Biomedical subjects

F C Colpaert

Publications and source records attributed to F C Colpaert.

At least 109 records · Page 6Linked to original sources

PubMed1990

Modification of nociception in a model of localized inflammatory pain by long-term administration of naloxone.

Inoculation of the right hind paw with Mycobacterium butyricum led to an inflammation reflected in a reduction in the threshold to respond to noxious pressure. Chronic perfusion of naloxone at a 'high' dose of 3.0 mg/kg/hr blocked the antinociceptive action of the mu-agonist, morphine, and the kappa-agonist, U69 593. In contrast, a 'low' dose of 0.16 mg/kg/hr antagonized the action only of morphine. Two days postimplantation, the hyperalgesia to pressure was potentiated in rats receiving the high, but not the low dose of naloxone. At 6 days, this difference was no longer seen. At 7 days, pumps were removed; one day later, in rats which had been receiving the high, (but not low) dose of naloxone, thresholds on the inflamed paw no longer differed from those on the uninflamed paw. This may reflect supersensitivity to an endogenous opioid. The data suggest that kappa-receptors may contribute to control of nociception in inflammatory pain. However, this role does not appear to be essential.

Animals↗

PubMed1990

N-methyl-D-aspartate antagonism and phencyclidine-like activity: a drug discrimination analysis.

The experiments examined the ability of competitive N-methyl-D-aspartate (NMDA) antagonists (CPP, CGS 19755), noncompetitive NMDA antagonists [phencyclidine (PCP), ketamine, MK-801], other putative excitatory amino acid antagonists (ifenprodil, PK 26124), and anticonvulsants (pentobarbital, chlordiazepoxide) to antagonize the discriminative stimulus (DS) effects of NMDA and to produce PCP-like DS effects. Rats were trained to discriminate NMDA (40 mg/kg) from saline. The DS effects of NMDA were blocked by the competitive NMDA antagonists but were antagonized at best partially by the other drugs tested. The response rate decreasing effects of NMDA were attenuated to varied extents by both the competitive and the noncompetitive NMDA antagonists. Some competitive and noncompetitive NMDA antagonists partially mimicked NMDA. To further examine their NMDA-antagonist properties, the compounds were also tested for antagonism of NMDA (160 mg/kg)-induced lethality in mice; only the competitive and noncompetitive NMDA antagonists completely protected against NMDA-induced lethality. In rats discriminating PCP (2.5 mg/kg) from saline, the competitive NMDA antagonists produced less drug-appropriate responding than the noncompetitive NMDA antagonists but more than was produced by the other drugs tested. The extent to which compounds antagonize behavioral effects of NMDA and produce PCP-like DS effects may depend partly on the effect measured and on the component of the NMDA receptor complex with which they interact. Although the competitive NMDA antagonists were more effective in blocking NMDA than the other drugs tested, they failed to act as pure antagonists of the DS effects of NMDA.

Animals↗

PubMed1989

Apparent hyperalgesic action of the 5-HT1A agonist, 8-OH-DPAT, in the rat reflects induction of spontaneous tail-flicks.

The 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induced a dose-dependent reduction in latency to withdraw the tail from noxious hot water (48 degrees C). However, a similar apparent 'hyperalgesia' was seen at a non-noxious temperature of 38 degrees C. Indeed, 8-OH-DPAT induced spontaneous 'tail-flicks' in the absence of external stimulation. This property was shared by lisuride and LSD, which also have high intrinsic activity at 5-HT1A sites. Agonists at other serotonin (5-HT) receptor types (5-HT1B, 5-HT1C, 5-HT2, 5-HT3) were inactive. Tail-flicks induced by 8-OH-DPAT could be antagonised by the 5-HT1 2 antagonist, methiothepin, but not by ritanserin or GR-38032F, which are antagonists at 5-HT2 and 5-HT3 sites, respectively. Ipsapirone and buspirone, partial 5-HT1A agonists, acted as antagonists. Further, BMY 7378, a proposed selective antagonist at 5-HT1A sites, also blocked the tail-flicks. Thus, the apparent 'hyperalgesia' induced by 8-OH-DPAT may reflect induction of spontaneous tail-flicks. These flicks appear to be mediated by 5-HT1A receptors and represent a novel model of 5-HT1A function in the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

1-5-Hydroxytryptophan-induced flat body posture in the rat: antagonism by ritanserin and potentiation after 5,7-dihydroxytryptamine.

