Search

Histamine activates pain-transmitting nerve fibres, releases pain-related neuropeptides, and is painful when injected into the skin. Histamine agonists mimic these effects, suggesting that histamine plays a role in mediating the signal transduction of tissue damage or other painful stimulus. Certain 'antihistamines' (histamine H1 receptor antagonists) and other antihistaminics are 'analgesic' in preclinical or clinical models. Potential sites of action of these agents include the brain and spinal cord and a specific histamine receptor subtype might be involved (three subtypes have been identified). However, it is possible that other mechanisms account for the analgesic effect.

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

The mechanism of the analgesic action of one of the world's most widely used drugs-acetaminophen (paracetamol)-remains largely unknown more than 100 years after its original synthesis. Based on the present findings, this elusiveness appears to have resulted from experimental strategies that concentrated on a single target site or mechanism. Here we report on the use of analyses that we previously developed to investigate possible brain/spinal-cord site-site interaction in acetaminophen-induced antinociception. Spinal (intrathecal) administration of acetaminophen to mice produced dose-related, naloxone-insensitive antinociception with an ED(50) value of 137 (S.E. = 23) microgram = 907 (S.E. =153) nmol. In contrast, supraspinal (i.c.v.) acetaminophen administration had no effect. However, combined administration of acetaminophen in fixed ratios to brain and spinal cord produced synergistic antinociception, ED(50) = 57 (S.E. = 9) microgram, that reverted toward additivity, ED(50) = 129 (S.E. = 23) microgram, when the opioid antagonist naloxone was given spinally (3.6 microgram = 10 nmol) or s.c. (3.6 mg/kg). These findings demonstrate for the first time that acetaminophen-induced antinociception involves a "self-synergistic" interaction between spinal and supraspinal sites and, furthermore, that the self-synergy involves an endogenous opioid pathway.

Objective: To summarize the published preclinical and clinical data that suggest the possible use of glutamate receptor agonists or antagonists as novel antipsychotic agents., Data Sources: Primary and review articles were identified by MEDLINE search (from 1966 to December 1999) and through secondary sources., Study Selection and Data Extraction: All of the articles identified from the data sources were evaluated and all information deemed relevant was included., Data Synthesis: The standard antipsychotic drugs, whose clinical activity correlates with affinity for dopamine D2 receptors, alleviate some of the positive symptoms of schizophrenia, but have limited impact on negative symptoms. Several lines of evidence implicate glutamate-receptor system dysfunction(s) in schizophrenia, either as causative or contributory factors. In addition, several standard antipsychotic drugs modulate glutamate or glutamate receptor activity, suggesting an alternative view of their mechanism of antipsychotic action. Preliminary studies have shown that drugs which modulate glutamate brain concentrations have positive effects in animal models of schizophrenia., Conclusions: A role for glutamate in the pathogenesis or pharmacotherapy of schizophrenia is suggested from anatomic (interactions between glutamatergic and dopaminergic systems in relevant brain regions), physiologic (implication of glutamate-receptor dysfunction), and pharmacologic (modulation of glutamate or glutamate receptors) evidence. Therefore, compounds that function at glutamate receptors might represent a novel approach to the treatment of the disease or to the amelioration of symptoms, either as monotherapy or as an adjunct to dopamine D2 receptor antagonists.

The subject of 'drug addiction' is multifaceted and many aspects of it (even some of the definitions) are controversial. Collateral medical problems include the spread of HIV and hepatitis C virus secondary to i.v. drug abuse and effects on prenatal brain development (1). Progress in the understanding of the causes of addictions and its treatment has been impeded by the lack of a unifying biochemical theory. However, recent evidence suggests that some common mechanism might underlie addictions to otherwise apparently unrelated drugs. A major hypothesis has emerged suggesting that the neurotransmitter dopamine (DA) might play a central role in the molecular mechanisms of at least some addictions. If so, it would represent an important target for discovery of effective pharmacotherapy and revolutionize the pharmacist's role in treating addictions. This short overview outlines the status of the theory of a common biochemical mechanism of drug addiction.

Opioid receptors are located throughout the respiratory tract. Yet, these have received relatively scant attention compared to other opioid receptors. The most abundant sites within the respiratory tract appear localized within the alveolar walls, other sites appear to line the smooth muscle within the trachea and main bronchi near the lumen. There is about 100-times greater [3H]morphine binding density within the bronchioles and lobes than in the main bronchi or trachea. In addition to the usual mu, delta and kappa types of opioid receptors, 'non-conventional' opioid binding sites have been suggested, although the function of these or of the other opioid receptors in the pulmonary tract is not known. However, they might explain the otherwise counterintuitive apparent utility of morphine treatment of dyspnea. Dyspnea is a common and distressing symptom in terminally-ill cancer patients and patients with chronic lung disease. It results from multiple causes, is difficult to treat and is a significant precipitating factor for late-stage hospital or hospice admissions. Nebulized morphine or other opioids have been reported to have beneficial effect, but the mechanism by which opioids might produce this seemingly contradictory effect is not clear. We review here lung opioid receptor distribution, pharmacology and possible clinical relevance in the treatment of dyspnea.

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).

Several lines of evidence implicate the neuropeptide substance P in depression, either in the pathogenesis or as a novel target for amelioration of symptoms. NK1 (substance P) receptor antagonists have been reported to have antidepressant-like actions in animal models. The first clinical trial of an NK1 antagonist showed promising results. A second trial, using a more potent compound, is underway. If the clinical trials show that NK1 (substance P) antagonism represents a well-tolerated, distinct mechanism for antidepressant activity, novel antidepressant agents will emerge as mono- or adjunct-therapy.

The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies., (Copyright 1999 Elsevier Science B.V.)

