Dopamine enhancement of dextrorphan-induced skin antinociception in response to needle pinpricks in rats

BackgroundDextrorphan with long-acting local anesthetic effects did not cause system toxicity as fast as bupivacaine, while catecholamines (i.e., epinephrine) with the vasoconstrictive characteristics enhanced the effects of local anesthetic drugs. The objective of the experiment was to examine the synergistic effect of local dopamine (a catecholamine) injection on cutaneous antinociception of dextrorphan.MethodsThe panniculus reflex in response to skin stimulation with a needle was used as the primary endpoint when dextrorphan (1.50, 2.61, 5.46, 10.20 and 20.40 μmol) alone, dopamine (16.20, 32.40, 51.60, 60.00 and 81.60 μmol) alone, or dopamine + dextrorphan (a ratio of ED₅₀ vs. ED₅₀) was injected subcutaneously on the rat's back. We used an isobolographic modelling approach to determine whether a synergistic effect would be observed.ResultsWe showed that dextrorphan, dopamine, or the mixture of dopamine and dextrorphan produced dose-related skin antinociception. The potency (ED₅₀, 50% effective dose) for cutaneous antinociception was dextrorphan [6.02 (5.93–6.14) μmol] greater than dopamine [48.91 (48.80–49.06) μmol] (p < 0.01). The duration of nociceptive inhibition induced by dopamine was longer than that induced by dextrorphan (p < 0.01) based on their equipotent doses (ED₂₅, ED₅₀, and ED₇₅). Enhancement and prolongation of skin antinociception occurred after co-administration of dopamine with dextrorphan.ConclusionsWhen compared to dopamine, dextrorphan was more potent and had a shorter duration of skin nociceptive block. Dopamine produced a synergistic effect on dextrorphan-mediated antinociception, and prolonged dextrorphan′s antinociceptive duration.     

Subcutaneous infiltration of doxylamine on cutaneous analgesia in rats

Background

We aimed to evaluate the effect of doxylamine, a first generation antihistamine, as a local analgesic agent by comparing its effect to bupivacaine.

Pharmacological profile of RWJ 20085: A new,potent, long-acting local anesthetic

RWJ 20085 is a potent, long-acting local anesthetic that has been studied in vivo and in vitro relative to several clinically active agents. In mice, RWJ 20085 [ED₅₀ = 0.0078% (0.0053–0.011%)] was more potent by perineural infiltration than bupivacaine [ED₅₀ = 0.035% (0.026–0.046%)], etidocaine [ED₅₀ = 0.025% (0.016–0.035%)], or lidocaine [ED₅₀ = 0.18% (0.13–0.26%)]. The onset of action of each compound was 5 minutes, and the duration was 90 minutes for RWJ 20085 and 30 minutes for bupivacaine or etidocaine while lidocaine was active for only 15 minutes. In the rabbit corneal assay, RWJ 20085 [ED₅₀ = 0.012% (0.0049–0.023%)] was more potent than bupivacaine [ED₅₀ = 1.4% (0.47–3.05%)]. The lowest topical local anesthetic ED₅₀ of each agent was observed within 5 or 15 minutes after administration, and RWJ 20085 was active for 300 minutes, whereas bupivacaine and etidocaine were active for 90 or 45 minutes, respectively. In the guinea pig intradermal assay RWJ 20085 [ED50 = 0.017% (0.0094–0.028%)], bupivacaine [ED₅₀ = 0.016% (0.0078–0.028%)], and etidocaine [ED₅₀ = 0.02% (0.0093–0.042%)] were equipotent while lidocaine [ED₅₀ = 0.072% (0.040–0.12%)] was less potent. The onset of action of each compound was 5 minutes. The duration of action of RWJ 20085 and etidocaine was 60 minutes, whereas bupivacaine and lidocaine were active for 45 and 15 minutes, respectively. In the frog isolated-sciatic nerve preparation, similar concentrations of RWJ 20085 (2.5 × 10^?3M) and lidocaine (5.0 × 10^?3M) produced a 50% reduction of the amplitude of the pretreatment action potential; however, bupivacaine and etidocaine were each effective at a lower concentration (5.0 × 10^?4M). When their intramuscular therapeutic ratios (TR = lethal dose LD₅₀/local anesthetic ED₅₀) were calculated in mice, the therapeutic ratio of RWJ 20085 (82) was less than that of etidocaine (103) but was larger than that of either lidocaine (36) or bupivacaine (29). Calculation of the therapeutic ratios by using the intravenous LD₅₀ values suggests that lidocaine would have the smallest margin of safety if inadvertently administered by the intravenous route. The therapeutic ratios of the other agents were larger than that of lidocaine; however, there was little difference among them. RWJ 20085 has a low potential for dermal irritation as shown in rabbits and has no liability for contact sensitization as shown in guinea pigs. RWJ 20085 may have clinical utility as an injectable and/or topical local anesthetic.     

