Buspirone-induced antinociception is mediated by L-type calcium channels and calcium/caffeine-sensitive pools in mice.

RATIONALE: Previous studies have shown that buspirone, a partial 5-HT(1A) receptor agonist, produces antinociceptive effects in rats and mice; Ca(2+) plays a critical role as a second messenger in mediating nociceptive transmission. 5-HT(1A) receptors have been proven to be coupled functionally with various types of Ca(2+) channels in neurons, including N-, P/Q-, T-, or L-type. It was of interest to investigate the involvement of extracellular/intracellular Ca(2+) in buspirone-induced antinociception. OBJECTIVES: To determine whether central serotonergic pathways participate in the antinociceptive processes of buspirone, and investigate the involvement of Ca(2+) mechanisms, particularly L-voltage-gated Ca(2+) channels and Ca(2+)/caffeine-sensitive pools, in buspirone-induced antinociception. METHODS: Antinociception was assessed using the hot-plate test (55 degrees C, hind-paw licking latency) in mice treated with either buspirone (1.25-20 mg/kg i.p.) alone or the combination of buspirone and fluoxetine (2.5-10 mg/kg i.p.), 5-HTP (25 mg/kg i.p.), nimodipine (2.5-10 mg/kg i.p.), nifedipine (2.5-10 mg/kg i.p.), CaCl(2) (25-200 nmol per mouse i.c.v.), EGTA (5-30 nmol per mouse i.c.v.), or ryanodine (0.25-2 nmol per mouse i.c.v.). RESULTS: Buspirone dose dependently increased the licking latency in the hot-plate test in mice. This effect of buspirone was enhanced by fluoxetine, 5-HTP, nimodipine, and nifedipine. Interestingly, central administration of Ca(2+) reversed the antinociceptive effects of buspirone. In contrast to these, ryanodine or EGTA administered centrally potentiated buspirone-induced antinociception. CONCLUSIONS: Decreasing neuronal Ca(2+) levels potentiated buspirone-induced antinociception; conversely, increasing intracellular Ca(2+) abolished the antinociceptive effects of buspirone. These results suggest that Ca(2+) influx from extracellular fluid and release of Ca(2+) from Ca(2+)/caffeine-sensitive microsomal pools may be involved in buspirone-induced antinociception.

Peripheral electric stimulation attenuates the expression of cocaine-induced place preference in rats.

The present study was designed to investigate the effect of peripheral electrical stimulation (PES), with high (100 Hz) or low (2 Hz) frequencies, on the expression of cocaine-induced conditioned place preference (CPP). Rats were trained with cocaine (0.1-10 mg/kg, i.p.) under a biased paradigm in a three-compartment chamber for the development of a CPP. One day following the last conditioning, the total time spent in each compartment was recorded after the deliverance of PES. Naloxone (1, 5, and 10 mg/kg, i.p.) was applied to investigate whether endogenous opioid receptor pathways play any role in the effect of PES. It was found that (1). 1 mg/kg and higher doses of cocaine, but not 0.5 mg/kg, produced significant place preference, (2). cocaine-induced CPP, once developed, maintained for more than 13 days in a cocaine-free state, (3). PES of 100 Hz, but not 2 Hz, significantly attenuated the expression of cocaine-induced CPP (P<0.01), (4). PES per se did not influence the natural place preference in rats, and (5). the inhibition of cocaine CPP induced by 100 Hz PES could be reversed by naloxone pre-treatment at 10 mg/kg, but not at lower doses. These results suggest that PES could inhibits cocaine-induced CPP in a frequency-dependent manner. This effect is probably mediated by an endogenous kappa-opioid mechanism.

Effect of 7-nitroindazole on drug-priming reinstatement of D-methamphetamine-induced conditioned place preference.

The study investigated the role of nitric oxide (NO) in the relapse to drug-seeking behavior induced by D-methamphetamine. After the induction of D-methamphetamine (1 mg/kg) conditioned place preference, the rewarding effect became extinct 6 weeks later. The extinguished place preference was reinstated by D-methamphetamine (0.125 mg/kg) injection, an effect which was attenuated by 7-nitroindazole (12.5 and 25 mg/kg) pretreatment. The results demonstrate that NO is involved in relapse primed by D-methamphetamine injection.