Objective: To review preclinical and clinical information related to pharmacologic modulation of dopamine D2 receptors as potential novel antipsychotic therapy. Specifically, to summarize the data that suggest a modulatory action of adenosine A2A receptors on dopamine D2 receptors and, therefore, a possible rational role of adenosine A2A agonists as novel antipsychotic agents., Data Sources: Primary and review articles were identified by MEDLINE search (from 1966 to May 1998) and through secondary sources., Study Selection and Data Extraction: All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review., Data Synthesis: For all of the older and many of the newer antipsychotic agents, there is a strong correlation between clinical antipsychotic activity and affinity for dopamine D2 receptors. Unfortunately, dopamine D2 receptors are believed to also be involved in the adverse effect profile of these agents. The indirect modulation of dopamine D2 receptors, rather than direct block, might produce antipsychotic effects without the usual adverse reactions. Several lines of evidence from animal studies suggest that the use of selective A2A agonists might represent a novel approach to the treatment of psychoses., Conclusions: Dopamine receptor modulation might represent a novel antipsychotic approach or adjunct therapy. The data regarding adenosine agonists (particularly selective A2A receptor agonists) are inconclusive at the present time. Direct clinical demonstration of effectiveness is required.

Graded doses of morphine sulfate and clonidine hydrochloride were administered intrathecally to mice that were then tested for antinociception in the 55 degrees C tail immersion test. The dose-effect relations of each compound were used in calculations that permitted the construction of a three-dimensional plot of the expected additive effect (vertical scale) against the planar domain of dose pairs representing combinations administered simultaneously. This additive response surface became the reference surface for viewing the actual effects produced by three different fixed-ratio combinations of the drugs that were used in our tests. Each combination produced effects significantly greater than indicated by the additive surface, thereby illustrating marked synergism and a method for quantifying the synergism. This quantification, measured by the value of the interaction index (alpha), was found to be dependent on the fixed-ratio combination; accordingly, the actual response surface could not be described by a single value of the index alpha. Furthermore, we found that application of the common method of isoboles gave estimates of the index that agreed well with those obtained from the more extensive surface analysis. These results confirm earlier studies, which found synergism for these drugs while also providing surface views of additivity and synergism that form the basis of isobolographic analysis.

A core concept in pharmacology is drug-receptor affinity, i.e., the tendency of a drug molecule to bind to one or more receptors due to the collective influence of multiple molecular forces. The estimation of affinity as a dissociation constant (reciprocal of the equilibrium constant) is extraordinarily valuable. However, elucidation of the nature of the underlying concept--i.e., what accounts for affinity--is not achievable using such a static measure. Observing how the system responds to a perturbation (e.g., to a change in temperature) reveals more fundamental information. The present review summarizes the general concepts of thermodynamic analysis applied to drug-receptor interactions and discusses 'extrathermodynamic' phenomena, such as enthalpy-entropy 'compensation'. Together, these concepts may provide insight into the nature of drug-receptor interactions, begin to elucidate the forces that underlie such interactions--and begin to define and refine more nebulous terms such as affinity.

Objective: To review preclinical information related to possible antidepressant mechanism(s) of action of St. John's wort in order to address the issue of whether its purported clinical effectiveness has a rational pharmacologic basis., Data Sources: Primary and review articles were identified by a MEDLINE search (1966-January 1998) and through secondary sources. Many of the original German articles had English abstracts, but where necessary, German articles were translated into English. The results of a new screen of hypericin activity at receptor and uptake sites are summarized., Study Selection and Data Extraction: All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review., Data Synthesis: The neuropharmacology of St. John's wort has been examined in only a few studies. A mechanism similar to that of the synthetic antidepressants, such as the selective serotonin-reuptake inhibitors or monoamine oxidase (MAO) inhibitors, might play a role, but other mechanisms are possible., Conclusions: Hypericum extracts have only weak activity in assays related to mechanisms of the synthetic antidepressants, that is, inhibition of MAO, catechol O-methyltransferase, or serotonin reuptake. It has been postulated that the clinical efficacy of St. John's wort could be attributable to the combined contribution of several mechanisms, each one too weak by itself to account for the overall effect. The recent demonstration of a significant affinity of hypericin for sigma receptors presents new possibilities for consideration.

The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid receptor stably expressed in Chinese hamster ovary (CHO) cells were investigated. For every ligand, the Kd or Ki values at 0 degrees C, 12 degrees C, 25 degrees C and 37 degrees C were determined, a van't Hoff plot was generated and deltaH degrees' , deltaS degrees' and -TdeltaS degrees' and deltaG degrees' were calculated. Changes in free energy (deltaG degrees') ranged from -10.35 to -15.65 kcal/mol. The binding of sufentanil, ohmefentanyl, diprenorphine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamineThr-NH2 (CTAP) was endothermic (deltaH degrees' > 0) and driven by an increase in entropy (-TdeltaS degrees' = -13.08 to -18.57 kcal/mol). The binding of naltrexone was exothermic (deltaH degrees' = -12.56 kcal/mol) and essentially enthalpy-driven. The binding of morphine, methadone, pentazocine, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) was exothermic (deltaH degrees' = -3.53 to -9.95 kcal/mol) and occurred with an increase in entropy (-TdeltaS degrees' = -2.48 to -7.92 kcal/mol). Plots of enthalpy versus entropy and enthalpy versus free energy were linear, although enthalpy-entropy compensation was not evident. The entropy changes were not correlated with apparent lipophilicity of the compounds. These results suggest that: (1) opioid ligands bind to the mu receptor by specific mechanisms, unrelated to lipid solubility; (2) the mechanism of binding is not universally different for peptide and non-peptide ligands; (3) the nature of binding does not a priori determine intrinsic activity. The results reveal a novel differentiation of opioid ligands into two groups (group 1: ohmefentanyl, sufentanil, diprenorphine, CTAP and PL017; group 2: naltrexone, morphine, methadone, DAMGO, pentazocine), based on two distinct relationships between enthalpy versus free energy of binding, the details of which are yet to be elucidated.

