Francis C. Colpaert

Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis

Capsaicin (20-80 mg/kg, s.c.) reduced the inflammatory response to inoculation with Mycobacterium butyricum in the rat. The effect was apparent within 24 h, was partial, persisted for well over 20 days, and occurred irrespective of whether capsaicin was administered before or after the onset of inflammation, or at the time when the pathology reached peak. Capsaicin also attenuated the increase in substance P content in sciatic nerve, saphenous nerve, dorsal root ganglia, dorsal roots, and dorsal spinal cord (L4, L5) which occurs in rats with adjuvant arthritis. The data are consistent with a possible role of substance P in the peripheral manifestations of adjuvant arthritis.

Evidence that adjuvant arthritis in the rat is associated with chronic pain

&NA; The paper reviews evidence that adjuvant arthritis in the rat is associated with chronic pain and discusses the time course and measurement of this putative pain. The available evidence is consistent with the view that arthritic rats suffer pain, but it appears difficult to formally establish the occurrence of chronic pain in animals. The data suggest the pain to be severe during weeks 2 and 3 and to persist during weeks 4 and 5 after inoculation. The continuing inflammation of joints likely results in movement‐induced acutely elicited pains that may persist till about the 8th week. The severe pain during weeks 2 and 3 may be associated with a depression of some drives, and the entire week 2–8 period is likely associated with varying levels of chronic stress. Neurochemical and neurophysiological studies indicate that adjuvant arthritis profoundly influences several of the neurotransmission and neuroendocrine functions of brain and spinal cord; among the affected systems are substance P‐ergic, serotonergic and endorphinergic systems. Adjuvant arthritis in the rat constitutes the only laboratory animal model of chronic pain that has been validated to a significant extent. It is suggested that the model be examined further and that additional animal models of chronic pain be developed.

Increase of substance P in primary afferent nerves during chronic pain

Abstract Substance P was found to be increased in the sciatic nerve of rats suffering chronic pain due to adjuvant-induced polyarthritis. This increase of substance P in primary afferents is assumed to reflect adaptive changes initiated by chronic noxious events such as inflammation.

Discriminative stimulus properties of narcotic analgesic drugs

Abstract This paper presents a comprehensive review on the experimental data relevant to the discriminative stimulus properties of narcotic analgesic drugs. The narcotic cue is defined as the discriminative stimulus complex which is exclusively associated with the specific central action(s) of narcotic analgesic drugs. The first part of this review discusses evidence that narcotics can act as a discriminative stimulus, and that this cue is an exclusive, complexly composed, and centrally originating property of narcotics. The pharmacological and biochemical specificity of the narcotic cue is supported by findings indicating (1) that chemically heterogenous narcotics generalize with narcotic agonist training drugs, (2) a close correlation between narcotic cuing and analgesic potency of narcotics, (3) that the requirement of steric specificity applies, and (4) the naloxone-reversibility of this cue. The comparative data so far available are thus consistent with the assumption that the narcotic cue in laboratory animals relates intimately to, and can serve as a preclinical model for opiate-like subjective effects in man. Further discussion is concerned with the involvement of various neurotransmitter substances in the narcotic cue; much as it appears likely that multiple and diffusely organized brain sites rather than discrete brain areas are involved, there is no evidence at this stage that any single transmitter would play a unique role in this cue. The other issues being discussed here are (1) the role of training drug dose, (2) the tolerance problem, (3) the relation between the narcotic cuing and the analgesic activity of narcotics, (4) the involvement of neuropeptides, (5) drug cue conditioning to environmental stimuli; (6) drug cues and drug states, and (7) the internal discriminative stimulus control of behavior by endogenous opioid substances.

PPARα and PPARδ activators inhibit cytokine-induced nuclear translocation of NF-κB and expression of VCAM-1 in EAhy926 endothelial cells

Abstract Endothelium injury is a primary event in atherogenesis, which is followed by monocyte infiltration, macrophage differentiation, and smooth muscle cell migration. Peroxisome proliferator-activated receptors (PPARs) are transcription factors now recognized as important mediators in the inflammatory response. The aim of this study was to develop a human endothelial model to evaluate anti-inflammatory properties of PPAR activators. PPAR proteins (α, δ and γ) are expressed in EAhy926 endothelial cells (ECs). Pirinixic acid (Wy-14643), fenofibrate, fenofibric acid, the Merck ligand PPARδ activator L-165041, 15-deoxy-Δ 12,14 -prostaglandin J 2 , but not rosiglitazone (BRL-49653) inhibited the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by enzyme linked immunosorbent assay (ELISA), and monocyte binding to activated-EAhy926 cells. The PPARδ activator L-165041 had the greatest potency to reduce cytokine-induced monocyte chemotactic protein-1 (MCP-1) secretion. All PPAR activators tested which impaired VCAM-1 expression reduced significantly nuclear p65 amount. These results show that EAhy926 endothelial cells are an adequate tool to substantiate and characterize inflammatory impacts of PPAR activators.

Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites

We determined the affinity of several typical and atypical antipsychotics for the 5-HT1C and 5-HT2 sites using radioligand binding assays. Most of the antipsychotics tested appeared to bind to 5-HT2 sites with affinities that were fairly high (i.e. pKi values between 7 and 9) and significantly higher than for 5-HT1C sites. In contrast, clozapine was found to have a significantly higher affinity for 5-HT1C than for 5-HT2 sites. Clozapine had the highest affinity for 5-HT1C sites of all the compounds tested. These findings are consistent with the hypothesis that an interaction with 5-HT2 receptors may be relevant to the clinical activity of typical antipsychotics. The findings also suggest, however, that an interaction with 5-HT1C sites may be relevant to the mechanism of clinical action of clozapine and, perhaps, of other atypical antipsychotics.

Behavioral and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rat

The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced headtwitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

Theoretical and methodological considerations on drug discrimination learning

A method is described which allows the assessment of discriminative stimulus properties of drugs, and the ability of amphetamine (0.16 mg/kg, s.c), chlordiazepoxide (5 mg/kg, p.o.), desipramine (5 mg/kg, s.c), and haloperidol (0.02 mg/kg, s.c.) to produce a discriminative stimulus complex (DSC) is evidenced. The method is found to yield clear-cut data that are specifically related to drug discrimination learning without being possibly confounded by state dependent effects. In addition, the experimental procedure is designed so as to provide an appropriate measurement of operant response modulating drug effects.

Discriminative stimulus properties of cocaine: Neuropharmacological characteristics as derived from stimulus generalization experiments ☆ ☆☆

The experiments reported here were undertaken to examine the neuropharmacological characteristics of drugs inducing stimulus generalization with cocaine as a cue. Experiment 1 indicated that d-amphetamine (ED50: 0.17 mg/kg), 1-amphetamine (0.45 mg/kg), methylamphetamine (0.15 mg/kg), methylphenidate (0.55 mg/kg) and nomifensine (0.32 mg/kg) induce stimulus generalization with cocaine in rats trained to discriminate 10 mg/kg cocaine from saline; this generalization occurred in 100% of the animals, proceeded along steep slopes (s: 1.27 to 1.88 in log-probit plots), and was not associated with behaviorally toxic effects. Amantadine (57.8 mg/kg; s=1.85), apomorphine (0.33 mg/kg; s=1.77), piribedil (8.4 mg/kg; s=10.6) and bromocryptine (>40 mg/kg) also induced stimulus generalization to some extent, but this generalization was partial in some cases, proceeded along a shallow slope with piribedil, and was invariably associated with severe rate depressant effects. Ten mg/kg, but not 1.25 mg/kg hydroxyamphetamine induced generalization in 3 out of 8 rats. Experiment 2 revealed that tranylcrypromine (2.5 mg/kg; s=1.7), fentanyl (0.068 mg/kg; s=1.34), morphine (>10 mg/kg), phencyclidine (0.81 mg/kg; s=1.43), and benztropine (9.2 mg/kg) induce stimulus generalization with cocaine, whereas lidocaine, procaine, chlordiazepoxide, imipramine, desipramine, mescaline, LSD, isopropamide, and atropine do not. Experiment 3 shows that propranolol (1.25 to 40 mg/kg) and isoproterenol (0.63 to 2.5 mg/kg) induce a biphasic generalization with cocaine. Experiment 4 discloses that rats trained to discriminate 10 mg/kg propranolol from saline generalize their training drug along a linear gradient, but generalize cocaine along a biphasic gradient. It is suggested (a) that stimulus generalization with cocaine may be contingent upon increasing the functional availability of endogenous dopamine and, perhaps, of norepinephrine irrespective of the presynaptic mechanism from which such increase may result and (b) that differential stimulus generalization of drugs with cocaine (in terms of dose, subjects, slope, and rate effects) may parallel their differential primary reinforcing properties.

Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rat

The experiments characterized the dose- and time-dependence of parkinsonian motor signs induced by reserpine in rats and a standardized system of manipulation of animals, evaluation of symptoms and analysis of data was devised. The assay procedure yielded no more than 0.5, 4.5 and 0.0% false positives with the evaluation of tremor, rigidity and hypokinesia, respectively. A dose-dependent and often complete blockade of all three signs was obtained with L-DOPA plus carbidopa (10:1) as well as with other classes of pharmacological agents that are used in the treatment of Parkinsons disease, i.e. direct or indirect dopamine (DA) agonists (amantadine, pergolide, lisuride) and inhibitors of monoamine oxidase (MAO) (clorgyline, pargyline, deprenyl, tranylcypromine). The inhibitor of the uptake of DA, nomifensine, and anticholinergics, 5-hydroxytryptamine (5-HT) antagonists, histamine antagonists and tricyclic antidepressants exerted little or no effect. The effects of putative agonists and antagonists at alpha 1- and alpha 2-adrenoceptors were also examined. Yohimbine blocked tremor and rigidity, but not hypokinesia, at 0.66 and 0.28 mg/kg, respectively. It is suggested that alpha-adrenergic mechanisms and, in particular, alpha 2-adrenoceptors, may be involved in reserpine-induced tremor and rigidity. Noradrenergic and dopaminergic systems can conceivably interact to progressively generate these different motor signs.