Acute extrapyramidal syndrome in Cebus monkeys: development mediated by dopamine D2 but not D1 receptors.

The present study assessed the role of dopamine D1 and D2 receptors in the production of an extrapyramidal syndrome (EPS) in Cebus apella monkeys. Previous studies have shown the development of EPS in both old and new world monkeys with haloperidol administration. We now report that repeated weekly administration of a selective D1 antagonist, SCH 23390, does not produce this syndrome in cebus monkeys. Cebus monkeys were treated with either vehicle (n = 6), the specific D2 antagonist haloperidol (0.3 mg/kg p.o., n = 9) or the specific D1 antagonist SCH 23390 (10.0 mg/kg p.o., n = 9) once a week for approximately 1 year and behavioral effects were observed and scored. The drug doses used in this study produced similar sedative scores when given acutely and sedation increased over the first 12 weeks of the study for both treatment groups. However, by the 12th week of dosing with haloperidol all the monkeys showed a profound EPS characterized by limb extensions, head pushing, tongue protrusions and sometimes severe biting movements. In contrast, none of the SCH 23390-treated monkeys showed any abnormal movements, suggesting D1 antagonists have a low EPS side-effect liability. The profile of the incidence of EPS seen with classical neuroleptic drugs in cebus monkeys and their blockade of EPS by anticholinergic drugs mimics the profile seen in humans. The models presented appear to be predictive of the production of the EPS in humans and could be used to screen neuroleptics for EPS liability. Furthermore, the EPS is probably due to the selective blockade of dopamine D2 receptors with its associated enhancement of cholinergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Similarity of clozapine and SCH 23390 in reserpinized rats suggests a common mechanism of action.

Clozapine at doses up to 100 mg/kg p.o. did not antagonize apomorphine-induced stereotypy in vehicle pre-treated rats. However, if the animals were injected with reserpine (30 mg/kg i.p.) 24 h prior to the test, then clozapine (3-100 mg/kg p.o.) produced a dose-related blockade of apomorphine-induced stereotypy. The blockade of apomorphine-induced stereotypy in reserpinized rats by clozapine was attenuated by the D-2 selective agonist LY 171555 but not the D-1 selective agonist SKF 38393. This profile of agonist reversal of antagonist blockade of apomorphine-induced stereotypy seen with clozapine was identical to that seen with the selective D-1 antagonist SCH 23390. Presumably, the D-2 agonist was active because D-1 receptor systems were inhibited (either at the receptor or at some other post-synaptic site) by clozapine or SCH 23390; this allowed a partial restoration of apomorphine-induced stereotypy via the D-2 system. Therefore, these data indicate that clozapine and SCH 23390 share a common mechanism of action via D-1 receptor systems.

Pharmacological effects of SCH 30497--a novel analgesic substance.

SCH 30497 (2-[3-(1,2,3,6-tetrahydro-4-2(methylphenyl)-pyridin-1-yl) -propyl]-1,2,4-triazolo[4,3-a] pyridin-3-(2H)-one) was tested for analgesic effects in the rat, mouse and squirrel monkey. SCH 30497 showed dose-related analgesic effects in the rat yeast-paw test; at peak times the ED7sec (95% confidence limits) in mg/kg via the oral, subcutaneous, intramuscular and intravenous routes of administration were as follows, respectively: 4.7 (2.1-9.8), 5.7 (3.4-9.6), 6.4 (4.1-9.8) and 1.4 (0.6-3.2). SCH 30497 was also analgesic in the acetic acid-induced writhing test in mice (ED50 = 1.9 mg/kg p.o.) and the squirrel monkey shock titration test (ED50 = 14.5 mg/kg p.o.). It was inactive in the mouse (100 mg/kg p.o.) and rat (40 mg/kg p.o.) tail-flick tests. Thus, SCH 30497 was efficacious versus chemical, mechanical and electrical nociceptive stimuli. Naloxone antagonism of the analgesic effects of SCH 30497 was species specific with significant inhibition observed only in the rat and not in the mouse or monkey. SCH 30497 did not produce Straub tail or hyperactivity in mice. Twice daily dosing at 30 mg/kg p.o. to rats for 5 days failed to produce tolerance; in separate experiments, daily injections for 10 days at 20 or 100 mg/kg p.o. failed to induce signs of dependence following naloxone challenge. SCH 30497-induced analgesia was not attenuated in rats previously made tolerant to narcotics by implantation of a morphine pellet. SCH 30497 showed a weak ability to displace 3H-Met5-enkephalin from its binding sites on rat brain membranes (IC50 = 48 microM). SCH 30497 (100 microM) did not affect prostaglandin synthesis in vitro. In vivo, the drug did not have anti-inflammatory or ulcerogenic effects up to 80 mg/kg p.o. Acute behavioral, neurological and autonomic side effects were primarily depressant in rodents and occurred at doses greater than 15 times those that were analgesically relevant. Moderate doses in the monkey (2.5 times the ED50) and high doses in mice produced convulsions. It is hypothesized that SCH 30497-like drugs represent a new class of analgesics based on this unique pharmacological spectrum of activity.