Tramadol hydrochloride, (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is an orally-active, centrally-acting analgesic with a putative dual mechanism of action, including an opioid and non-opioid component. The analgesic properties of tramadol and the possible co-existence of dual mechanisms has been postulated to be due to complementary and interactive pharmacologies of its enantiomers. We examined the ability of tramadol, its enantiomers, and morphine as reference to suppress c-fos-like immunoreactivity (c-fos-ir) in rat spinal cord and brain regions following a noxious stimulus (i.p. administration of 3.5% acetic acid). c-fos-ir was measured by immunocytochemistry and the stained cells in each region were counted 2 h after the acetic-acid injection (2:25 h after tramadol or morphine). Equi-analgesic doses of s.c. morphine (10 mg/kg) or tramadol (30 mg/kg) significantly suppressed c-fos-ir in all areas examined, except dorsal central gray of the spinal cord. The enantiomers of tramadol had distinctive patterns of suppression, neither one suppressed c-fos-ir in all of the regions, and hence neither one alone accounted for the suppression produced by the racemate. These findings support differential and complementary effects of tramadol enantiomers in sub-populations of spinal and supraspinal nociceptive neurons, consistent with the proposed antinociceptive interaction between the enantiomers.

FMRFamide (Phe-Met-Arg-Phe-NH2) and several analogs produce centrally-mediated, naloxone-reversible antinociception, but have minimal affinity for opioid receptor (sub)types. In the present study, the antinociception in mice (55 degrees C tail-flick test) produced by supraspinal (intracerebroventricular; i.c.v.) administration of [D-Met2]-FMRFamide (a stable analog of FMRFamide) was attenuated by pretreatment with i.c.v. oligodeoxyribonucleotide antisense to the opioid mu receptor or by antisense to the Gi2alpha G-protein subunit. These data suggest that [D-Met2]-FMRFamide produces its antinociception via an opioid interneuron.

A recent review calls attention to the discrepant results resulting from studies that have examined the nociceptive or antinociceptive properties of orphanin-FQ/nociceptin (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-ArgLys-Leu-Ala-Asn-Gln; OFQ/N), the heptadecapeptide isolated from rat (nociceptin) and pig (orphanin FQ) brain that binds with high affinity to the opioid 'orphan' receptor (a seven transmembrane protein with sequence homology to opioid receptors), but exhibits only low affinity binding with conventional opioid ligands. Some of the discrepancy might result from differences in species, test, route of administration or time-course. We undertook a comprehensive examination of the effects of spinal (i.t.) or supraspinal (i.c.v.) administration of OFQ/N in mice and rats. Mice treated with OFQ/N either i.t. or i.c.v. demonstrated no significant nociceptive effect in the hot plate, warm-water or radiant heat tail-flick tests (except for the highest and most sedative dose of 10 nmol i.c.v. in the mouse warm-water tail-flick test). Pretreatment with the opioid antagonist naloxone or with peptidase inhibitors did not enhance the nociceptive effects of OFQ/N peptide in the warm-water tail-flick test. The motor activity in mice administered OFQ/N i.c.v. decreased significantly compared to controls. Rats administered i.c.v. or i.t. OFQ/N displayed no significant difference from vehicle-treated animals in similar noxious stimulus tests and OFQ/N-treated rats did not exhibit allodynia in a paw-withdrawal test. Overall, OFQ/N was ineffective in significantly altering response to noxious stimuli, regardless of whether the peptide was given at supraspinal or spinal sites in mice or in rats. In addition, i.c.v. or i.t. application of antisense or mismatch ODN to the orphan receptor did not modify tail-flick latency in either mice or rats, arguing against a tonic nociceptive tone mediated via the OFQ/N receptor.

The hypothesis that mu-opioid agonists having low antinociceptive efficacy might be more susceptible to interference with G-protein coupling than mu-opioid agonists having higher antinociceptive efficacy was tested. Supraspinal antinociceptive efficacy for the three mu-opioid agonists morphine, [D-Ala2, NMePhe4, Gly5-ol]-enkephalin (DAMGO) and sufentanil in the mouse 55 degrees C warm-water tail-flick test was evaluated 18-24 h after intracerebroventricular (i.c.v.) administration of beta-funaltrexamine (beta-FNA). The beta-FNA pretreatment (0.2-2.0 nmol) attenuated antinociception in the order morphine > DAMGO > sufentanil, consistent with previous reports of their relative antinociceptive efficacy. The association of efficacy with G-protein coupling was then assessed by determining sensitivity to i.c.v. (0.1-3.0 micrograms) pertussis toxin (PTX) or cholera toxin (CTX). The effect of PTX on equiantinociceptive doses was in the inverse order of agonist efficacy. CTX augmented sufentanil-induced antinociception. Morphine- and DAMGO-induced antinociception were unaffected by CTX. These data suggest that: (i) highly efficacious mu agonists (viz., sufentanil) couple more efficiently to PTX-sensitive inhibitory Gi-proteins than do agonists of lower efficacy (viz., morphine, DAMGO) and (ii) highly efficacious mu agonists have greater capacity to utilize CTX-sensitive stimulatory Gs-proteins than do mu-agonists with lower efficacy.

