Uta Muth-Selbach

Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation.

BACKGROUND Prostaglandin play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E2 (PGE2) in antinociception produced by intraperitoneally administered acetaminophen. METHODS The PGE2 concentrations in the dorsal horn of the spinal cord were measured after formalin was injected into the hind paw of rats. The effect of antinociceptive doses of acetaminophen (100, 200, and 300 mg/kg given intraperitoneally) on PGE2 levels and flinching behavior was monitored Spinal PGE2 and acetaminophen concentrations were obtained by microdialysis using a probe that was implanted transversely through the dorsal horn of the spinal cord at L4. Furthermore, the effects of acetaminophen on urinary prostaglandin excretion were determined. RESULTS Intraperitoneal administration of acetaminophen resulted in a significant decrease in spinal PGE2 release that was associated with a significant reduction in the flinching behavior in the formalin test Acetaminophen was distributed rapidly into the spinal cord with maximum dialysate concentrations 4560 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was not significantly altered after acetaminophen administration. CONCLUSIONS The data confirm the importance of PGE2 in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE2 release. The mechanism, however, remains unknown. The finding that urinary excretion of prostaglandins was not affected might explain why acetaminophen is antinociceptive but does not compromise renal safety.

Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration

The topical administration of non‐steroidal antiinflammatory drugs (NSAIDs) is widely used for the treatment of soft tissue pain. However, it is not known whether effective tissue concentrations are reached with the topical route.

Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state

To evaluate the extent of human cyclooxygenase‐1 (COX‐1) inhibition by meloxicam, which has been reported to preferentially inhibit cyclooxygenase‐2 (COX‐2). The effects of meloxicam were compared with those of diclofenac, a nonselective COX inhibitor.

Inhibition of noxious stimulus-induced spinal prostaglandin E2 release by flurbiprofen enantiomers: a microdialysis study.

Abstract: Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase‐inhibiting drugs are thought to depend on the inhibition of PG synthesis. R‐Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R‐flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R‐ and S‐flurbiprofen (9 and 27 mg kg‐1, respectively) were administered intravenously 10‐15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30‐45 min. Baseline PGE2 dialysate concentrations were 100.6 ± 6.4 pg ml‐1 (mean ± SEM). After formalin injection they rose about threefold with a maximum of 299.4 ± 68.4 pg ml‐1 at 7.5 min. After ∼ 1 h PGE2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin‐induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S‐ and R‐flurbiprofen at 9 mg kg‐1 produced a minimum of 15.8 ± 5.2 and 27.7 ± 14.9 pg ml‐1, respectively, and 27 mg kg‐1S‐ and R‐flurbiprofen resulted in 11.7 ± 1.7 and 9.3 ± 4.7 pg ml‐1, respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg‐1R‐flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S‐Flurbiprofen (27 mg kg‐1), however, led to a moderate reduction (∼40%). The data suggest that antinociception produced by R‐flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.

Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain

Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain. Since the concentration of glycine in the synaptic cleft is controlled by specialized proteins, the glycine transporters GlyT1 and GlyT2, manipulation of this system might have significant effects on nociception. In the present study, we investigated the effects of the spinally applied glycine transporter inhibitors ALX 5407 (GlyT1) and ALX 1393 (GlyT2) on nociceptive behavior in the chronic constriction injury model of neuropathic pain in male Wistar rats. After implementation of neuropathy, the animals were injected with three dosages of ALX 5407 and ALX 1393 (10, 50 and 100 microg) via an intrathecal catheter (n = 8 each). Subsequently, nociceptive behavior was evaluated regarding thermal hyperalgesia (Hargreaves method) and mechanical sensitization (von Frey filaments) over 240 min after application. Inhibition of GlyT1 by ALX 5407 had differential dose-dependent effects. While the highest and the lowest concentrations were antinociceptive, the medium dose evoked pronociceptive effects. The GlyT2 inhibitor ALX 1393 was only effective in the highest concentration at which it exerted significant antinociception. However, in the same dose, ALX 1393 caused remarkable side effects such as respiratory depression and motor deficits in three animals. Our findings indicate that inhibition of glycine transporters is capable of evoking significant effects on nociceptive behavior in neuropathic pain. Whether glycine transporter inhibitors have the capability to gain clinical relevance as analgesic compounds on the long run has to be elucidated in further investigations.

Risperidone-induced cholestatic hepatitis.

Risperidone, a widely used atypical and potent neuroleptic drug, is assumed to induce fewer hepatic side-effects than phenothiazine anti-psychotics. Recently, we observed a case of risperidone-induced cholestatic hepatotoxicity. A 37-year-old male developed a rapid increase in liver enzymes and cholestatic parameters after starting treatment with risperidone for paranoid psychosis. Work-up for other potential aetiologies was negative. The results of a percutaneous liver biopsy were consistent with drug-induced liver injury and cholestasis. Over the course of one month after the discontinuance of all anti-psychotic agents, the liver function test results returned to near-normal values. This observation supports the need to monitor cholestatic parameters in addition to liver function enzymes during initiation and the first weeks of risperidone intake.