1-5-Hydroxytryptophan (1-5-HTP)-induced flat body posture (FBP) was antagonized by ritanserin in doses that were lower than those needed to antagonize head-twitches (HTW) and forepaw treading (FPT). 5,7-Dihydroxytryptamine (5,7-DHT) potentiated 1-5-HTP-induced FBP but not HTW or FPT. Ritanserin interacted with 5-HT2 and 5-HT1c receptors. 1-5-HTP-induced FBP could be mediated by postsynaptic 5-HT1c receptors and could serve as a behavioral model of postsynaptic 5-HT1c receptor stimulation in the CNS.

5,7-Dihydroxytryptamine↗

PubMed1989

The phencyclidine (PCP) analog N-[1-(2-benzo(B)thiophenyl) cyclohexyl]piperidine shares cocaine-like but not other characteristic behavioral effects with PCP, ketamine and MK-801.

Phencyclidine (PCP) inhibits dopamine (DA) uptake and acts as a noncompetitive N-methyl-D-aspartate antagonist by binding to PCP receptors. The PCP analog N-[1-(2-benzo(b)thiophenyl) cyclohexyl]piperidine (BTCP, GK13) is a potent DA uptake inhibitor, but has low affinity for PCP receptors. The behavioral effects of BTCP were compared with those of PCP, ketamine, MK-801 and cocaine. In mice, BTCP, like cocaine, produced locomotion, sniffing and gnawing; haloperidol blocked these effects. PCP, ketamine and MK-801 produced locomotion, sniffing, swaying and falling. PCP, ketamine and MK-801 produced generalization in rats discriminating either cocaine, PCP or MK-801 from saline. Like cocaine, BTCP produced generalization in cocaine-discriminating rats only; haloperidol partially antagonized this effect. In pigeons, PCP-like catalepsy was produced by ketamine and MK-801, but not by BTCP. N-methyl-D-aspartate-induced convulsions in mice were antagonized by PCP, ketamine and MK-801, but not by BTCP or cocaine. Thus, BTCP shared only cocaine-like behavioral effects with PCP, ketamine and MK-801. A DA antagonist reduced the effects of BTCP. Therefore, the cocaine-like behavioral effects of BTCP may be mediated primarily by DA uptake mechanisms. However, PCP receptors, but not DA uptake mechanisms, may mediate the cocaine-like behavioral effects of PCP, ketamine and MK-801, because their order of potency in producing these effects (MK-801 greater than PCP greater than ketamine) is consistent with their potency order at PCP receptors, but not at DA uptake sites.

Animals↗

PubMed1988

Intrinsic activity and discriminative effects of drugs.

A conceptual framework has been proposed which coherently specifies the transduction mechanisms of opiate drug stimuli at the behavioral, pharmacological, and molecular levels. One assertion that is inherent in a one-receptor theory of opiate drug discrimination is that the different magnitudes of intrinsic activity that can be produced at the receptor are associated with discrimination effects that differ qualitatively. A number of theoretical inferences are made here concerning the apparent training drug-like agonist and training-drug antagonist effects of compounds that differ in the maximal intrinsic activity which they produce at the receptor. The predicted patterns of mixed and partial agonist and antagonist effects are consistent with available data on the effects of prototype opiate compounds.

Animals↗

PubMed1988

Enhancement by pain and stress of analgesia produced by epidural sufentanil in the rat.

This study examined whether pain or stress can enhance the analgesic effects of spinally administered opiates. The experiments determined the effects of mechanically produced pain and of the stress of being restrained on the analgesic effects of 0.63 microgram of epidural sufentanil in rats using a tail-withdrawal procedure. The painful, as well as the stressful, conditions appeared to increase the duration of opiate analgesia 3.7- and 3.0-fold, respectively. The data offer initial evidence that pain and other stressful conditions can enhance the analgesia produced by spinally administered opiates.

Analgesics, Opioid↗

PubMed1988

Respiratory effects of epidural and subcutaneous morphine, meperidine, fentanyl and sufentanil in the rat.