The mechanism of analgesic action of acetaminophen (paracetamol) remains unknown. However, a central component distinct from that of the NSAIDs (non-steroidal antiinflammatory drugs) seems likely. A recent report (NeuroReport 6:1546-1548, 1995) suggests the involvement of 5-HT3 receptors. In the present study, we measured the affinity of acetaminophen at 5-HT3, as well as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2, 5-HT2C, 5-HT4, 5-HT6, 5-HT7 and eleven other receptor sites and at serotonin and norepinephrine reuptake sites. At 10 microM, acetaminophen inhibited less than 10% specific radioligand binding at any site. These findings: (i) suggest that acetaminophen's effect on serotonergic pathways is indirect, and (ii) circumscribe acetaminophen's possible central analgesic mechanism(s).

In the same mice in which the intracerebroventricular (i.c.v.) administration of antisense oligodeoxyribonucleotide (oligo) directed against the Gi2alpha (but not Gi1alpha, Gi3alpha or G(s)alpha) G-protein subunits attenuated i.c.v. morphine-induced antinociception in the tail-flick test, none of the oligos altered naloxone-precipitated jumping (acute dependence). Likewise, none of the oligos significantly altered morphine-induced constipation. Hence, i.c.v. morphine-induced antinociception might be preferentially mediated via transduction pathway(s) different from constipation or acute dependence, offering novel opportunities for drug discovery.

An in vivo antisense strategy was used to examine the involvement of G-protein subunits in supraspinal (intracerebroventricular; i.c.v.) alpha2-adrenoceptor-mediated antinociception. Mice that were injected with 33-mer antisense oligodeoxyribonucleotides (6 nmol) or vehicle were tested (tail-flick) with an agonist (clonidine, guanfacine or BH-T 920) administered i.c.v. 18 - 24 h later. Gi3alpha antisense treatment attenuated BH-T 920 and clonidine-induced antinociception. Gi2alpha antisense produced differential effects on the three agonists. Gi1alpha and G(s)alpha antisense treatment had no significant effect. Together with the previous demonstration that i.c.v. mu-opioid antinociception is mediated via Gi2alpha, the present results suggest that different receptors may mediate antinociception via different G-protein subunits and, hence, that specific subunits might offer novel targets for drug discovery.

An isobologram is a Cartesian plot of pairs of doses that, in combination, yield a specified level of effect. It is a convenient and presently popular way of graphically displaying results of drug-combination and similar studies, because paired values of experimental points that fall below or above the line connecting the axial points (usually ED50 values) denote supra- and sub-additive combinations, respectively. However, an isobologram does not fulfill the criteria for standard least squares regression analysis. It is thus less useful for addressing questions related to the range of combination ratios over which synergy occurs. We describe herein a substitute for the isobologram in which log(total-dose) is plotted against the proportion of a component in a combination. One advantage is that a nonlinear curve-fitting procedure and determination of the confidence interval of a single parameter allow the determination of departure from additivity over a range of fixed proportion mixtures. An example is given of the combination of two analgesics (acetaminophen and tramadol hydrochloride). Another advantage of the new method is the reduction of animal use.

The C57BL/6J-bgJ/bgJ (beige-J) mutation imparts a blunted response to intracerebroventricular (i.c.v.) morphine in the tail-flick test, without altered micro-opioid receptor number or morphine affinity. We now report that co-administration of IP3 (36.1 nmol) restored morphine responsiveness of beige-J mice to essentially that of normal littermates (bg+/bg-; ED50 = 3.9 and 3.5 nmol, respectively). IP3 had no effect on morphine-induced antinociception in control animals. Neither myoinositol at 36.1 nmol nor IP6 at the highest testable dose (4.5 nmol) had a similar effect. Myo-inositol at 5.5 mumol restored beige-J responsiveness to that of littermates. These findings implicate some component of the phosphoinositide cycle in the antinociceptive defect of beige-J mice.

Morphine-induced antinociception is antagonized by the K(+)-channel blocker glibenclamide (glyburide; Glib), implicating ATP-sensitive (KATP) K+ channels in the analgesic effect of opioids. The present study examined the generality of this conclusion by measuring the effect of Glib on supraspinal (intracerebroventricular; i.c.v.) antinociception produced by representative mu-opioids and the non-opioids pilocarpine and two alpha 2-adrenoceptor agonists (clonidine and tizanidine) using the mouse tail-flick test. Concurrent administration of Glib (40 micrograms, i.c.v.) produced a significant rightward shift of the dose-response curve of morphine, levorphanol, methadone, pilocarpine, clonidine and tizanidine; a modest, but not statistically significant, rightward shift of the dose-response curves of the mu-selective peptides DAMGO ([D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin) and PL017 ([N-Me-Phe3,D-Pro4]-morphiceptin); and no shift of the dose-response curves of alfentanil, carfentanil, fentanyl, sufentanil, or beta-endorphin. Glib produced a leftward shift of the dose-response curve of etorphine. These data support the involvement of KATP-type K+ channels in mediation of supraspinal antinociception, differentiate Glib-sensitive and Glib-insensitive opioid agonists, and reveal fundamental differences among antinociceptive agents in the extent of demonstrable utilization of this transduction pathway.

The multiple clinical actions of clonidine have historically been linked to the same receptor (alpha 2-adrenoceptor) due to the belief that clonidine was a selective alpha 2-agonist. However, it is now recognized that clonidine binds with a similar affinity to alpha 2-adrenoceptors and to non-adrenergic imidazoline receptors. These two pharmacological targets (and subtypes of each alpha 2 and imidazoline receptors) provide the basis for a possible separation of cardiovascular and other targeted effects, such as analgesia. Consequently, the design of selective alpha 2-adrenoceptor (subtype) agonists as analgesics devoid of the cardiovascular effects associated with clonidine appears to be a rational approach to novel therapeutic agents. The present review focuses on alpha 2-adrenoceptor subtype/imidazoline diversity as a target for analgesic (and other CNS) drug discovery.