Interactions of caerulein and morphine on gastrointestinal propulsion in the mouse

Summary The effects of subcutaneously administered caerulein (ceruletide) and morphine hydrochloride on gastric emptying and gastrointestinal propulsion were studied in male mice. Drug effects were evaluated by the movement of Indian ink administered directly into the stomach after drug injection. Morphine inhibited both gastrointestinal propulsion (ED₅₀=2.1 mol/kg) and gastric emptying (ED₅₀=43 mol/kg). Caerulein enhanced gastrointestinal propulsion (ED₅₀=0.93 nmol/kg) but inhibited gastric emptying (ED₅₀=17 nmol/kg). Inhibition of gastric emptying was further potentiated by the combined administration of caerulein and morphine. Naloxone reversed both effects of morphine but not those of caerulein. Morphine antagonized the propulsion-enhancing effect of caerulein.     

Spinal nociceptin inhibits AMPA-induced nociceptive behavior and Fos expression in rat spinal cord

The effects of intrathecal nociceptin (NOCI) on the nociceptive behavior (biting, scratching and licking; BSL) and the spinal Fos expression induced by intrathecal administration of N-methyl-D-aspartate (NMDA, 4 microg/rat) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA, 2 microg/rat) were studied. Coadministration of NOCI (3 and 10 nmol/rat) with NMDA did not modify the NMDA-induced BSL or Fos expression. In contrast, NOCI (0.1-3 nmol/rat) dose-dependently inhibited the BSL behavior induced by AMPA. Furthermore, coadministration of NOCI (3 and 10 nmol/rat) significantly reduced the AMPA-induced expression of Fos protein in the superficial layers of the spinal dorsal horn. In order to test whether classical or opioid receptor-like type 1 (ORL1) receptors are involved in the inhibitions by NOCI of AMPA-evoked BSL, the corresponding antagonists were assayed. The administration of the nonselective opioid receptor antagonist, naloxone (10 mg/kg i.p.), did not modify the NOCI-induced inhibition of AMPA-evoked BSL. However, the selective ORL1 receptor antagonist, [N-Phe(1)]nociceptin-(1-13)-NH(2) (90 nmol/rat i.t.), completely prevented the NOCI-mediated inhibition of the nociceptive responses evoked by AMPA. In conclusion, NOCI, acting at ORL1 receptors can, at least in part, induce spinal analgesia by blocking the nociceptive responses produced through the stimulation of AMPA receptors.     