This study compared the respiratory effects of subcutaneous and epidural morphine, meperidine, fentanyl, and sufentanil in rats breathing air or 8% CO2 in air. A whole body plethysmographic technique was used to measure minute volumes of breathing. The ED50s of subcutaneously injected morphine, meperidine, fentanyl, and sufentanil in depressing the minute volume response to 8% CO2 in air were 2300 micrograms/kg, 8800 micrograms/kg, 20 micrograms/kg, and 2.3 micrograms/kg, respectively. These doses were nearly the same as the subcutaneous ED50s of these compounds in producing analgesia, found in an earlier study. Roughly equianalgesic doses of the four opiates after epidural injection, however, failed to cause any detectable respiratory effect. Fourfold greater doses increased significantly the incidence of low minute volumes with fentanyl and sufentanil, but soon after epidural injection, i.e., at the time that analgesia was produced. None of the epidurally injected opiates had a significant delayed effect on respiration. However, one of the seven rats treated epidurally with the higher dose of morphine developed depression of the minute volume response to 8% CO2 in air as late as 7 hours after the injection. We conclude that epidural injection, in contrast to subcutaneous injection, of analgesic doses of morphine, meperidine, fentanyl, and sufentanil produces no significant respiratory effects.

Animals↗

PubMed1987

A model of chronic pain in the rat: high-resolution neuroanatomical approach identifies alterations in multiple opioid systems in the periaqueductal grey.

Inoculation of the tail base of rats with Mycobacterium butyricum led to an arthritic swelling and inflammation of the limbs which displayed a hyperalgesia to noxious pressure: these effects peaked at 3 weeks postinoculation. In vitro autoradiography of coronal sections of rat brain was used for a parallel determination of binding to mu-, delta- and kappa-opioid binding sites. In only two regions, the dorsomedial and dorsolateral parts of the periaqueductal grey (PAG), was a significant change seen: this comprised an increase in binding to kappa-sites, whereas mu- and delta-sites therein were unaffected. This region was analysed for opioid peptides derived from each of the three opioid peptide families known. While no change was seen in levels of immunoreactive (ir)-dynorphin1-17 A (DYN) and ir-Met-enkephalin, a decrease was detected in those of ir-beta-endorphin (beta-EP): this change was restricted to the PAG. These data demonstrate a highly localized and selective influence of chronic arthritic pain upon multiple opioid systems in the PAG of the rat, a structure playing a key role in the control of pain and in the expression of the antinociceptive actions of opioids. The data suggest a possible significance of PAG pools of beta-EP and kappa-receptors in the response to and modulation of chronic pain.

Animals↗

PubMed1987

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 Parkinson's 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.

Animals↗

PubMed1987

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

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.

Animals↗

PubMed1987

Epidural and subcutaneous morphine, meperidine (pethidine), fentanyl and sufentanil in the rat: analgesia and other in vivo pharmacologic effects.

The experiments examined the characteristics of analgesia produced by different doses of morphine, meperidine (pethidine), fentanyl, and sufentanil after epidural and subcutaneous injection in rats. The specificity of the analgesia was also determined; other in vivo pharmacologic activities (i.e., blockade of pinna and cornea reflexes and production of skeletal muscle rigidity) were monitored as pharmacologic indices of opiate drug activity in the brain. After subcutaneous injection, the opiates produced dose-dependent analgesia, blocked the pinna and cornea reflexes, and induced muscle rigidity. After epidural injection, all four compounds produced dose-dependent analgesia and had greater potency, earlier onset, shorter duration, and greater specificity of analgesic action than was the case after subcutaneous injection. Specificity is defined here as the ratio of the ED50 dose that blocked the pinna reflex to the ED50 dose that produced analgesia. The gains in potency and specificity, but not the gains in onset time and the losses in duration of analgesia, differed considerably among the compounds that were examined. The subcutaneous-to-epidural potency ratio related in a linear manner with the lipid-to-water partition coefficient. The gain in specificity also appeared to be related to lipid solubility. The microgram X kg-1 doses at which the opiates produced analgesia in rats correlate well with the potency of these compounds in producing analgesia after epidural injection in humans. The rat epidural preparation reflected the doses, onset, and specificity, but not the duration, of analgesia produced by epidural opiates in humans.