The present study utilized an in vivo antisense strategy to examine the functional interaction of supraspinal mu-opioid receptors with the G protein subunits Gi1 alpha, Gi2 alpha, Gi3 alpha and Gs alpha. Mice were injected intracerebroventricularly (i.c.v.) with 33-base phosphorothioate oligodeoxyribonucleotides (12.5 micrograms) or with vehicle in equal volume (sterile water, 5 microliters) and the antinociceptive responses to i.c.v. morphine [D-Ala2,NMePhe4,Gly5-ol]enkephalin (DAMGO) or sufentanil were determined 18-24 h later using the tail-flick test. Treatment with antisense to Gi2 alpha, but not the other subunits, significantly attenuated morphine-induced antinociception. The degree of attenuation for the three mu-opioid agonists was in the order morphine > DAMGO > sufentanil, the inverse of their intrinsic efficacy.

Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.

The binding affinities at opioid receptor subtypes in rat or guinea pig brain membranes were determined for the neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2), the two mammalian-derived FMRFamide-related peptides F-8-Famide (NPFF; Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe- NH2) and A-18-Famide (Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe -NH2), and the two other FMRFamide-related peptides Tyr-Phe-Met-Arg-Phe-NH2 (Tyr-FMRFamide) and Pro-Gln-Arg-Phe-NH2 (Pro-Gln-RFamide). The mu and delta sites were labeled in rat brain membranes using tritiated [D-Ala2, N-MePhe4,Gly-ol5] enkephalin ([3H]DAMGO) and [D-Ala2,D-Leu5]enkephalin ([3H]DADLE), respectively. The kappa sites were labeled in guinea pig brain using [3H]U-69,593 after treatment with BIT and FIT for kappa 1 and [3H]bremazocine after pretreatment with BIT and FIT for kappa 1 and [3H]bremazocine after pretreatment with BIT and FIT for kappa 2. The kappa 2a binding sites were assayed using [Leu5]enkephalin to block kappa 2b sites and the kappa 2b sites were assayed using (-)-(1S,2S)-U50,488 to block kappa 2a sites. Neither FMRFamide nor any of the FMRFamide-related peptides (up to 61.0 microM) displayed significant affinity at any of the subtypes of opioid receptor. Hence, the known ability of FMRFamide and FaRPs to interact with the opioid system does not appear to be related to direct binding to these opioid receptors.

Morphine was administered intracerebroventricularly to normal or recombinant inbred CXBK (mu-opioid receptor deficient) mice and antinociception was determined against two different stimuli. Morphine-induced antinociception against acetylcholine was strain-dependent, whereas against endothelin-1 it was not. The antinociception was mediated via opioid mu receptors (blocked by beta-FNA, but not naltrindole, ICI 174,864 or nor-BNI) through separate pathways, one naloxonazine-sensitive and the other naloxonazine-insensitive. Taken together, these results appear to demonstrate supraspinal morphine-induced antinociception through distinct subtypes of the mu opioid receptor, supporting the possibility of novel subtype-selective therapeutic agents with greater separation between analgesia and side-effects or physical dependence. Furthermore, the methodology described herein provides model systems for the in vivo screening of such agents.

The prevailing view is that supraspinal mu opioid-mediated antinociception in mice is mediated via the mu 1 subtype. The purpose of the present study was to determine if the highly mu-selective compound etonitazene could produce supraspinal (intracerebroventricular; i.c.v.) antinociception in CXBK mice, which are deficient in brain mu1, but not mu2, opioid receptors. CXBK or normal Crl:CD-1 (ICR)BR mice were administered graded doses of etonitazene i.c.v. and 15 min later antinociception was assessed by a standard radiant-heat or 55 degrees C water tail-flick test. Etonitazene produced dose-related antinociception that was blocked by naloxone and by beta-FNA (demonstrating a mu opioid mechanism), but not by either ICI-174,864 or naltrindole (demonstrating the lack of involvement of delta opioid receptors). These findings suggest that mu2 opioid receptors are important contributors to opioid-induced supraspinal antinociception in mice.

Dissociation constants (KA) for [D-Pen2,5]enkephalin (DPDPE) inhibition of the electrically evoked twitch of the mouse isolated vas deferens preparation (MVD) were calculated at five temperatures (25, 30, 34, 37 and 40 degrees C). These values were determined from the equiactive concentrations obtained before (A) and after (A') partial irreversible blockade of a fraction of the receptor population by beta-chlornaltrexamine (beta-CNA) plotted as (1/A') where KA = (slope -1)/intercept. The values of KA tended to increase (approximately doubled) over this temperature range, indicating that the affinity of DPDPE for the opioid delta receptor is an inverse function of temperature. From these results, thermodynamic parameters were calculated from a Van't Hoff plot of 1n(KA) against 1/T. The relative magnitudes of the change in enthalpy (delta Ho' = -6.67 kcal mol-1), the change in entropy (delta So' = +0.009 kcal mol-1 degrees K-1) and the change in free energy (delta Go' = -9.43 kcal mol-1) suggest that the interaction between DPDPE and the delta-opioid receptor in MVD is an exothermic exergonic reaction, predominantly enthalpy-driven and results in an increase in the entropy of the system.

A selective non-responsiveness to the analgesic effects of opioid mu receptor-, but not opioid delta receptor-, mediated antinociception in the tail-flick test has been identified in C57BL/6J-bgJ (beige-J) mice. The beige-J mutation is also known to give rise to multiple immunological disorders and immune cell dysfunctions. A link between these apparently disparate manifestations has been examined in a series of studies using, for example, adoptive transfer of spleen cells. The findings appear to have broad implications for the link between the immune and opioid systems.

