牙痛灵喷雾剂对小鼠实验性疼痛的镇痛作用

目的：观察牙痛灵喷雾剂的镇痛作用,为其临床应用提供一定的实验依据。方法：制备小鼠实验性疼痛模型,观察牙痛灵喷雾剂的镇痛作用。（1）扭体法：取昆明种小鼠50只,随机分为5组,每组10只,雌雄各半。空白对照组灌胃给予生理盐水10mL／kg;牙痛灵喷雾剂低、中、高剂量组分别灌胃牙痛灵喷雾剂0．36、1．08、3．24g／kg。阳性对照组灌胃阿司匹林0．4g／kg。每日用药1次,10d后观察各组动物腹腔注射醋酸后5～20min内的扭体反应次数。（2）热板法：将小鼠放在（55±1）℃的热板上,以小鼠舔后足为疼痛反应指标,观察小鼠的热痛阈值。选用痛觉阈值在5～30s的雌性小鼠50只,随机分为5组,每组10只,分组与给药方法与（1）同。给药10d后记录各组小鼠热板法痛阂值,比较各组间的差异。结果：（1）扭体法实验结果显示,牙痛灵喷雾剂0．36、1．08、3．24g／kg灌胃10d使腹腔注射醋酸所致的小鼠扭体反应次数较空白对照组明显减少,对扭体反应次数的抑制率分别为25．6％、30．6％和43．5％（P〈0．05,P〈0．01）。（2）热板法实验结果显示,给药前各组小鼠热痛阈值无统计学差异（P〉0．05）;给药10d后牙痛灵喷雾剂各剂量组小鼠热痛阂值均较给药前显著提高,与空白对照组比较,牙痛灵喷雾剂组给药后热痛阈值显著延长（P〈0．05,P〈0．01）。结论：牙痛灵喷雾剂对小鼠实验性疼痛具有良好的镇痛作用。     

New insights of dimethyl sulphoxide effects (DMSO) on experimental in vivo models of nociception and inflammation

DMSO is one of the most common solvents used experimentally to dissolve hydrophobic substances for in vivo and in vitro purposes. A wide range of pharmacological effects exerted by DMSO has been documented in both animal and human experimental models. However, only a few and sometimes contrasting data about the effects of DMSO in animal models of nociception and inflammation are presently available. In this study, we evaluated the effects induced by DMSO and a DMSO-containing saline on thermal and chemical nociception, inflammation and locomotor activity in CD1 mice. We demonstrated that centrally or orally administered DMSO displayed anti-nociceptive effects to thermal (hot plate and tail-flick test) and chemical (formalin test) stimuli. Conversely, DMSO was able to increase both nociceptive phases in the formalin test when applied subcutaneously in the dorsal surface of the mouse hind paws 10 min before formalin administration. Oral administration of DMSO produced anti-inflammatory effects on zymosan-induced edema in the mouse paw, whereas local administration potentiated the inflammatory action exerted by zymosan. Oral and central, but not local, administration of DMSO improved the mouse locomotor activity. These results suggest that DMSO displayed opposite effects on nociception and inflammation, depending on the route of administration. New and helpful evidence about DMSO laboratory applications need to be considered in the in vivo studies to assess correctly the pharmacological properties of investigated drugs.     

Effects of (-)-linalool in the acute hyperalgesia induced by carrageenan, L-glutamate and prostaglandin E2

