Wen-hsien Wu

Nifedipine-Induced Analgesia After Epidural Injection in Rats

We explored the analgesic effect of epidural nifedipine in male Sprague-Dawley rats. By using an implanted epidural catheter, the rats were given 35 microL of dimethylsulfoxide (DMSO) alone or DMSO containing 2.5, 5, 10, or 20 microM of nifedipine. Analgesia was measured by tailflick (TF) involving spinal reflexes, and by hotplate (HP) requiring an intact central nervous system. The latencies were recorded up to 120 min after the injection. The cutoff time of the noxious stimuli was 20 s in the TF and 60 s in the HP to prevent tissue damage. The TF technique revealed a significant difference from the control at doses of 5, 10, and 20 microM with no difference among the groups. Maximum latencies (cutoff time) lasted for 15, 30, and 40 min at doses of 5, 10, and 20 microM, respectively. The HP technique disclosed a dual effect: a significant decrease at the dose of 2.5 microM, no effect at 5 microM, and an increase at 10 and 20 microM. However, the median latency did not reach the cutoff time. We conclude that nifedipine, given epidurally, possesses antinociceptive properties at the dose of 5 microM and higher, detected better by the TF than HP. Our data suggest that the antinociceptive effect of nifedipine, at the studied doses, is more prominent at the spinal than the supraspinal level.

Cocaine depresses GABAA current of hippocampal neurons.

Although blockade of dopamine re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary mechanism of cocaine-induced seizures, it is possible that other neurotransmitters such as gamma-aminobutyric acid (GABA) are involved. To examine this possibility, the effects of cocaine on the whole cell GABA current (IGABA) of freshly isolated rat hippocampal neurons were investigated with the patch-clamp technique. Preincubation or acute application of cocaine reversibly suppressed IGABA. The IC50 was 127 microM when cocaine was applied before the application of GABA. The concentration-response relations of cocaine in various GABA concentrations revealed that cocaine inhibited IGABA non-competitively. This effect of cocaine appeared to be independent of voltage. The present study suggests that the GABA receptor/channel complex is also a target for cocaines action. The suppression of IGABA may contribute to cocaine-induced seizures.

Ondansetron modulates GABAA current of rat central nervous system neurons

Abstract We examined the effect of ondansetron, a 5-HT3 receptor antagonist, on the whole cell current response of freshly isolated hypothalamic and hippocampal neurons of rats to γ-aminobutyric acid (GABA). The nystatin perforated patch technique was used to minimize run-down of the GABA current. While 1–150 μM ondansetron had no effect on membrane conductance, co-application with agonist reversibly depressed the maximal end GABA current. The concentration–response relation of GABA reveals a non-competitive mechanism. However, the inhibitory effect was more potent when ondansetron was co-applied with lower concentrations of GABA: i.e., the ondansetron concentration needed to depress the current induced by 5 μM GABA to half amplitude was 7 μM compared to 28 μM for the current induced by 10 μM GABA. Analysis of the current–voltage relationship with and without ondansetron indicated that the effect of ondansetron is not voltage dependent. Current–voltage relations also showed that the effect of ondansetron was not due to activation of a GABA-independent current because the reversal potentials were the same with and without ondansetron. The present data suggest that ondansetrons suppression of GABA-activated current may be the molecular basis of ondansetron-induced seizures observed in vivo.

Ondansetron blocks nifedipine-induced analgesia in rats

The serotonergic system is involved in pain transmission and the 5-hydroxytryptamine (5-HT3) receptor subtype mediates some of these effects at the spinal level. Therefore, we explored the effects of the serotonergic system on nifedipine-induced analgesia by using the 5-HT3 receptor antagonist ondansetron. Male Sprague-Dawley rats were pretreated with ondansetron (1 mg/kg intraperitoneally) or normal saline. After 15 min, rats received injections of nifedipine (15 mg/kg intraperitoneally) or dimethylsulfoxide (DMSO), solvent for nifedipine, as a control. Nociception was assessed by tail-flick method. Rats treated with nifedipine alone had an increase in tail-flick latency of 122%, as measured by the area under the curve, compared to rats treated with DMSO alone. Pretreatment with ondansetron, however, completely blocked the analgesic effect of nifedipine, with tail-flick latency remaining at baseline throughout the measurement period. These results indicate that the 5-HT (3) receptor plays an important role in the analgesic response to nifedipine and that medications that block this receptor may decrease the analgesic effectiveness of this type of therapy. (Anesth Analg 1996;82:498-500)

The effects of serotonin biosynthesis inhibition on nicotine and nifedipine-induced analgesia in rats.