L-type Ca(2+) channel blockers inhibit the development but not the expression of sensitization to morphine in mice.

The relationship between opioid actions and L-type Ca(2+) channel blockers has been well documented. However, there is no report relevant to L-type Ca(2+) channel blockers and morphine sensitization, which is suggested to be an analog of behaviors that are characteristic of drug addiction. We now studied systematically the effects of three L-type Ca(2+) channel blockers, nimodipine, nifedipine and verapamil, on morphine-induced locomotor activity, the development and the expression of sensitization to morphine. The results showed that both nimodipine and verapamil attenuated, while nifedipine had only a tendency to decrease morphine-induced locomotor activity. All three drugs inhibited the development of sensitization to morphine. However, none of them showed any effects on the expression of morphine sensitization. These results indicate that blocking L-type Ca(2+) channel attenuates the locomotor-stimulating effects of morphine and inhibits the development but not the expression of morphine sensitization.

The effect of 7-nitroindazole on the acquisition and expression of D-methamphetamine-induced place preference in rats.

The present study investigated the role of nitric oxide (NO) in the rewarding effects of D-methamphetamine using 7-nitroindazole, a potent inhibitor of neuronal nitric oxide synthase (nNOS), as determined by the conditioned place preference paradigm. Male Sprague-Dawley rats treated with D-methamphetamine (1 mg/kg) or saline every other day for 8 days (four drug and four saline sessions) developed marked place preference for the drug-paired side. The administration of 7-nitroindazole (12.5-50 mg/kg) 30 min prior to the exposure to D-methamphetamine dose-dependently attenuated the acquisition of D-methamphetamine-induced conditioned place preference. In addition, when it was acutely administered 30 min prior to the testing session of an already established D-methamphetamine-induced conditioned place preference, 7-nitroindazole (12.5-50 mg/kg) attenuated the expression of this conditioned response in a dose-dependent manner, while 7-nitroindazole (25 and 50 mg/kg) alone showed no place preference effects. These findings indicate that nitric oxide (NO) is involved in the rewarding properties of methamphetamine and suggest that selective nNOS inhibitors maybe useful in the management of methamphetamine abuse.

Tramadol reduces the 5-HTP-induced head-twitch response in mice via the activation of mu and kappa opioid receptors.

Tramadol, an atypical opioid analgesic, stimulates both opiatergic and serotonergic systems. Here we have investigated the effect of tramadol in mice on 5-hydroxyptrytophan (5-HTP)-induced head twitch response (HTR), which is an animal model for the activation of the CNS 5-HT(2A) receptors in mice. Tramadol attenuated 5-HTP-induced HTR in a dose-dependent manner as morphine. Furthermore, the nonselective opioid receptor antagonists, naloxone and diprenorphine (M5050), reversed the effect of tramadol on 5-HTP-induced HTR dose-dependently. Interestingly, in contrast to the selective delta opioid receptor antagonist NTI, beta-FNA, a selective mu receptor antagonist, and nor-BNI, a selective kappa opioid receptor antagonist, antagonized the attenuation of 5-HTP-induced HTR by tramadol. In conclusion, administration of tramadol systemically inhibits 5-HTP-induced HTR in mice by activating opiatergic system in the CNS. Our findings show that mu and kappa opioid receptors, but not delta opioid receptor, play an important role in the regulation of serotonergic function in the CNS.

Nerve growth factor protects R2 cells against neurotoxicity induced by methamphetamine.

It is well known that methamphetamine is a neurotoxic drug of abuse to cause cell death both in vitro and in vivo. In this study, the protective effect of nerve growth factor on methamphetamine-induced neurotoxicity was examined in R2 cells. Treatment of R2 cells with methamphetamine for 48 h induced apoptotic-like death as determined by cell viability assay, DNA fragmentation on agarose gel and flow cytometric analysis. Co-treatment of R2 cells with nerve growth factor (10-1000 U/ml) in the presence of methamphetamine increased cell viability, decreased the intensity of methamphetamine-induced DNA fragmentation and reduced the number of apoptotic cells with flow cytometry. These results indicate that nerve growth factor may be useful for the treatment of methamphetamine users.