A series of studies performed in our laboratory have shown that (-)-linalool, the natural occurring enantiomer in essential oils, possesses anti-inflammatory and antinociceptive effects in different animal models. The antinociceptive effect of (-)-linalool has been ascribed to the stimulation of the cholinergic, opioidergic and dopaminergic systems, to its local anesthetic activity and to the blockade of N-methyl-D-aspartate (NMDA) receptors. In this study, we investigated the effect of systemic administration of (-)-linalool in the paw withdrawal test in rats, a model of thermal hyperalgesia induced by monolateral subplantar injection of carrageenan, L-glutamate or prostaglandin E(2). Carrageenan and L-glutamate induced a hyperalgesic effect on the injection side. In contrast, prostaglandin E(2) induced hyperalgesia in both the injection side and the contralateral side. Pretreatment with (-)-linalool (50-150 mg/kg) inhibited the development of acute hyperalgesia induced by carrageenan in the injected paw, with no effect on the contralateral paw. Furthermore, (-)-linalool at the highest dose used (200 mg/kg), reduced and reverted the decrease in paw withdrawal latencies induced by L-glutamate on the ipsilateral side, showing antihyperalgesic and antinociceptive effects. An antinociceptive effect was apparent also in the contralateral paw. Finally, (-)-linalool (200 mg/kg) increased paw withdrawal latency on the side contralateral to prostaglandin E(2) injection, but not on the side of the injection. The efficacy of (-)-linalool in decreasing the hyperalgesia induced by carrageenan, L-glutamate and prostaglandin E(2) suggests that this compound might be useful in pain conditions sustained by the development of neuronal sensitization.     

Analgesic activity of 3-mono-substituted derivatives of dihydrofuran-2-one in experimental rodent models of pain

Three derivatives of dihydrofuran-2-one (L-PP, L-PP1, and L-SAL) were administered by intraperitoneal injection and their analgesic activity was assayed in several models of pain. The activity of these derivatives were tested using a hot plate test, a writhing test, capsaicin- and glutamate-induced nociception, along with two models of local anesthesia, including a test for infiltration anesthesia in guinea pigs and the modified tail immersion test in mice. The results of these in vivo experiments show that these three derivatives of dihydrofuran-2-one possess analgesic activity in rodents. The ED₅₀ values of the tested compounds are lower or comparable to the ED₅₀ values of reference compounds (acetylsalicylic acid or morphine). For the most active derivative of dihydrofuran-2-one, L-PP1 (3-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride), the ED₅₀ value was: 1.34 mg/kg, 0.79 mg/kg, 2.01 mg/kg and 3.99 mg/kg in the hot plate, writhing, capsaicin- and glutamate-induced pain tests, respectively.     

Antidepressant and antinociceptive activities in animal models and in vitro assessment of the anti-thyroid activity of bis(DL-pyroglutamate)magnesium complex

BackgroundMagnesium is an essential element related with biochemistry of the brain and different types of depression have been associated with its deficiency.MethodsThe structure of a novel magnesium bis(DL-pyroglutamate) (Mg(DL-pGlu)₂) was elucidated by X-ray crystallography. Wistar rats were used in the in vivo experiments. The antidepressant-like effect was assessed by the forced swim test (FST) and the antinociceptive activity was evaluated using hot plate test. In both, non-specific effects were evaluated by the open field test. Anti-thyroid activity was examined using Lang’s method. Albumin binding behavior was evaluated by 3D fluorescence spectroscopy.ResultsFor the Mg(DL-pGlu)₂ complex (30 mg/kg), the FST test on Wistar rats revealed a decrease of 22% in the immobility time and an increment of 106% in the swimming time. The compound alters neither the locomotor activity nor the body weight after chronic administration. At the same dose, it showed antinociceptive activity, increasing the response latency. It blocks iodination reactions generating a charge transfer complex with iodine hence indicating anti-thyroid activity (K_c = 45366.5 ± 29 M^?1). Albumin 3D fluorescence spectroscopy experiments showed intensity increase of peak A and decrease of peak B.ConclusionsThe results showed that the new compound produced a lowering of the immobility time and an increment of the swimming ability of the rats. The compound is able to increase the response latency in 70.0%, to capture iodine (anti-thyroid activity) and to interact with albumin through covalent type of interaction of the free NH groups.     