Influence of age on venodilator effect of isoproterenol and amrinone

Objective: To investigate the influence of age on the venodilator effect of isoproterenol, a β-adrenoceptor agonist, and amrinone, a selective phosphodiesterase (PDE) III inhibitor, in human subjects. Methods: In eight young and eight elderly male subjects, the drugs were infused into a dorsal hand vein preconstricted with phenylephrine and its diameter was measured using a linear variable differential transformer. Results: The maximum venodilation (E_max) induced by isoproterenol was significantly smaller and the infusion rate of isoproterenol required to induce 50% of maximum venodilation (ED₅₀) was significantly larger in the elderly than in the young subjects [E_max: 29.8 vs 95.1%, ED₅₀: 97.3 vs 51.6 ng ⋅min^–1]. A significant age-related change in E_max or ED₅₀ was not observed for amrinone (E_max: 95.8 vs 100.8%, ED₅₀: 40.1 vs 31.6 μg ⋅min^–1). Conclusion: The data show that the venodilator effect of amrinone is not influenced by age. As amrinone increases cyclic AMP by inhibition of PDE III, it is suggested that the action of cyclic AMP is not altered by age. The decreased effect of isoproterenol might be caused by reduced production of cyclic AMP in elderly subjects. Received: 18 April 1995/Accepted in revised form: 15 August 1995     

Synthesis and Biological Activity of Some Mono- and Bis-ω-Ammonioalkyluracil Bromides

Compounds possessing anticholinesterase activity have been found in a series of mono- and bis-tetraalkylammonium derivatives containing uracil cycles at various distances from onium groups. These compounds are subdivided into high/moderate toxicity (in mice) and low/zero toxicity (in daphnia). Under the functional loading conditions (treadmill test in mice upon i.p. drug injection), compounds with an alkylammonium chain length of n = 5 are more effective and less toxic than the reference drugs (proserine [neostigmine] and BW284c51) and induce the development of a clearly pronounced myorelaxant effect with a duration of not less than 5 days with ED₅₀ = 0.06 – 0.13 μM/kg and LD₅₀/ED₅₀ = 20.0 – 188.0. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 5, pp. 15 – 19, May, 2005.     

Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 μg kg^–1, i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED ₅₀) were, respectively, 117±21 μg kg^–1 (251±45 nmol kg^–1) and 184±42 μg kg^–1 (396±91 nmol kg^–1); the highest dose caused reductions of 84±3% and 77±4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT_1B/1D receptor antagonist GR127935 (0.5 mg kg^–1). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT_1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients. Received: 9 February 1998 / Accepted: 28 March 1998     

Morphine as a discriminative cue in gerbils: Drug generalization and antagonism

Gerbils were trained in an electrified, T-shaped maze to discriminate between one of the three training doses of morphine (8, 16, or 32 mg/kg) and the nondrug condition. The rate of acquisition of the morphine discriminations was a function of dose, the high dose being the most rapidly discriminable condition. Dose generalization tests with morphine showed that the higher the training dose, the higher the ED₅₀ value in producing 50% morphine-appropriate responding. Antagonism of the discriminable effects of morphine by naltrexone (dose range tested: 0.025–0.40 mg/kg) also was related to the training dose of morphine; i.e., the higher the training dose of morphine, the higher the corresponding ED₅₀ value for blockade by naltrexone. A stereoisomeric requirement for morphine discrimination was evident since levorphanol, but not the analgesically inactive dextrophan, yielded morphine-appropriate responses when tested by substitution.A portion of the results was presented at the Fifth Scandinavian Meeting on Physiology and Behavior, May 20–22, 1977, Helsinki, Finland     

Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol

Rationale Drug discrimination can be used to examine tolerance and dependence in agonist-treated animals by establishing an appropriate antagonist as a discriminative stimulus.Objective Establish intravenous SR 141716A as a discriminative stimulus in four rhesus monkeys pretreated with a relatively small dose of Δ⁹-tetrahydrocannabinol (Δ⁹-THC).Methods Rhesus monkeys received i.v. Δ⁹-THC (0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5 schedule of stimulus-shock termination.Results The discriminative stimulus effects of SR 141716A were dose-dependent (ED₅₀=0.33 mg/kg) and were mimicked by the CB₁ antagonist AM 251 (ED₅₀=0.98 mg/kg), but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose (0.32 mg/kg in addition to 0.32 mg/kg administered before the session) of Δ⁹-THC shifted the SR 141716A dose–effect curve 3-fold rightward. Omitting Δ⁹-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Δ⁹-THC (ED₅₀=0.13 mg/kg), CP 55940 (ED₅₀=0.013 mg/kg), and WIN 55212-2 (ED₅₀=0.35 mg/kg); midazolam and ketamine did not attenuate responding on the SR 141716A lever. SR 141716A (1 mg/kg) shifted the Δ⁹-THC and CP 55940 dose–effect curves 3.4-fold rightward; the WIN 55212-2 dose–effect curve was not significantly modified by a dose of 1 mg/kg of SR 141716A.Conclusions SR 141716A can be established as a discriminative stimulus in animals pretreated with Δ⁹-THC, and this assay is selective for cannabinoid activity. Differential antagonism of cannabinoids by SR 141716A might indicate that the mechanism of action of WIN 55212-2 is not identical to other cannabinoids. This study demonstrates that, under the appropriate conditions, drug discrimination has utility for examining cannabinoid dependence and withdrawal.     

Discriminative stimulus effects of S(−)–methcathinone (CAT): a potent stimulant drug of abuse

Methcathinone (“CAT”) is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the present study, S(−)-methcathinone [S(−)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established, the S(−)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60–90 min. In tests of stimulus generalization (substitution), the S(−)-CAT (ED₅₀ = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED₅₀ = 0.17 mg/kg), S(−)-cathinone (ED₅₀ =  0.19 mg/kg), S(+)-amphetamine (ED₅₀ = 0.23 mg/kg), aminorex (ED₅₀ = 0.27 mg/kg), (±)-CAT (ED₅₀ = 0.25 mg/kg), (±)-cathinone (ED₅₀ = 0.41 mg/kg), R(+)-CAT (ED₅₀ = 0.43 mg/kg), cis-4-methylaminorex (ED₅₀ = 0.49 mg/kg), methylphenidate (ED₅₀ = 0.83 mg/kg), and cocaine (ED₅₀ = 1.47 mg/kg). S(−)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol (AD₅₀ = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(−)-CAT stimulus. It is concluded that S(−)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic mechanism. Received: 4 August 1997/Final version: 27 March 1998     

Discriminative stimulus control with olanzapine: generalization to the atypical antipsychotic clozapine

 The present study was conducted to determine if the putative atypical antipsychotic olanzapine could be established as a discriminative stimulus in rats. Seven rats were successfully trained to discriminate olanzapine (0.5 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure (mean number of acquisition sessions=39.3). Generalization testing with olanzapine (0.0625–2.0 mg/kg) yielded an ED₅₀ of 0.170 mg/kg (95% confidence interval=0.118–0.246 mg/kg). The atypical antipsychotic clozapine (0.156–10.0 mg/kg) fully substituted for olanzapine in all rats at the 2.5 mg/kg dose with 99.0% drug-lever responding, in six rats at the 0.625 mg/kg dose, and in five rats at the 1.25 and 5.0 mg/kg doses (ED₅₀=0.259 mg/kg, 95% confidence interval=0.089–0.755 mg/kg). This study is the first demonstration that rats can be trained to discriminate olanzapine from vehicle in a two-lever drug discrimination procedure and that the olanzapine discrimination cue generalizes to clozapine. Received: 11 June 1996 / Final version: 19 July 1996     

Effects of avitriptan, a new 5-HT1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential

Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-N-methyl-1H-indole-5-methanesulfonamide monofumarate), a new 5-HT_1B/1D receptor agonist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 μg·kg^–1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean ± SEM i.v. dose of avitriptan eliciting a 50% decrease (ED₅₀) in the porcine carotid arteriovenous anastomotic blood flow was calculated to be 76 ± 23 μg·kg^–1 (132 ± 40 nmol·kg^–1) and the highest dose (300 μg·kg^–1) produced a 72 ± 4% reduction. In recent comparative experiments (DeVries et al. 1996), the mean ± SEM ED₅₀ (i.v.) of sumatriptan in decreasing carotid arteriovenous anastomotic blood flow was 63 ± 17 μg·kg^–1 (158 ± 43 nmol·kg^–1), with a reduction of 76 ± 4% by 300 μg·kg^–1, i.v. Both avitriptan (pD₂: 7.39 ± 0.09; E_max: 13.0 ± 4.5% of the contraction to 100 mM K⁺) and sumatriptan (pD₂: 6.33 ± 0.09; E_max: 15.5 ± 2.3% of the contraction to 100 mM K⁺) contracted the human isolated coronary artery. The above results suggest that avitriptan should be able to abort migraine headaches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demonstrated the therapeutic action of the drug in acute migraine. Received: 23 August 1996 / Accepted: 19 October 1996     

Synthesis and hemolytic activity of cyclopentane and hydrindane 2-acetyl-1,3-diones

A series of 16 cyclopentane and hydrindane 2-acetyl-1,3-diones were synthesized. The hemolytic properties of these compounds were studied on erythrocytes of white mongrel mice at various pH values. Bifosin (bifonazole), saponin (Fluka, BioChemika, Germany), and triton X-100 were used as reference preparations. It was found that 2-acetylcyclopent-4-ene-1,3-dione (III), 2-acetyl-4-chlorocyclopent-4-ene-1,3-dione (VI), 2-acetyl-4-bromocyclopent-4-ene-1,3-dione (VII), and 2-acetyl-4,5-dichlorocyclopent-4-ene-1,3-dione (IX) exhibited rather strong (as compared to bifosin and saponin) hemolytic action on erythrocytes. The effect was more pronounced at pH 7.4 (ED₅₀ = 0.42 – 4.9 μg/mL) than at pH 6.0 (ED₅₀ = 6.5 – 39.9 μg/mL). It was also established that triketones I, XI, and XV exhibited selective hemolytic effects at pH 6.0. However, the level of their activity was not sufficiently high (ED₅₀ = 55.6 – 72.6 μg/mL). Some of the studied compounds are of interest as potential cytotoxic and antitumor agents.     

Pharmacological characterization of the nociceptin receptor mediating hyperphagia: identification of a selective antagonist

Rationale: Central injections of nociceptin (NC) stimulate feeding in rats. Objective: The present study evaluated the effect of N-terminal partial sequences or analogues of NC on food intake in male Wistar rats, to characterize pharmacologically the NC receptor mediating the hyperphagic effect. Methods: NC and related peptides were injected into the lateral (LV) or third (3V) cerebroventricle in freely feeding rats. Results: In the LV, NC stimulated feeding. The N-terminal fragment NC(1–13)NH₂ proved to be the least active sequence with hyperphagic activity; NC(1–12)NH₂ and NC(1–9)NH₂ were inactive. [Phe¹ψ(CH₂-NH)Gly²]NC(1–13)NH₂ ([F/G)]NC(1–13)NH₂), an analogue of NC(1–13)NH₂, markedly stimulated feeding and, coadministered in the LV with NC, never reduced the hyperphagic effect of the natural sequence. These findings suggest that [F/G)]NC(1–13)NH₂, which has been reported to act as a NC receptor antagonist in peripheral tissues, be- haves as a full agonist at the central NC receptors controlling feeding. The hyperphagic potencies of NC and [F/G)]NC(1–13)NH₂ were much higher following injection into the 3V than in the LV. Another analogue of NC(1–13)NH₂, namely [Nphe¹]NC(1–13)NH₂, injected into the 3V did not stimulate feeding, but reduced the effect of NC. [Nphe¹]NC(1–13)NH₂ at a dose of 16.8 nmol/rat significantly reduced, and at 168 nmol/rat almost completely abolished the effect of NC (1.68 nmol/rat). The latter dose of [Nphe¹]NC(1–13)NH₂ significantly reduced also feeding induced by food deprivation, but did not modify the hyperphagic effect of neuropeptide Y (0.3 nmol/rat). Conclusions: The present results confirm the orexigenic effect of NC in freely feeding rats and indicate that [Nphe¹]NC(1–13)NH₂ may represent a selective NC receptor antagonist to study the physiological and pathophysiological role of NC in feeding behaviour. Received: 18 July 1999 / Final version: 30 September 1999     

Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat

1. The present study was designed to investigate further the effects of the newly discovered orphanin FQ (OFQ)–the endogenous ligand for the orphan opioid receptor (called, e.g., ORL₁ and LC132)–on pain modulation in the rat. We used the tail-flick assay as a nociceptive index.
2. When injected into a cerebral ventricle, OFQ (4 fmol–10 nmol) has no effect on basal tail-flick latency by itself at any dose, but dose-dependently antagonizes systemic morphine analgesia (400 fmol–50 nmol).
3. Injected intrathecally, OFQ (3 and 10 nmol) displayed an analgesic effect without producing motor dysfunction, and potentiated morphine analgesia (1 and 10 nmol).
4. The anti-opioid effect of OFQ in rat brain and the high level of expression of LC132/ORL₁ receptor in the locus coeruleus indicated a possible role of OFQ in the precipitation of opiate withdrawal symptoms. However, no such precipitation was observed by OFQ in morphine-dependent rats.

     

Effects of L-trans-pyrrolidine-2,4-dicarboxylate, a glutamate uptake inhibitor, on NMDA receptor-mediated calcium influx and extracellular glutamate accumulation in cultured cerebellar granule neurons

Glutamate uptake inhibitor, L-trans-pyrrolidine-2,4-dicarboxylate (PDC, 20 μM) elevated basal and N-methyl-D-aspartate (NMDA, 100 μM)-induced extracellular glutamate accumulation, while it did not augment kainate (100 μM)-induced glutamate accumulation in cultured cerebellar granule neurons. However, pretreatment with PDC for 1 h significantly reduced NMDA-induced glutamate accumulation, but did not affect kainate-induced response. Pretreatment with glutamate (5 μM) for 1 h also reduced NMDA-induced glutamate accumulation, but did not kainate-induced response. Upon a brief application (3–10 min), PDC did neither induce elevation of intracellular calcium concentration ([Ca²⁺]_i) nor modulate NMDA-induced [Ca²⁺]_i elevation. Pretreatment with PDC for 1 h reduced NMDA-induced [Ca²⁺]_i elevation, but it did not reduce kainate-induced [Ca²⁺]_i elevation. These results suggest that glutamate concentration in synaptic clefts of neuronal cells is increased by prolonged exposure (1 h) of the cells to PDC, and the accumulated glutamate subsequently induces selective desensitization of NMDA receptor.     

The effects of benzamide analogues on cocaine self-administration in rhesus monkeys

