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Biomedical subjects

J H Woods

Publications and source records attributed to J H Woods.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacological profile of a potent, efficacious fentanyl derivative in rhesus monkeys.

The recent synthesis of fentanyl derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that mu opioid efficacy might be altered systematically by modifications in the parent compound fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the kappa agonist ethylketocyclazocine and did substitute for the mu agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with mu receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious mu agonist of similar potency to alfentanil. Large differences in apparent efficacy at mu receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.

Animals↗
PubMed1992

Discriminative stimulus effects of cyclorphan: selective antagonism with naltrexone.

The opioid antagonist, naltrexone, was used to identify some of the receptor mechanisms responsible for the discriminative stimulus effects of cyclorphan in the pigeon. Subjects were trained to discriminate 10 mg/kg IM injections of either morphine or dextrorphan from saline injections in a two key drug discrimination procedure in which responding was maintained by food presentation. The dextrorphan-trained birds generalized to l-cyclorphan at 10 mg/kg; naltrexone did not alter the l-cyclorphan dose-response curve for this effect. In the morphine-trained group, l-cyclorphan produced only partial generalization, and naltrexone greatly increased the dose of l-cyclorphan necessary to produce this effect. These results are consistent with the conclusion that in morphine-trained pigeons the partial generalization to l-cyclorphan is mediated by opioid receptors. Moreover, limited intrinsic efficacy at mu opioid receptors may be the characteristic of l-cyclorphan that prevents full generalization in morphine-trained pigeons. d-Cyclorphan produced partial generalization in both groups, but the involvement of opioid receptor mechanisms could not be confirmed, as 1 mg/kg naltrexone did not antagonize d-cyclorphan in either group.

Animals↗
PubMed1992

Differential influence of N-dealkylation on the stimulus properties of some opioid agonists.

The capacity of several opioid agonists and their N-dealkylated derivatives (normetabolites) to substitute for the discriminative and reinforcing stimulus properties of codeine was evaluated in rhesus monkeys, and the affinity of these compounds in binding to mu receptors in rhesus monkey brain membranes was determined. Heroin (0.1 mg/kg), 6-acetylmorphine (0.1 mg/kg), methadone (0.6 mg/kg), 3-acetylmorphine (1 mg/kg), morphine (1 mg/kg) and codeine (1.8 mg/kg) substituted for the codeine cue, but the normetabolites of heroin, 6-acetylmorphine, morphine and codeine did not (up to 10 mg/kg). l-alpha-Acetylmethadol (3 mg/kg) and its mono (0.1 mg/kg) and double (0.6 mg/kg) N-dealkylated derivatives all substituted. In self administration, subjects responded for morphine (0.1 mg/kg/injection) and codeine (0.3 mg/kg/injection), but not for norcodeine (up to 1 mg/kg/injection) or normophine (up to 3 mg/kg/injection). l-alpha-Acetylmethadol (up to 0.3 mg/kg/injection) did not maintain responding, but its mono (0.1 mg/kg/injection) and double (0.1 mg/kg/injection) normetabolites did. In receptor binding, the normetabolites of morphine and 6-acetylmorphine were less potent than their parent agonists in displacing [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol, but the normetabolites of l-alpha-acetylmethadol had greater affinity than their parent. Codeine and norcodeine were inactive in binding. If l-alpha-acetylmethadol is converted only slowly to its active normetabolites, this may explain the lack of efficacy found with this compound in the self administration procedure.

Animals↗
PubMed1992

Clocinnamox: a novel, systemically-active, irreversible opioid antagonist.