Genotoxic effects of (-)-cubebin in somatic cells of mice

(?)‐Cubebin belongs to the dibenzylbutyrolactone lignan group, which is widely distributed in the plant kingdom. Because this compound shows interesting biological activities, it is extremely important to evaluate its possible genotoxic activity to allow its safe use in humans. Thus, the present study was performed to investigate the genotoxicity potential activity of (?)‐cubebin assessed by two assays: micronucleus in bone marrow cells and comet test in peripheral blood leukocytes of Swiss mice. In the (?)‐cubebin dose range‐finding assays, the maximum tolerated dose was greater than 2000 mg kg^?1. The compound was administered by an oral route at single doses of 250, 500 and 2000 mg kg^?1 body weight. Cytotoxicity was assessed by scoring 200 consecutive total polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE/NCE ratio). Under our experimental conditions, micronucleus and comet assays, respectively, showed that (?)‐cubebin caused dose‐related clastogenic and genotoxic effects in the somatic cells investigated. PCE/NCE ratio showed no cytotoxicity for the three doses of the compound. The data suggest caution in the ingestion of (?)‐cubebin by humans, especially at high doses. Copyright © 2010 John Wiley & Sons, Ltd.     

Identification of two biologically crucial hydroxyl groups of (-)-epigallocatechin gallate in osteoclast culture

(-)-Epigallocatechin gallate (EGCG) induces cell death of osteoclasts in an Fe(2+)- and H(2)O(2)-dependent manner. In the present study, we further explore the cytotoxic mechanism of EGCG using four EGCG analogues. Molecules methylated at position 4' in the B ring (EGCG-4'-O-Me) or at position 4' in the D-ring (EGCG-4'-O-Me) showed markedly decreased cytotoxicity to osteoclasts, indicating that hydroxyl groups at these two positions of EGCG are crucial for inducing cell death of osteoclasts. EGCG-4'-O-Me also showed the lowest Fe(3+)-reducing activity among five EGCGs. The Fe(3+)-reducing activity of EGCG was enhanced under conditions whereby protonated EGCG levels were increased, indicating that the protonated status of EGCG was involved in the Fe(3+)-reducing activity. The hydroxyl group at position 4' in the D-ring was shown by quantum chemical calculation to be preferentially deprotonated among all of the hydroxyl groups in EGCGs. It was also shown that the highest occupied molecular orbital (HOMO) was localized to the B-ring of EGCGs, except for EGCG-4'-O-Me. We report here that the HOMO on the B-ring plays crucial roles in both the Fe(3+)-reducing activity of EGCG and the cytotoxicity of EGCG to osteoclasts, while deprotonation of the hydroxyl group at position 4' in the D-ring plays a supplementary role.     

Synthesis and antinociceptive activity of (5-chloro-2(3<Emphasis Type="Italic">H</Emphasis>)-benzoxazolon-3-yl) propanamide derivatives

In this study, (5-chloro-2(3H)-benzoxazolon-3-yl)propanamide derivatives were synthesized. The chemical structures of the compounds were elucidated by their IR and 1H-NMR spectral data and microanalysis. The compounds were tested for antinociceptive activity by using the tail clip, tail flick, hot plate, and writhing methods. The varying levels of antinociceptive activity of the compounds were compared with those of dipyrone and aspirin. Among these compounds, compound 5e, 5g, and 5h have been found to be significantly more active than the others and the standards in all the tests.     

Lack of antinociceptive activity of clonidine in two pain models: Comparison with other analgesics and CNS active drugs

The antinociceptive activity of clonidine was investigated in two models of pain using the modified Haffner tail clip test (MHA) in mice and the formalin test (FT) in rats. Morphine was used as a positive control for comparison. Clonidine at does from 0.5 mg/kg to 8 mg/kg SC was not effective in MHA while morphine administration resulted in a dose-dependent increase in the latency to bite the clip and an ED₅₀ of 1.2 mg/kg SC. No antinociceptive activity was observed for clonidine using the FT up to a dose of 4 mg/kg SC which causes severe behavioral depression. The ED₅₀ for morphine in FT was 1.7 mg/kg SC. From these studies we conclude that clonidine is not active in all tests used to predict analgesic efficacy in man. Additional analgesic and centrally acting drugs were also included for comparative purposes. Of the compounds tested only the opiates active in FT and MHA and cholinesterase inhibitors (active in MHA only) showed analgesic effects.     