An in vitro preparation of rabbit thoracic aorta was tested in order to determine whether isometric contractile force induced by endothelin-1 (ET-1) in this preparation is changed when the tissue is exposed to ultraviolet (UV) light. After constriction of an aortic segment to a steady-state level of tension with ET-1, a flash of UV light induced a transient decrease in tension that returned exponentially to equilibrium. This response was endothelium-independent and sensitive to the extracellular sodium concentration. The rate of return to the baseline tension after photorelaxation increased with increasing concentrations of ET-1. UV light had only a slight photorelaxing effect at very low and very high ET-1 concentrations and a much larger effect at concentrations near the A50 value of ET-1. Since an irreversible antagonist does not yet exist for ET-1, the partial irreversible blockade method for getting the dissociation constant (KD) functionally was not possible. The relaxation method, using UV light as a perturbation of ligand-receptor equilibrium, was used instead to obtain KD as well as the forward (k1) and reverse (k2) rate constants of ET-1 in this tissue.

2-Substituted 1-azabicycloalkanes (3- and 5-aryloctahydroindolizines 2 and 11, 3-cyclohexyloctahydroindolizine 12, 4-aryloctahydroquinolizines 13, and 3-arylhexahydropyrrolizines 14) constitute a new class of non-opiate antinociceptive agents. These compounds demonstrated activity in the mouse abdominal constriction test and many were active in the mouse tail-flick test. trans-3-(2-Bromophenyl)octahydroindolizine (2a) did not bind to the opiate receptor nor did it affect arachidonate metabolism. 3-Aryloctahydroindolizines were prepared by catalytic hydrogenation of 1-aryl-3-(2-pyridinyl)-2-propen-1-ones. The X-ray crystal structure of (-)-2a was determined and absolute stereochemistry assigned as 3-R,8a-R.

Previous work demonstrated that a single subcutaneous injection of LiCl (10 mmol/kg; 18 h prior) significantly reduces the antinociceptive action of centrally administered (intracerebroventricular; i.c.v.) morphine in the tail-flick and that inositol-1,4,5-trisphosphate (IP3; 20 micrograms) restores the morphine response in LiCl-pretreated mice, implicating a phosphoinositide second messenger pathway in the mediation of morphine-induced analgesia. We now report that LiCl pretreatment shifted the antinociceptive dose-response curve produced by the opioid agonists morphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin (DAMGO) and sufentanil in inverse order of their intrinsic efficacy. These results implicate the phosphoinositide pathway(s) as important determinant(s) of opioid efficacy and are interpreted as evidence for the existence of a second-messenger reserve for opioids of high efficacy and the possible role of the phosphoinositide pathway in the development of morphine tolerance.

The ability of Phe-Met-Arg-Phe-NH2 (FMRFamide) or [D-Met2]-FMRFamide to produce antinociception in mice, or to block morphine-induced antinociception, was examined using the tail-flick and tail-immersion (55 degrees C) tests. [D-Met2]-FMRFamide dose-dependently produced antinociception following intracerebroventricular (i.c.v.) administration with ED50 values (95% confidence limits) of 5.0 (2.2-7.2) and 12.8 (8.1-19.9) micrograms in the tail-flick and tail-immersion tests, respectively. FMRFamide did not produce a maximal effect in the tail-flick test. Naloxone (administered s.c. 20 min prior to the i.c.v. administration of [D-Met2]-FMRFamide) dose-dependently attenuated [D-Met2]-FMRFamide-induced antinociception. The shift in the [D-Met2]-FMRFamide dose-response curve was parallel and a pA2 value for naloxone of 6.3 +/- 0.3 was determined from a Schild plot analysis. Mice made tolerant to the antinociceptive effect of morphine were cross-tolerant to the antinociceptive effect of [D-Met2]-FMRFamide. FMRFamide and [D-Met2]-FMRFamide both produced rightward, parallel shifts of the morphine antinociceptive dose-response curve. The findings that [D-Met2]-FMRFamide both elicited naloxone-sensitive antinociception and attenuated morphine-induced antinociception are consistent with the view that FMRFamide-related peptides (FaRPs) are weak agonists at opioid receptors and, further, appear to reconcile the apparently chimeric agonist and antagonist properties of these peptides observed in vivo.

The antinociceptive efficacy of [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta 1 agonist) and [D-Ala2,Glu4]deltorphin (delta 2 agonist) was evaluated following intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration in CD-1 and CXBK strains of mice using the radiant heat tail-flick test. Following i.c.v. administration, [D-Ala2,Glu4]deltorphin was effective in CD-1, but not CXBK, mice; DPDPE was approximately equiactive in both strains. While i.c.v. [D-Ala2,Glu4]deltorphin did not produce antinociception in the CXBK mouse, it effectively antagonized the antinociceptive actions of i.c.v. DPDPE. [D-Ala2,Glu4]deltorphin was effective following i.t. administration in both strains. These data suggest possible differences in the supraspinal populations of opioid delta receptor subtypes in the CXBK strain. On the basis of previously established selectivity of these agonists, the CXBK mouse may have a predominate population of supraspinal opioid delta 1, rather than delta 2, receptors.

Pretreatment (18 h) of mice with a single s.c. injection of LiCl (10 mmol/kg) reduced the antinociceptive action of centrally administered (i.c.v.) morphine in the tail-flick test (ED50 = 7.7 micrograms) compared to vehicle-treated controls (ED50 = 1.8 micrograms). The coadministration of inositol-1,4,5-trisphosphate (IP3; 20 micrograms) with morphine restored the morphine-induced antinociception (ED50 = 2.4 micrograms) in LiCl-pretreated mice to control levels. These finding implicate a LiCl-sensitive (possibly phosphoinositide) second messenger pathway in the mediation of morphine-induced analgesia.