The warm water (55 degrees C) tail-withdrawal procedure was used to assess the analgesic effects of the prototypic mu opioid agonists, morphine and fentanyl, in mice. Both drugs produced full analgesic effects under these conditions, which were dose-dependently antagonized by naltrexone. The pA2 values for naltrexone with morphine and with fentanyl were not significantly different. Low doses (e.g., 0.32 mg/kg) of clocinnamox [C-CAM.14 beta-(p- chlorocinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnormorphin one mesylate] produced rightward shifts in the dose-effect curves for each drug, whereas high doses (e.g., 32 mg/kg) depressed the maximal analgesic response. In addition, it was observed that higher doses of C-CAM were required to produce a shift down in the fentanyl dose-effect curve than were required to produce a shift down in the morphine dose-effect curve, which suggests that fentanyl is more efficacious than morphine. The highest dose of C-CAM (32 mg/kg) antagonized the analgesic effect of morphine for up to 8 days. In contrast, the antagonist activity of naltrexone (100 mg/kg) against morphine lasted for only 2 days. Finally, when naloxone was administered simultaneously with 32 mg/kg C-CAM 2 days before determination of the morphine dose-effect function, the antagonist effect of C-CAM was prevented in a dose-dependent manner. Taken together, these results suggest that C-CAM may be producing its antagonist action at opioid receptors through a nonequilibrium mechanism.

Analgesia↗
PubMed1992

Opioid and non-opioid effects of novel butyrophenone analogues.

Haloperidol, haloperidol propionate, and a haloperidol analogue N-3-(p-fluorobenzoyl) propyl-4-phenyl-4-propionyl-oxypiperidine (NIH 10495) were evaluated in several in vitro and in vivo tests of opioid effects. Haloperidol bound to opioid receptors with very low affinity and had no opioid agonist effects in the other test systems. Haloperidol propionate was 10 times less potent than NIH 10495 in the binding assay and in the smooth-muscle assay. Both of these haloperidol analogues decreased the rate and volume of respiration in air and in 5% CO2 with NIH 10495 being approximately 50 times more potent than haloperidol propionate. The NIH 10495, but not the haloperidol propionate, attenuated naltrexone-like discriminative stimulus effects in morphine-dependent withdrawn rhesus monkeys. Intravenously delivered NIH 10495 maintained higher rates of responding than did haloperidol propionate when evaluated for reinforcing effects. These drugs appear to have novel spectra of action that suggest possible value for this synthetic approach to the development of clinically useful analgesics and to the development of novel neuroleptics.

Animals↗
PubMed1992

The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors.

Pigeons were trained to discriminate i.m. injections of the atypical antipsychotic clozapine (1.0 mg/kg) from saline in a two-key operant procedure. In substitution tests, compounds that shared antagonistic action at 5-hydroxytryptamine (5-HT)1C and 5-HT2 receptors produced discriminative stimulus effects similar to clozapine: cyproheptadine, metergoline, mianserin, pizotifen and fluperlapine. 5-HT antagonists selective for 5-HT2 vs. 5-HT1C receptors (e.g., ketanserin, pirenperone, risperidone and methiothepin) failed to produce substantial clozapine-appropriate responding. Other serotonergic compounds failed to produce substantial clozapine-appropriate responding: the 5-HT3 antagonist, ondansetron; the 5-HT1A agonists, (+-)-8-hydroxy-2-(di-n-propylamino)tetralin and BMY 14802; the 5-HT1A/1B agonist, RU24969; the 5-HT1A partial agonist, NAN190; the 5-HT1C/2 antagonist, mesulergine; the 5-HT1 agonist, I-5-hydroxytryptophane; and the 5-HT1C/2 agonist, quipazine. Other reference compounds such as the typical antipsychotics, chlorpromazine and thioridazine; the selective dopamine D-2 antagonists, droperidol and sulpiride; the dopamine D-1 antagonist, SCH 23390; the antimuscarinics, atropine and scopolamine; the antihistamines, pyrilamine and diphenhydramine; the alpha-1 antagonist, prazosin; and the antidepressants, imipramine and chloromipramine also failed to produce clozapine-appropriate responding. Promethazine, cinanserin and amitriptyline produced only partial generalization to the clozapine cue. The results suggest that blockade of both 5-HT2 and/or 5-HT1C receptors is important in the pharmacological mediation of the discriminative stimulus effects of clozapine. Blockade of 5-HT2 receptors appears not to be sufficient to produce clozapine-like discriminative stimulus effects. The precise role of 5-HT1C receptors in the clozapine discriminative stimulus is unclear due to the lack of compounds selective for this receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Tolerance to the cataleptic effect of the N-methyl-D-aspartate (NMDA) receptor antagonists in pigeons: cross-tolerance between PCP-like compounds and competitive NMDA antagonists.