The calcium channel blocker nifedipine has analgesic properties that are enhanced by nicotine.Although it is not known how this analgesic state might affect the awareness of anginal pain and impending myocardial infraction, recent studies have shown an increased mortality associated with the use of large doses of nifedipine. Because both nifedipine- and nicotine-induced analgesia involve serotonergic mechanisms, we studied the effects of the serotonin biosynthesis inhibitor parachlorophenylalanine (pCPA) on nifedipine- and nicotine-induced analgesia. Nociception was assessed by tail-flick method. Rats pretreated with pCPA (300 mg/kg intraperitoneally [IP]) followed by either nifedipine (15 mg/kg IP) or nicotine (1 mg/kg subctaneously) had a increase in tail-flick latency of 41% (P = 0.09) and 50% (P = 0.05), respectively, compared with animals that did not receive pCPA. Additionally, rats pretreated with pCPA followed by a combination of nicotine and nifedipine doubled their tail-flick latency (P = 0.0001) compared with animals that were not treated with pCPA. These data further support the involvement of the serotonergic system in both nifedipine- and nicotine-induced analgesia and suggest that drugs that affect serotonin levels, including tricyclic antidepressants and serotonin-specific reuptake inhibitors, may also affect the analgesia induced by nifedipine and nicotine. Implications: This study examines the effect of serotonin depletion on nicotine- and nifedipine-induced analgesia. Nifidipine is a calcium channel blocker used to treat high blood pressure. It also has pain-relieving properties that are enhanced by nicotine. Because both nifedipine- and nicotine-induced analgesia involve the neurotransmitter serotonin, it is important to know how changes in serotonin concentration might affect both nicotine- and nifedipine-induced analgesia. This study not only supports the involvement of the serotonergic system in both nifidipine- and nicotine-induced analgesia, but also suggests that drugs that affect serotonin levels may also affect analgesia induced by nifidipine and nicotine. (Anesth Analg 1998;87:1109-12)

Laser photobiostimulation-induced hypoalgesia in rats is not naloxone reversible.

Laser photobiostimulation (LPBS) at the pulsing frequency of 4 Hz applied to the low resistance point located at the base of the tail of the rat, (Governing Vessel Meridian 1), produced a hypoalgesic effect, measured by tail-flick and hot-plate techniques. Pre-treatment with low dose naloxone (2 mg/kg) did not reverse the hypoalgesic effect of LPBS. High dose naloxone (20 mg/kg) reversed only partially, but significantly, the hypoalgesic effect of LPBS measured by hot-plate, but not that measured by the tail-flick technique. These data suggest that mechanisms other than endogenous opioids may be involved in LPBS-induced hypoalgesia.

2,3-Butanedione monoxime protects mice against the convulsant effect of picrotoxin by facilitating GABA-activated currents

While adult mice receiving picrotoxin (PTX) alone responded with clonic and tonic-clonic seizures, this response was greatly suppressed for mice simultaneously injected with 2,3-butanedione monoxime (BDM). For example, 60% and 10% of the mice convulsed when injected (i.p.) with 3.0 mg/kg PTX alone or PTX plus 205 mg/kg of BDM, respectively. In contrast, a non-oxime analogue of BDM, 2,3-butanedione (BTD), did not have this anticonvulsant effect. In order to explore the basis for the anticonvulsant effect of BDM, we recorded GABA-activated currents (IGABA) of frontal cortical as well as ventromedial hypothalamic neurons before, during and after exposure to this oxime. BDM had a biphasic effect on IGABA. That is, high concentrations (100 microM-40 mM) decreased and lower concentrations (0.01 microM-0.001 microM) potentiated IGABA; these effects of BDM reversed upon washout of the oxime. In contrast, BTD had no effect on IGABA. Finally, when 0.001 microM BDM, 10-30 microM PTX and GABA were co-applied the inhibitory effect of the toxin on IGABA was markedly suppressed. These data suggest that the anticonvulsant effect of oximes involves facilitation of the inhibitory action of GABA.