Intracerebroventricular (i.c.v.) administration of either Phe-Met-Arg-Phe-NH2 (FMRFamide; molluscan cardioexcitatory neuropeptide; 3-30 micrograms) or the FMRFamide analog Phe-D-Met-Arg-Phe-NH2 ([D-Met2]FMRFamide; 15 micrograms) to conscious unrestrained spontaneously hypertensive rats (SHR) produced a relatively long lasting (greater than 1 h) increase in heart rate. The increase in heart rate produced by [D-Met2]FMRFamide was attenuated by i.c.v. injection of the opiate antagonist naloxone (2 micrograms). These results extend to a second endpoint an apparent opioid agonist-like (naloxone-reversible) action of [D-Met2]FMRFamide.

A growing body of evidence suggests that the number of drug receptors on cell surfaces is not fixed, but is dynamically regulated by circumstances that include exposure to the ligand itself. Because most traditional theories of drug action are based on the assumption of a fixed number of receptors, it is desirable to examine the importance of this regulatory process on the interpretation of dose-effect data. Of special interest is the impact of a variable receptor number on the equation of competitive antagonism and associated pA2 which, in the traditional theory, is a quantitative measure of antagonist-receptor affinity. Using a simple model of drug-induced endocytosis or exocytosis, it is shown that if the rate of either is appreciable, the pA2 is no longer a simple measure of affinity.

The Ki values for etoperidone, trazodone and MCPP (m-chlorophenylpiperazine dihydrochloride) at 5-HT1A sites (using rat cerebral cortical synaptosomes and [3H]8-OH-DPAT) were determined to be 20.2, 23.6 and 18.9 nM, respectively. In an effort to elucidate the functional nature of the interaction at 5-HT1A sites in vivo, the ability of each compound to elicit reciprocal forepaw treading (RFT) or to block the RFT induced by 8-OH-DPAT in reserpinized rats was tested. Specifically, 8-OH-DPAT (1.0 mg/kg SC)-challenged or non-challenged (control) reserpinized (1.0 mg/kg SC) rats were administered etoperidone, trazodone or MCPP (IP) and scored for the elicitation of RFT (indicative of 5-HT1A agonistic activity) or for block of RFT induced by 8-OH-DPAT (indicative of 5-HT1A antagonistic activity). Reference compounds confirmed the specificity of the test. We report that etoperidone, trazodone and MCPP inhibited 8-OH-DPAT-induced RFT (ID50 = 17.4, 23.8 and 13.4 mg/kg, respectively). Only marginal RFT was produced in non-challenged animals by etoperidone and trazodone at a high dose (40 mg/kg). Taken together, the results suggest a predominant antagonistic activity of etoperidone, trazodone and MCPP at 5-HT1A receptor sites in rat central nervous system. However, one cannot rule out the possibility that these compounds are weak partial agonists. This activity may be relevant to the antidepressant action of these compounds.

The effect of lowering extracellular ion concentration on ultraviolet (UV) light-induced photorelaxation of norepinephrine(NE)-constricted rabbit isolated thoracic aorta was investigated. The magnitude of the photorelaxation response (similar to acetylcholine-induced, but not nitroprusside-induced, relaxation) progressively declined, in the absence of an effect on NE-induced vasoconstriction, as the total extracellular ion concentration was progressively reduced. This diminution in the photorelaxation response was duplicated by isosmotic lowering of the extracellular concentration of Na+, but not other ions, from 145 to 25 mM and was not restored by the replenishment of the Na+ deficiency by equimolar amounts of mannitol or Li+. In contrast, choline fully substituted for Na+. These findings suggest a fundamental difference in the ion dependency (and, hence, the mechanisms) of UV-induced photorelaxation and the vasorelaxations induced by acetylcholine or sodium nitroprusside.

The ability of XAMI (2,3-xylylaminomethyl-2'-imidazoline), the most potent agonist of cAMP-associated octopamine-sensitive adenylate cyclase in cockroach (Periplaneta americana) nerve cord yet reported, and DCDM (N-demethylchlordimeform), a partial octopamine agonist in this preparation, to produce centrally mediated antinociception in mice was evaluated. The antinociception produced by these compounds was compared to that previously reported for p-octopamine, a phenylethylamine and endogenous mammalian hydroxyphenolic analog of norepinephrine. Consonant with the reported greater agonistic activity of XAMI on octopamine-sensitive adenylate cyclase, XAMI was more potent than p-octopamine by spinal or supraspinal administration in the abdominal constriction test (E50 = 0.013 micrograms i.t., 1.45 micrograms i.c.v.) and in the 48 degrees C hot-plate test (ED50 = 0.06 micrograms i.t., 0.4 micrograms i.c.v.), but was inactive in the tail-flick test (up to 4.0 micrograms i.c.v. or i.t.). Unlike p-octopamine, both XAMI and DCDM were active by peripheral routes of administration. DCDM was orally active in the mouse acetylcholine-induced abdominal constriction test (ED50 = 9.98 mg/kg p.o.) and was active via the s.c. route in this test (ED50 = 2.36 mg/kg), the 48 degrees C hot-plate test (ED50 = 5.40 mg/kg) and the tail-flick test (ED50 between 15 and 30 mg/kg). It appeared to be a full agonist against these endpoints. XAMI produced dose-related antinociception in the abdominal constriction test (ED50 = 0.10 mg/kg s.c.) and in the 48 degrees C hot-plate test (ED50 = 3.71 mg/kg p.o. and 0.46 mg/kg s.c.), where the antinociceptive response persisted for at least 60 min following subcutaneous or oral administration. Both compounds were less potent via peripheral routes than clonidine (as reference) in these tests. Mechanistically, XAMI-induced antinociception was antagonized by yohimbine and idazoxan, but not the opiate antagonist naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of central or peripheral administration of serotonin on colonic expulsion time (CE) of a glass bead were evaluated after i.p. or free hand i.c.v. administration to mice. Serotonin (5-HT) caused an inhibition of CE when administered centrally but stimulated propulsion after i.p. administration. Several selective serotonin agonists were then tested. Inhibition after i.c.v. administration was produced by 8-OH-DPAT (5-HT1a), RU-24969 (5-HT1b), and 2-methyl serotonin (5-HT3), but not DOI (5-HT2) which augmented propulsion. Relative potencies for inhibition (ED50S) were RU (0.9 micrograms, 3.9 nM) greater than 8-OH-DPAT (3 micrograms, 9.1 nM) greater than 5-HT (7.8 micrograms, 20.1 nM) greater than 2-methyl serotonin (43 micrograms, 140 nM). After i.p. administration 5-HT stimulated propulsive motility (ED50 = 16.1 micrograms, 41.4 nM) while 8-OH-DPAT (ED50 = 55 micrograms, 167 nM) and RU-24969 (ED50 = 54 micrograms, 236 nM) inhibited. DOI and 2-MS had no dose-related activity. The finding that several of the serotonin receptor agonists were capable of inhibiting propulsive motility either by i.p. or i.c.v. administration is a new finding and may help to explain drug-induced constipating activity in man. No selective agonist completely mimicked the effect of serotonin.