The Spinal Antinociceptive Effect of Nocistatin in Neuropathic Rats Is Blocked by D-Serine

Background: The neuropeptide nocistatin (NST) has been implicated in the modulation of nociceptive responses in the spinal cord. Depending on the dose, both pronociceptive and antinociceptive effects have repeatedly been reported. The pronociceptive effect is most likely attributable to inhibition of synaptic glycine and &ggr;-aminobutyric acid release and a subsequent reduction in the activation of inhibitory glycine and &ggr;-aminobutyric acid receptors, but the mechanisms of its antinociceptive action have hitherto remained elusive. It has recently been demonstrated that synaptically released glycine contributes to N-methyl-d-aspartate receptor activation. The authors therefore investigated whether a reduction in glycine release might also account for the antinociceptive action of NST in neuropathic rats. Methods: The authors analyzed the effects of spinally applied NST in the chronic constriction injury model of neuropathic pain. NST was injected intrathecally from nanomolar to picomolar doses and its effects on thermal paw withdrawal latencies were monitored. Furthermore, we tested whether D-serine (100 &mgr;g per rat), a full agonist at the glycine binding site of the N-methyl-d-aspartate receptor, would interfere with the effects of NST. Results: At high doses (10 nmol/rat), intrathecally injected NST was pronociceptive, whereas lower doses (1 pmol/rat) elicited antinociception. The antinociceptive, but not the pronociceptive, action was occluded by intrathecal pretreatment with D-serine. L-serine, which does not bind to N-methyl-d-aspartate receptors, affected neither the pronociceptive nor the antinociceptive effect. Conclusions: These results demonstrate that NST produces a biphasic dose-dependent effect on neuropathic pain. The spinal antinociception by NST is most likely attributable to inhibition of glycine-dependent N-methyl-d-aspartate receptor activation.

Mirtazapine and its enantiomers differentially modulate acute thermal nociception in rats

The antidepressant mirtazapine is an optically active drug and currently marketed as a racemic compound consisting of its S(+) and R(-)-enantiomers in a 50:50 mixture. As stereochemistry of antidepressants has become increasingly important to consider for the relevance of their analgesic properties, we investigated the effect of (+/-)-mirtazapine and its enantiomers in an animal model of acute thermal nociception. Wistar rats were injected intrathecal with either (+/-)-mirtazapine, R(-)-mirtazapine, S(+)-mirtazapine from 1 to 0.001 mg/kg and vehicle (0.9% NaCl), respectively. The effects on thermal paw withdrawal thresholds were monitored using the Hargreaves test. (+/-)-Mirtazapine exerted pro- and antinociceptive effects in acute thermal nociception, whereas R(-)-mirtazapine showed solely antinociceptive and S(+)-mirtazapine pronociceptive properties. These results clearly demonstrate a differential effect of (+/-)-mirtazapine and its enantiomers on nociception. As R(-)-mirtazapine exerts the antinociceptive activity of the racemic mixture it may be a putative candidate for an enantioselective use as analgesic.

Racemic intrathecal mirtazapine but not its enantiomers acts anti-neuropathic after chronic constriction injury in rats.

The unique noradrenergic and specific serotonergic antidepressant mirtazapine acts antinociceptive. It is optically active and currently marketed as racemate. In an animal model of acute pain it has been shown that the enantiomers exhibit differential effects: the R(-)-enantiomer showed anti-, the S(+)-enantiomer pronociceptive properties while the racemate acted antinociceptive at low doses and profoundly pronociceptive after high-dose application. Aim of the present study was to evaluate potential enantioselective effects of mirtazapine in neuropathic pain. In a chronic constriction injury model of neuropathic pain, Wistar rats were injected (+/-)-mirtazapine and the enantiomers intrathecally. All substances were dosed between 0.001 and 1mg/kg and compared to vehicle in a randomized and blinded approach. Thermal hyperalgesia and mechanical allodynia were assessed. In contrast to the acute pain results, only racemic mirtazapine exerted significant sustained analgesic effects up to 48 h. Antinociception was observed at all dosages with a maximum in the range of 0.01 mg/kg. Surprisingly, neither enantiomer was pro- nor antinociceptive at any dose or time. Our findings suggest that the synergism of both enantiomers is required to evoke a significant analgesic effect for the treatment of neuropathic pain. Our study gained no evidence for the use of either R(-) nor S(+)-mirtazapine alone. Due to the unique characteristics of (+/-)-mirtazapine and its proven efficacy in acute pain our results suggest that racemic mirtazapine may be a particularly useful antidepressant in the adjunctive treatment of chronic neuropathic pain states and could provide additional benefit to current therapeutic options.

Effect of continuous posttraumatic intrathecal nocistatin on the development of mechanical allodynia.

Background and Objectives: The neuropeptide nocistatin has a variety of effects on nociception and other central nervous system functions. It has shown to exert diverging effects on nociceptive behavior in various experimental pain models depending on the dose administered. The inhibitory effect of spinal nocistatin on the release of glycine and &ggr;-aminobutyric acid is thought to be responsible for pronociceptive effects, whereas the antinociceptive action of nocistatin can be attributed to diminished glycine-dependent N-methyl-d-aspartate receptor activation. So far, nocistatin has only been investigated in experimental models of already established pain and has been injected as a bolus. Methods: In the present study, we investigated the effects of continuous intrathecal administration of nocistatin on the development of mechanical allodynia in the chronic constriction injury model of neuropathic pain in rats. The spinal infusion via intrathecal catheters connected to osmotic minipumps was started immediately after the surgical procedure and lasted 24 hrs. The development of mechanical allodynia was assessed with von Frey-type filaments for 2 weeks after chronic constriction injury. Results: Despite a wide range of doses used, the continuous spinal application of nocistatin had no significant effect on the development of pathological nociceptive behavior at any time point, that is, mechanical allodynia developed equally in all groups in the injured paw, whereas nociceptive behavior was unchanged in comparison with baseline values in the uninjured paw in all groups. Conclusions: Because nocistatin has well-documented effects on established pathological pain, it is conceivable that its effect on nociception is only effective when spinal circuitry is pathologically altered.