Analgesia↗

PubMed1987

A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems.

Intradermal inoculation of rats at the tail base with Mycobacterium butyricum led to the gradual development of an arthritic swelling of the limbs which peaked at 3 weeks and subsided thereafter. Arthritic rats displayed a loss of body weight, hypophagia, and hypodipsia in addition to a disruption of the diurnal rhythms of ingestive behavior and of core temperature. The activity of adenohypophyseal beta-endorphin-(beta-EP) secreting corticotrophs, in contrast to prolactin-(PRL) secreting lactotrophs, was increased in arthritic rats. Indeed, hypertrophy of the adrenal glands was seen. Arthritic rats also showed an elevation in spinal cord levels of immunoreactive dynorphin (DYN), an endogenous ligand of the kappa-opioid receptor. The paws and tail of arthritic rats showed lower thresholds in response to noxious pressure (hyperalgesia), higher thresholds in response to noxious heat (hypoalgesia), and no change in their response to noxious electrical stimulation. Neither naloxone nor ICI-154, 129 (a preferential delta-receptor antagonist) modified the responses of the paw or tail to pressure. However, MR 2266 (an antagonist with higher activity at kappa-receptors) decreased thresholds to pressure in arthritic, but not control, rats; that is, it potentiated the hyperalgesia. This action was stereospecific. None of the antagonists modified the response to heat. MR 2266 did not affect the response to pressure in rats with acute inflammation produced by yeast. Thus, the potentiation of pressure hyperalgesia by MR 2266 in chronic arthritic rats is highly selective. Arthritic rats showed a reduced response to the analgesic effect of a kappa-agonist (U-50,488H), whereas the response to a mu-agonist (morphine) was enhanced. These effects were specific to nociception in that their influence upon endocrine secretion (PRL and beta-EP) was otherwise changed. The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U-50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats. It is suggested that polyarthritis is a complex condition entailing many changes, both behavioral and endocrinological. Further, arthritic rats cannot simply be described as "hyperalgesic": of critical importance is the nature of the nociceptive stimulus applied. The parallel alterations in spinal cord pools of DYN and kappa-receptors (see also Millan et al., 1986) and the changes in the influence on nociception of kappa-agonists and kappa-antagonists suggest an increased activity of spinal DYN. Thus, spinal kappa-receptors may play a role in the modulation of nociception under chronic pain.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1987

Drug discrimination in behavioral toxicology.

Drug discrimination is a method of behavioral pharmacology which establishes drugs as discriminative stimuli to behavioral responses. The drug discrimination paradigm typically involves the training of animals to discriminate the administration of a given chemical from that of its vehicle. Prominent features of the paradigm are its exquisite pharmacological specificity, reliability and sensitivity. Toxicology can utilize drug discrimination in at least two ways. Firstly, discriminative effects often signal the presence of chemicals to exposed subjects. Secondly, drug discrimination offers a standardized and well controlled preparation in which measurements are available that are sensitive to possible defects in numerous neurobiological and behavioral functions. Drug discrimination is thus sensitive to defects in neurotransmitter systems, drug-receptor interactions, learning, memory, arousal, motor control, drives, etc. Drug discrimination can be viewed as an encompassing and sensitive technique for the advanced toxicological evaluation of drugs and environmental chemicals.

Animals↗

PubMed1986

A method for quantifying state-dependency with chlordiazepoxide in rats.

A state-dependency procedure is described in which changes from the chlordiazepoxide state yield a robust and dose-dependent response decrement in rats. The format of data that are obtained with this procedure permits that the response decrement following a state change be defined accurately in individual animals, and that transfer be quantified. Dose-response studies revealed 13 (7.4-22) mg/kg to be the ED50 of chlordiazepoxide at which transfer occurred in animals that had acquired the response with 40 mg/kg chlordiazepoxide; the ED50 acquisition dose of chlordiazepoxide at which transfer to saline failed to occur was 3.7 (2.2-6.4 mg/kg).

Animals↗

PubMed1986

The shock probe conflict procedure. A new assay responsive to benzodiazepines, barbiturates and related compounds.