When injected intraperitoneally into mice, endothelins ET-1, ET-2, ET-3 and big-endothelin-1[1-38] (big-ET-1[1-38]) produced a dose-related, robust and easily quantified abdominal constriction response within 20 min. The ED50 values for this response were 0.026, 0.005, 0.131, and 0.043 mg/kg, respectively. Hence, this test could provide a convenient in vivo endpoint for endothelin activity. The results also imply that ET-1, ET-2, ET 3 or big-ET-1[1-38] may be nociceptive under certain conditions. Morphine (4 mg/kg, s.c.) administered 30 min prior completely blocked the response produced by ET-1. Thus, in conjunction with other indicators, the test may also serve as an in vivo screen for agents useful in the treatment of abdominal or visceral pain. The effect of big-ET-1[1-38], but not ET-1, was blocked by pretreatment with the enzyme inhibitor phosphoramidon (10 mg/kg, s.c., 30 min prior), implying that the big-ET-1[1-38] must first be enzymatically cleaved, presumably to ET-1, in order to elicit the abdominal constriction response. This test might also serve as a discriminative antinociceptive screen, because the response to ET-1 was not blocked by acetaminophen (400 mg/kg, p.o.), ibuprofen (75 mg/kg, p.o.) or indomethacin (1.0 mg/kg, p.o.).

Intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of morphine to mice antagonized the abdominal constriction induced by an i.p. injection of endothelin-1 (ET-1; 0.1 mg/kg). The ED50 values (95% confidence intervals) were 39.3 (16.5-80.2) ng and 1.5 (0.8-4.9) ng, respectively. The antagonism of ET-1-induced abdominal constriction by morphine was blocked by naloxone (1.0 mg/kg, s.c.) or by 24 h pretreatment with beta-funaltrexamine (beta-FNA; 8.84 micrograms, i.c.v.). These results demonstrate for the first time that the stimulus resulting from an i.p. injection of ET-1 is transmitted via ascending (pain) pathways that are subject to attenuation by opioid (mu) receptor activation. Hence, ET-1-induced abdominal constriction is a new pain model which, given the other pharmacology of ET-1, might represent a unique model with potential specific utility for anginal or other visceral pain.

The present studies were an attempt to examine the mechanism of action of the novel antinociceptive compound RWJ-22757, (+/-)-trans-3-(2-bromophenyl)-octahydroindolizine (McN-5195). Intracerebroventricular (i.c.v.) administration of RWJ-22757 produced dose-related antinociception in the mouse tail-flick (48 degrees C) and rat hot-plate (51 degrees C) tests (ED50 = 243.3 and 261.3 micrograms, respectively). In contrast, intrathecal (i.t.) administration was without effect. The antinociception produced by peripherally (i.p.) or centrally (i.c.v.) administered RWJ-22757 was attenuated by i.t. administration of 2 micrograms phentolamine, 5 micrograms yohimbine, or 10 micrograms methysergide. I.t. administration of naloxone, at a dose (0.5 micrograms) that significantly attenuated the antinociceptive effects of peripherally or centrally administered morphine, had no effect on RWJ-22757-induced antinociception. We conclude from these results, coupled with the overall pharmacological and neurochemical profile of RWJ-22757, that the data are consistent with the hypothesis that RWJ-22757 produces antinociception predominantly at a site or sites located supraspinally with little or no activity at the spinal level and that RWJ-22757 activates adrenergic and serotonergic descending inhibitory pathways, increasing the tonic activity of endogenous antinociceptive systems.

Rats were injected intraperitoneally with loreclezole (R 72063), diazepam, or scopolamine 60 min prior to acquisition of a passive avoidance task and tested 18 h later for retention of the learned (passive) behavior. The known impairment of performance produced by diazepam in this test is believed to be a model for the clinically observed diazepam-induced anterograde amnesia in humans. We report in this study that (1) consistent with the literature, pretreatment with diazepam (2.0-16.0 mg/kg i.p.) or scopolamine (3.0 mg/kg i.p.) produced impairment in passive avoidance performance of rats (anterograde amnesia), but (2) pretreatment with loreclezole (R 72063) (2.0-80.0 mg/kg i.p.) did not impair the acquisition, retention, or the retrieval (tested 18 h later) of passive avoidance behavior by rats at any dose. The results suggest that the anticonvulsant activity of loreclezole is mediated by a mechanism distinct from the one coupled to diazepam-like disruption of cognitive functions involved in the acquisition or posttraining information processing of passive avoidance behavior.