. We confirmed that Ca2+ channel blockers, administered after SR Ca2+ loading and before induction of Ca2+ release, caused a dose-dependent inhibition of both Ca2+- and Ag+-induced Ca2+ release rate. Moreover, if Ca2+ channel blockers were administered prior to SR Ca2+ loading, in spite of Ca2+ uptake inhibition the same reduction in Ca2+- and Ag+-induced Ca2+ release rate was seen. We showed that the inhibition of Ag+-induced Ca2+ release by L-channel blockers is more sensitive than Ca2+-induced Ca2+ release inhibition, so the IC50 for Ag+- and Ca2+-induced Ca2+ release was about 100 and 310 micromol/L for verapamil and 79 and 330 micromol/L for diltiazem, respectively. Our results support the evidence that Ca2+ channel blockers affect muscle microsome of chicken skeletal muscle by 2 independent mechanisms: first, reduction of Ca2+ uptake rate and Ca2+-ATPase activity inhibition, and second, inhibition of both Ag+- and Ca2+-induced Ca2+ release by Ca2+ release channels. These findings confirm the direct effect of Ca2+ channel blockers on calcium release channels. Our results suggest that even if the SR is incompletely preloaded with Ca2+ because of inhibition of Ca2+ uptake by verapamil and diltiazem, no impairment in Ca2+ release occurs.