Rationale: Based on the differential distribution of dopamine (DA) D₃ receptors in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that D₃-selective antagonists (i.e., higher affinity at D₃- than D₂-receptors) would be more potent than D₂-selective antagonists at decreasing total cocaine intake relative to disrupting rates of responding. Objective: To evaluate the effects of acute administration of seven DA antagonists with varying affinities for D₂ and D₃ receptors in monkeys self-administering cocaine. Methods: Rhesus monkeys were trained to self-administer intravenous cocaine (0.01–0.3 mg/kg per injection) under a fixed-interval (FI) 5-min schedule during daily 4-h sessions. The use of a FI schedule allowed for independent assessment of rate effects and changes in reinforcement frequency as a consequence of drug pretreatments. The compounds examined, in order of D₃ binding affinity, were: 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3.1]nonan-3β-yl benzamide (MABN) = eticlopride = 5-bromo- 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benz-amide (BBP) > spiperone > fluoroclebopride (FCP) > 2,3-dimethoxy-N-(p-fluorobenzyl)piperdin-4-yl benzamide (MBP) > haloperidol. Results: In the absence of any pretreatments, cocaine-maintained responding varied as a function of dose and was characterized as an inverted U-shaped function, while cocaine intake increased in a dose-related fashion. When the dose of cocaine that maintained peak rates was available, all DA antagonists decreased response rates and cocaine intake in a dose- dependent manner. Increases in cocaine dose attenuated the effects of the DA antagonists, resulting in rightward shifts of the cocaine dose–response curves. Based on the ratio of behavioral potency at decreasing response rates relative to intake (ED₅₀ rate/ED₅₀ intake) when the highest cocaine dose was available, the order of potency and ED₅₀ ratio values were: MABN (2.5) > eticlopride (1.63) > BBP = spiperone (1.5) > FCP (1.35) > MBP = haloperidol (0.89). This order parallels each compound’s affinity at D₃ receptors (r ²=0.84) to a greater degree than D₂ receptor affinity (r ²=0.34). Conclusions: These results, using a FI schedule of cocaine self-administration, suggest that D₃ receptor antagonists are more likely to selectively decrease intake relative to response rates than D₂ receptor antagonists. Received: 8 January 1999 / Final version: 15 June 1999     

Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat

 The potential of centrally (ICV) or systemically (SC) administered M6G to substitute for morphine in a drug discrimination task was characterized in the present study. Rats with a cannula in the lateral cerebral ventricle were trained to discriminate between injections of morphine (3 mg/kg, SC) and saline using a discrete-trial avoidance/escape procedure. Substitution tests were conducted with SC or ICV morphine, morphine-3-β-d-glucuronide (M3G), or morphine-6-β-d-glucuronide (M6G) and response latency in a tail-flick test was measured before each session began. The stimulus effects of morphine (ED₅₀=1.02 mg/kg SC or 2.1 μg/kg ICV) were fully shared by M6G, with potency dependent on route of administration (ED₅₀=3.12 mg/kg SC or 0.34 μg/kg ICV). The stimulus effects of M6G were highly correlated with its antinociceptive activity (r=0.84 SC or 0.46 ICV) and, at equipotent systemic doses, they lasted longer (t1/2=391 min) than those of morphine (t1/2=185 min). M3G was inactive in both procedures by both routes of administration. Naltrexone SC, given 30 min prior to testing, completely attenuated the stimulus effects of ICV M6G (AD₅₀=0.011 mg/kg), indicating that they are mediated by opioid receptors. The results of this study suggest that M6G might contribute to the interoceptive effects of morphine that underlie its potential for abuse. Received: 29 January 1998 / Final version: 21 March 1998     

Intrathecal N-methyl-D-aspartate (NMDA) induces paradoxical analgesia in the tail-flick test in rats

The intrathecal (IT) administration of NMDA in rodents has usually been reported to produce hyperalgesic reactions, although some articles describe that spinal NMDA can lead to analgesia. We show here that the nociceptive behavior (biting, scratching, licking; BSL) observed after NMDA injection (1-8 microg/rat; IT) is followed by a long period of increased tail-flick latencies, not longer detected 24 h after NMDA administration. The NMDA-receptor antagonist CPP (10-100 ng/rat; IT) blocked the BSL behavior induced by NMDA. In the tail-flick test, this antagonist induced analgesia by itself, and was able, at 30 ng/rat, to prevent the NMDA-mediated analgesia. The implication of opiate mechanisms was discarded since naloxone (3 and 10 mg/kg; IP) did not antagonize NMDA-induced analgesia. Finally, the involvement of the intracellular calcium binding protein calmodulin was assessed. The calmodulin inhibitor, calmidazolium (30-300 microg/rat; IT) only blocked the excitatory effect (BSL) without modifying the tail-flick analgesia produced by NMDA (4 microg). These results show that a single intrathecal administration of NMDA sequentially induces both nociceptive and antinociceptive, nonopiate responses in rats.