Rats that are placed in a novel environment containing a probe will explore the environment and the probe. Exploration of the probe is reduced when the probe is electrified. We here report that chlordiazepoxide blocks this inhibition, and have determined some of the pharmacological features of this new experimental procedure. The procedure appears to be sensitive to the effects of several benzodiazepines, barbiturates, and related compounds. Limited activity was observed with most 5-HT antagonists, ritanserin, an anticholinergic, a beta-adrenergic blocker and a neuroleptic. Of the antidepressants, only imipramine had some limited activity. Inactive compounds in this procedure include benzodiazepine antagonists, buspirone, convulsants, opiates, an opiate antagonist, stimulants, a putative DA agonist and antagonist, histamine antagonists, a cholinomimetic, anticholinergics, a NE antagonist, alpha 2 agonists, an alpha 2 antagonist, MAO inhibitors, 5-HTP and LSD.

Animals↗

PubMed1986

Agonist and antagonist effects of prototype opiate drugs in fentanyl dose-dose discrimination.

The experiments characterized the effects of fentanyl, morphine, naloxone, cyclazocine, nalorphine, ketocyclazocine and N-allylnormetazocine in rats that were trained to discriminate 0.04 mg/kg from 0.02 mg/kg fentanyl (dose-dose discrimination). The data are compared to results obtained previously in rats discriminating 0.04 mg/kg fentanyl from saline (drug-saline discrimination). In the dose-dose discrimination fentanyl and morphine produced responding appropriate to 0.04 mg/kg fentanyl at doses which were 3.0- and 1.6-fold higher, respectively, than in drug-saline discrimination. Naloxone antagonized the stimulus effects of 0.04 mg/kg fentanyl at 9.8-fold lower doses than in drug-saline discrimination. The dose-effect curves of fentanyl and naloxone in rats discriminating 0.04 mg/kg from 0.02 mg/kg fentanyl, were steeper than in rats discriminating 0.04 mg/kg fentanyl from saline. While cyclazocine, nalorphine and N-allylnormetazocine acted as mixed and partial agonists/antagonists in drug-saline discrimination, those compounds acted as pure and complete antagonists of 0.04 mg/kg fentanyl in dose-dose discrimination. The rank order of compounds in antagonizing the stimulus effects of 0.04 mg/kg fentanyl in dose-dose discrimination was naloxone greater than N-allylnormetazocine greater than cyclazocine greater than nalorphine. It is suggested that a greater magnitude of opiate activity is required for producing generalization with the same 0.04 mg/kg dose of fentanyl in dose-dose as compared with drug-saline discrimination. Dose-dose discrimination may afford a more accurate method of the discriminative stimulus properties of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Symptoms and behavioral features induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an old Java monkey [Macaca cynomolgus fascicularis (Raffles)].

The study concerns symptoms and behavioral characteristics induced by MPTP in a 20-year-old Macaca cynomolgus fascicularis, their evolution over 7 months, and the animal's response to 1-dopa treatment. The symptoms which the animal developed include those that have been described earlier in Macaca mulatta and Saimiri sciureus, i.e., rigidity, action tremor, postural tremor, postural flexion, hypokinesia, and bradykinesia. In addition, however, the animal developed a 3.8 Hz resting tremor which in humans is pathognomonic of Parkinson's disease, as well as cogwheeling, the glabellar tap sign, drooling, impaired ability to relax, and many other symptoms. Also unlike previously described MPTP monkeys, the animal's symptoms neither improved spontaneously, nor did they remain stable shortly after MPTP injection. Instead, symptoms steadily progressed to reach a severe status 2 months after MPTP, and further progression was apparent after another 5 months. Therapeutic responses to 1-dopa required accumulation of or kindling by the 100 mg unit doses that were spaced 4 hr apart, were often organized in time as ON episodes that alternated with OFF episodes, and were associated with dyskinesias and bizarre behavior. Of particular interest is that the animal showed kinesia paradoxa which, in humans, constitutes a feature that is unique to Parkinson's disease among the extrapyramidal disorders. In addition to available evidence, the present findings validate the syndrome induced by MPTP in monkey as an animal analogue of Parkinson's disease. Taxonomic category, age, and the occurrence of shock in response to MPTP are discussed as variables that may possibly co-determine the pathology which MPTP may induce in monkey.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