Anti-inflammatory effects of compounds alpha-humulene and (-)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea

This study evaluated the anti-inflammatory properties of two sesquiterpenes isolated from Cordia verbenacea's essential oil, alpha-humulene and (-)-trans-caryophyllene. Our results revealed that oral treatment with both compounds displayed marked inhibitory effects in different inflammatory experimental models in mice and rats. alpha-humulene and (-)-trans-caryophyllene were effective in reducing platelet activating factor-, bradykinin- and ovoalbumin-induced mouse paw oedema, while only alpha-humulene was able to diminish the oedema formation caused by histamine injection. Also, both compounds had important inhibitory effects on the mouse and rat carrageenan-induced paw oedema. Systemic treatment with alpha-humulene largely prevented both tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) generation in carrageenan-injected rats, whereas (-)-trans-caryophyllene diminished only TNFalpha release. Furthermore, both compounds reduced the production of prostaglandin E(2) (PGE(2)), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) expression, induced by the intraplantar injection of carrageenan in rats. The anti-inflammatory effects of alpha-humulene and (-)-trans-caryophyllene were comparable to those observed in dexamethasone-treated animals, used as positive control drug. All these findings indicate that alpha-humulene and (-)-trans-caryophyllene, derived from the essential oil of C. verbenacea, might represent important tools for the management and/or treatment of inflammatory diseases.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Study of ocular pharmacokinetics of in situ gel system for S(-)-satropane evaluated by microdialysis

S(-)-Satropane is currently being developed to in situ forming ophthalmic gel, a new ophthalmic delivery system, for the treatment of glaucoma. To evaluate the pharmacokinetic profiles of S(-)-satropane, the microdialysis method was employed. The concentration of S(-)-satropane in dialysates was measured by using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Unlike the common solution prepared in normal saline, in which the level of S(-)-satropane in aqueous humor increased rapidly after instillation and reached the maximal level (C(max) of 1.508+/-0.297 microg ml(-1)) within 1h, S(-)-satropane exhibited 3.2-fold greater C(max) and 2.2-fold greater AUC(0-3h) (p<0.05) in the in situ forming gel. The results showed that the in situ forming gel system could improve the ocular bioavailability of S(-)-satropane.     

(-)-Hinokinin causes antigenotoxicity but not genotoxicity in peripheral blood of Wistar rats.

(-)-Hinokinin, a dibenzylbutyrolactone lignan, exhibits significant trypanocidal activity both in vitro and in vivo, and was obtained by partial synthesis from (-)-cubebin isolated from the dry seeds of Piper cubeba. Considering the good trypanocidal activity of (-)-hinokinin, as well as its potential for the development of new drugs, it is extremely important to evaluate its possible mutagenic activity to allow its safe use in humans. In the present study, we evaluated the antimutagenic effect of (-)-hinokinin on the chromosome damage induced by the chemotherapeutic agent doxorubicin (DXR). The test system employed was the analysis of micronucleated polychromatic erythrocytes in peripheral blood of Wistar rats. Additionally, the antioxidant activity of (-)-hinokinin was evaluated in in vitro experiments by measuring the production of hydrogen peroxide and other peroxides. Our results showed that animals treated with different doses of (-)-hinokinin (10, 20, and 40mg/kgb.w.) exhibited micronucleated cell frequencies similar to that of the negative control. In addition, treatment with combinations of (-)-hinokinin and DXR resulted in lower micronucleated cell frequencies than those observed for animals treated with DXR alone. The present study shows that (-)-hinokinin not only has no genotoxic effect, but is also effective in reducing the chromosome damage induced by DXR. (-)-Hinokinin exerted a significant antioxidant effect on parasite mitochondria in the protocol used, which might be one possible mechanism by which this compound may exert a protective effect on the chromosome damage induced by the free radicals generated by DXR.     