The effects of chronic administration of phencyclidine (PCP) or CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid) on the cataleptic effects of N-methyl-D-aspartate (NMDA) receptor antagonists were studied in pigeons. PCP, a channel blocker of the NMDA receptor complex, or CGS 19755, a competitive NMDA antagonist, was administered i.m. to separate groups of pigeons each day. Tolerance developed to the cataleptic effects in both PCP- and CGS 19755-treated pigeons. PCP tolerance was characterized initially by 5-fold rightward shift and, with an increased chronic PCP dose, a complete downward shift of the PCP dose-effect curve. CGS 19755 tolerance was indicated by a 10-fold rightward shift of its dose-cataleptic effect curve. Cross-tolerance was obtained from PCP to other PCP-like compounds including dizocilpine (MK 801), ketamine, dextrorphan, 1-(2-thienyl)-cyclohexyl-piperidine and [(+)-SKF 10047] [(+)-N-allyl-normetazocine] as well as to the competitive NMDA antagonist, CGS 19755. Cross-tolerance also developed from CGS 19755 to another competitive NMDA antagonist, CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] as well as to PCP-like compounds. The pharmacological selectivity of tolerance was evident because there was equal sensitivity to etomidate or pentobarbital in tolerant and nontolerant pigeons. The symmetric cross-tolerance between PCP-like compounds and competitive NMDA antagonists suggests the cataleptic effects of the two classes of NMDA antagonists are probably mediated via a similar mechanism of inhibition of neurotransmission at the NMDA excitatory synapse.

Animals↗
PubMed1979

Cocaine, d-amphetamine, and pentobarbital effects on responding maintained by food or cocaine in rhesus monkeys.

The effects of IM injections of cocaine, d-amphetamine, and pentobarbital were studied in rhesus monkeys whose lever-press responding was maintained under a second-order fixed-interval, fixed ratio schedule of reinforcement. Within each session, fixed-interval components, ending with the IV injection of 30 microgram/kg cocaine (one group of monkeys) or the delivery of a 300 mg food pellet (second group of monkeys), alternated with fixed-interval components ending without an injection of cocaine or the delivery of food (extinction). Drug pretreatments generally caused comparable dose-related decreases in the overall rates of responding reinforced either by cocaine or by food. Response rates during extinction usually increased and then decreased as the dose of each drug increased. An analysis of the drug effects on response rates in different temporal segments of the fixed intervals showed that in both the reinforcement and extinction components, the normally low control rates of responding which occurred earlier in the intervals were usually increased, while higher control rates which occurred later in the intervals were increased less or decreased. Thus, the effects of these drugs were relatively independent of the reinforcing event (food or cocaine) and tended to depend more on the ongoing rate of responding under these conditions.

Animals↗
PubMed1979

Electromotor feeding responses of primate ileum and colon.

Serosal bipolar electrodes to record spike discharges and strain gauge force transducers to record circular muscle contractions were placed in pairs on the terminal ileum, cecum, right colon at the ileocecal valve, ascending colon, and proximal transverse colon of sixteen primates. After an overnight fast, electromotor responses to continued fasting or to ingestion of a meal (randomized order) were recorded in awake animals. Feeding led to increased spike discharges and increased frequency of muscle contractions at all sites. The onset of these responses usually was within 6 minutes after feeding; the responses increased progressively during 30 to 45 minutes and then remained more or less at a constant plateau of increased activity. Atropine completely blocked the postcibal responses of ileum and proximal colon for up to 30 minutes. Transit time data of labeled meals excluded direct stimulation by a food bolus as the mechanism of the observed postcibal colonic response. The pattern of response was consistent with humoral mediation.

Animals↗