The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Sep 1998
Apparent insensitivity of the hotplate latency test for detection of antinociception following intraperitoneal, intravenous or intracerebroventricular M6G administration to rats.
Although morphine-6-glucuronide (M6G) has been shown to be analgesically active, the relative involvement of spinal and supraspinal structures in mediating M6G's pain-relieving effects following central and systemic administration to rats is unclear. As the tail flick and hotplate latency tests are reported to quantify antinociception mediated primarily by spinal and supraspinal mechanisms respectively, these methods were used to determine the comparative "apparent" levels of antinociception (expressed as percentage maximum possible effect, % MPE) achieved after M6G or morphine administration. Following i.v. or i.p. ⋯ By contrast, antinociception evoked by i.v. morphine (10 micromol) exceeded 50% MPE using both the hotplate and tail flick tests although the "apparent" potency was approximately 2.5 times greater using the tail flick test. After i.c.v. dosing, M6G (0.22-3.3 nmol) was significantly (P < .05) more potent when assessed using the tail flick compared with the hotplate test. Taken together, these data strongly indicate that following central and systemic administration, M6G's antinociceptive effects are mediated primarily by spinal structures whereas both spinal and supraspinal mechanisms contribute to systemic morphine's antinociceptive effects.
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J. Pharmacol. Exp. Ther. · Aug 1998
Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia.
Opioid receptors are synthesized in dorsal root ganglia and transported into peripheral terminals of primary afferent neurons. Activation of such receptors results in antinociceptive effects that are most prominent in inflammation. In addition, opioid receptors located on sympathetic postganglionic neuron terminals may be involved in these effects. ⋯ These effects increased linearly between 6 and 24 hr, but did not change between 24 and 96 hr of inflammation, whereas the doses of the irreversible antagonists beta-funaltrexamine, [D-Ala2,Leu5,Cys6]enkephalin or (+/-)-(5beta,7a,8beta)-3, 4-dichloro-N-[3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspir[4, 5]dec-7-yl]benzeneacetamide required to abolish the respective agonist effects increased between 12 and 96 hr. Pretreatment with capsaicin (30, 50, 70 mg/kg s.c. over 3 days) but not with 6-hydroxydopamine (75 mg/kg i.p. over 3 days) reversed the hyperalgesia in inflamed paws and almost abolished antinociceptive effects of all three agonists. These results suggest that the increased opioid agonist efficacy is due to an increased number of peripheral opioid receptors at later stages of inflammation and that peripheral opioid antinociceptive effects are primarily mediated by mu, delta and kappa opioid receptors on primary afferent neurons.
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J. Pharmacol. Exp. Ther. · Aug 1998
Cotreatment with racemic fenfluramine inhibits the development of tolerance to morphine analgesia in rats.
As a follow-up study to an earlier report that racemic fenfluramine can acutely potentiate the analgesic effects of morphine in humans, we investigated the effects of fenfluramine on the development of tolerance to morphine analgesia in rats. Antinociceptive effect, as measured by the tail-flick latency, was studied over 8 days in rats that received continuous i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day of fenfluramine, 3) both drugs concomitantly or 4) saline. Infusion with morphine alone resulted in a peak analgesia of 100% maximal possible effect, which declined with time; full tolerance was reached by day 4. ⋯ ED50 of morphine was elevated to 7.0 mg/kg in the morphine-infused rats compared to 2.4 mg/kg in saline-infused rats. Coinfusion of fenfluramine increased ED50 to only 3.7 mg/kg. These results demonstrate that fenfluramine significantly attenuates tolerance development to morphine by modulating the pharmacological process responsible for tolerance development to morphine.
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J. Pharmacol. Exp. Ther. · Aug 1998
Felbamate increases [3H]glycine binding in rat brain and sections of human postmortem brain.
The anticonvulsant compound felbamate (2-phenyl-1,3-propanediol dicarbamate; FBM) appears to inhibit the function of the N-methyl-D-aspartate (NMDA) receptor complex through an interaction with the strychnine-insensitive glycine recognition site. Since we have demonstrated previously that FBM inhibits the binding of [3H]5, 7-dichlorokynurenic acid (DCKA), a competitive antagonist at the glycine site, we assessed the ability of FBM to modulate the binding of an agonist, [3H]glycine, to rat forebrain membranes and human brain sections. In contrast to its ability to inhibit [3H]5,7-DCKA binding, FBM increased [3H]glycine binding (20 nM; EC50 = 485 microM; Emax = 211% of control; nH = 1.8). ⋯ FBM-enhanced [3H]glycine binding was attenuated by Zn++ and not inhibited by Mg++ in human brain. These results suggest that FBM increases [3H]glycine binding in a manner sensitive to ions which modulate the NMDA receptor. These data support the hypothesis that FBM produces anticonvulsant and neuroprotective effects by inhibiting NMDA receptor function, likely through an allosteric modulation of the glycine site.
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J. Pharmacol. Exp. Ther. · Jul 1998
Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury.
Myocardial injury after ischemia (I) and reperfusion (R) is related to leukocyte activation with subsequent release of cytokines and oxygen-derived free radicals as well as complement activation. In our study, the cardioprotective effects of exogenous C1 esterase inhibitor (C1 INH) were examined in a rat model of myocardial I + R (i.e., 20 min + 24 hr or 48 hr). The C1 INH (10, 50 and 100 U/kg) administered 2 min before reperfusion significantly attenuated myocardial injury after 24 hr of R compared to vehicle treated rats (P < .001). ⋯ In this regard, C1 INH administration abolished expression of P-selectin and ICAM-1 on the cardiac vasculature after myocardial ischemia and reperfusion. Blocking the classical complement pathway by exogenous C1 INH appears to be an effective means to preserve ischemic myocardium from injury after 24 and 48 hr of reperfusion. The mechanisms of this cardioprotective effect appears to be due to blocking of complement activation and reduced endothelial adhesion molecule expression with subsequent reduced PMN-endothelium interaction, resulting in diminished cardiac necrosis.