Anticonvulsant and neuroprotective effect of (S)-3,4-dicarboxyphenylglycine against seizures induced in immature rats by homocysteic acid

The present study has examined the anticonvulsant and neuroprotective effect of (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG), a highly selective agonist for subtype 8 of group III metabotropic glutamate receptors (mGluRs), against seizures induced in immature 12-day-old rats by bilateral icv infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the animals which had received (S)-3,4-DCPG (0.25 nmol/each side, 15-20 min prior to infusion of DL-HCA or saline). This agonist provided a pronounced anticonvulsant effect, generalized clonic-tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these seizures were either normalized (decrease of glucose and glycogen) or markedly reduced (an accumulation of lactate). Anticonvulsant effect of (S)-3,4-DCPG was also evident from the EEG recordings, nevertheless, it was not complete. In spite of the absence of obvious motor phenomena, sporadic ictal activity could be seen in some animals. Isolated spikes could also be observed in some animals after administration of (S)-3,4-DCPG alone. The neuroprotective effect of (S)-3,4-DCPG was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas pretreatment with (S)-3,4-DCPG provided substantial neuroprotection. The present findings suggest that receptor subtype 8 of group III mGluRs may be considered a promising target for drug therapy in childhood epilepsies in the future.     

The dietary flavonoids apigenin and (-)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA(A) receptors

The dietary flavonoids apigenin, genistein and (-)-epigallocatechin gallate (EGCG) inhibited the activation by GABA (40 microM) of recombinant human alpha1beta2gamma2L GABA(A) receptors expressed in Xenopus laevis oocytes with IC(50) values of 8, 30 and 15 microM, respectively. Apigenin and genistein also acted as GABA antagonists at flumazenil-insensitive alpha1beta2 GABA(A) receptors, indicating that they were not acting as negative modulators through flumazenil-sensitive benzodiazepine sites on GABA(A) receptors. In addition to these GABA(A) antagonist effects, a novel second order modulatory action was found for apigenin and EGCG on the first order enhancement of GABA responses by diazepam. Apigenin (1 microM) and EGCG (0.1 microM) enhanced the modulatory action of diazepam (3 microM) on the activation by GABA (5 microM) of recombinant human alpha1beta2gamma2L GABA(A) receptors by up to 22% and 52%, respectively. This was not found with genistein, nor was it observed with enhancement by allopregnanolone or pentobarbitone.     

Neurobehavioral and physiological effects of low doses of polybrominated diphenyl ether (PBDE)-99 in male adult rats

Polybrominated diphenyl ethers (PBDEs) are flame retardants. Because of their high lipophilicity and persistence, PBDEs bioaccumulate in all abiotic and biological matrices. The aim of this study was to investigate the long-term neurobehavioral and physiological effects of exposure to environmental doses of PBDE-99 in adult rats. Rats received a daily administration of PBDE-99 for 90 days by oral gavage at 0.15, 1.5 and 15 μg/kg, doses which are relevant of human exposure. Before and after the 90 days of exposure, behavioral tests including the open-field and the elevated plus-maze tests for locomotor activity and anxiety, and the Morris water maze for spatial learning were conducted. Physiological measures such as body weight, food and water consumption, organs weight, hepatic enzymes levels and PBDE-99 concentration in adipose tissue were also evaluated at the end of exposure. There was no effect on body weight, food and water consumption, organs weight, hepatic enzymes levels despite rising PBDE-99 concentration in adipose tissue with the doses tested. Moreover, there was no effect on locomotor activity and exploration, and spatial learning. Deleterious effects of PBDE-99 at high doses have often been highlighted in many studies after an acute dose whereas exposure during 90 days at realistic doses would have no significant effect in adult rats.     

Prior,repeated exposure to cocaine potentiates locomotor responsivity to central injections of corticotropin-releasing factor (CRF) in rats

Rationale There is considerable evidence that the stress-related neuropeptide, corticotropin-releasing factor (CRF), plays an important role in mediating behavioural changes induced by prior experience with cocaine. From this perspective, it is conceivable that repeated exposure to cocaine induces a form of sensitization in CRF systems that makes animals more responsive to CRF following prolonged drug-free periods.Objectives To study the effects of repeated cocaine exposure on locomotor activity induced by different doses of CRF after drug-free periods ranging from 24 h to 28 days.Methods Male Wistar rats were injected once daily for 7 days with cocaine (15 mg/kg, IP on days 1 and 7 in locomotor chambers; 30 mg/kg, IP, on days 2–6 in home cages) or saline. In experiment 1, starting 10 days after the last injection, animals were tested for their locomotor response to intracerebroventricular (ICV) injections of vehicle and three doses of CRF (0.25, 0.5, and 5 µg). In experiment 2, animals were tested for their locomotor response to ICV injections of 0.5 µg CRF after drug-free periods of 1–2, 10–11 and 28–29 days.Results Compared to saline pre-exposed animals, cocaine pre-exposed animals showed a significantly greater locomotor response to CRF, relative to vehicle, at all doses tested (experiment 1) and after drug-free periods of up to 28 days (experiment 2). The effects were clear and extremely consistent in magnitude between experiments and conditions.Conclusions These results suggest that cocaine pre-exposure induces long-term changes in the responsivity of the central nervous system to CRF.     

8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物的设计、合成及抗真菌活性研究

目的 设计、合成一系列 8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物,测定其体外抗真菌活性。方法 以邻氟苯胺为起始原料,经与丙烯酸加成、在多聚磷酸（PPA）中环合制得中间体8-氟-2,3-二氢喹啉-4(1H)-酮;该中间体与各种 N⁴-取代的氨基脲缩合得到目标化合物。采用二倍浓度稀释法测试各目标化合物的体外抗真菌活性,实验选用 8 种临床上常用的致病真菌为测试菌株,以氟康唑、伊曲康唑为阳性对照药。结果与结论 16 个 8-氟-2,3-二氢喹啉-4(1H)-酮缩氨基脲类化合物均未见文献报道,其结构经¹H-NMR、MS 谱确证;活性测试结果表明,合成的多个目标化合物对测试真菌表现出较好的体外抑菌活性,尤其是对红色毛藓菌的活性均好于阳性对照药。     

The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol

Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively). NS7051 (1-30mg/kg, s.c.) produced a dose-dependent naloxone-reversible increase in the hot plate withdrawal latency, and was also analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception, NS7051 reversed flinching behaviours during interphase and second phase of the formalin test (ED(50)=1.7 and 1.8mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete Freund's adjuvant injection (ED50=1.2mg/kg, s.c.). In the chronic constriction injury model of neuropathic pain, mechanical allodynia and hyperalgesia were both reversed by NS7051 (ED50=6.7 and 4.9mg/kg, s.c.). Tramadol was also active in all pain models although at considerably higher doses (20-160mg/kg, s.c.). No ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for NS7051 and tramadol. The combined opioid receptor agonism and monoamine reuptake inhibitory properties of NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats.     

Behavioural effects of the nicotinic agonists N-(3-pyridylmethyl)pyrrolidine and isoarecolone in rats

The nicotinic agonists N-(3-pyridylmethyl)pyrrolidine (PMP) and isoarecolone have been compared with (–)-nicotine in three behavioural procedures and as inhibitors of [³H]-(–)-nicotine binding. Locomotor activity was recorded as movements between beams of infra-red light (ambulation). In experimentally naive rats, nicotine, PMP and isoarecolone reduced ambulation. In rats receiving nicotine chronically and previously exposed to the activity cages, nicotine and PMP increased ambulation in a dose-related manner. However, isoarecolone did not increase ambulation at doses that were active in other procedures. In rats trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement, there was full generalization to PMP. It was also found that PMP potently inhibited the binding of [³H]-(–)-nicotine to rat brain membranes in vitro. These results were discussed with previous data for the discriminative stimulus and ligand-binding effects of isoarecolone obtained under similar conditions. The relative potency of PMP in different behavioural procedures was similar to that of (–)-nicotine. However, isoarecolone was relatively 10 times more potent in decreasing ambulation than would have been expected from its potency in the ligand-binding and discriminative stimulus procedures. The results suggest that the pharmacodynamic action of isoarecolone differs from that of nicotine and PMP, and that it will be a useful probe in further analyses of central nicotinic mechanisms.