Subplantar yeast injection induces a non-naloxone reversible antinociception in spontaneously hypertensive rats.

Spontaneously hypertensive (SH), Wistar Kyoto (WKY) or Sprague-Dawley (SD) rats were tested for their responsiveness to noxious mechanical pressure before and after a subplantar yeast injection to the right rear paw. Prior to the yeast injection, hypertensive animals were less responsive to pain relative to normotensive animals, as seen in the significantly greater pre-yeast latencies of SH compared to WKY or SD rats. Subplantar yeast injection produced hyperreactivity in the inflamed paws of WKY or SD rats, with no effect on the contralateral non-injected paw. However, identical subplantar yeast injections to hypertensive animals produced a robust, long-lasting antinociceptive effect in both rear paws of SH rats. This effect was not reversed by naloxone (opiate antagonist), labetalol (beta-blocker/vasodilator antihypertensive), or hydralazine (peripheral vasodilator antihypertensive); the antinociception was not potentiated by thiorphan (enkephalinase inhibitor). However, the alpha 2-receptor antagonist yohimbine (0.1-5 mg/kg s.c.), produced a dose-related reversal of the yeast-induced antinociception in SH rats. These results suggest that the subplantar yeast injection is triggering descending noradrenergic pain inhibitory pathways in SH rats.

Effect of cyclo-leucyl-glycine in the rat yeast-paw test.

Cyclo-leucyl-glycine (CLG) was tested for its ability to produce an antinociceptive effect in the rat yeast-paw test under conditions in which Z-prolyl-(L)leucine (ZPLL) was effective. CLG at doses from 0.1 to 200 mg/kg p.o. given once per day for three days failed to produce an analgesic effect; at 300 mg/kg per day p.o., CLG produced a slight increase in response latencies (less than 1 s). ZPLL (5 mg/kg per day p.o.) tested similarly in the same experiment produced a strong analgesia (greater than 10 s increase in response latencies). Since CLG and ZPLL have both been shown to inhibit opioid tolerance/dependence, whereas only ZPLL has been demonstrated to produce analgesia, it appears as if the mechanisms underlying these two effects are different.

Determination of analgesic drug efficacies by modification of the Randall and Selitto rat yeast paw test.

This report describes a modified Randall and Selitto (1957) rat yeast paw test that can evaluate differences in efficacy of different analgesics. The modifications consist of a decrease in the rate of acceleration of the noxious stimulus (mechanical pressure) on the inflamed paw from 20 to 12.5 mmHg/sec and an extension of the cut-off time from 15 to 60 sec. All the narcoticlike drugs tested (morphine, codeine, and pentazocine) increased the response latencies of the inflamed paws to the cut-off time. The nonsteroidal antiinflammatory-like drugs tested (acetylsalicylic acid, acetaminophen, indomethacin, phenylbutazone, and proquazone) showed plateaus in their analgesic effects (i.e., increasing the dose failed to produce significantly greater increases in the response latencies compared to the next lower dose). Zomepirac (80-240 mg/kg p.o.) did not show this plateau effect, but was unable to increase response latencies to greater than 30 sec because of the toxicity of higher doses (320 mg/kg p.o.). Flunixin NMG (the meglumine salt of flunixin), a nonnarcotic analgesic, did not display a plateau effect and increased response latencies to maximum values. The methodology was therefore able to discriminate analgesics active against mild to severe clinical pain (narcoticlike) from those only useful against mild to moderate pain (nonnarcotic-like).

Potentiation of stress-induced analgesia (SIA) by thiorphan and its block by naloxone.

Exposure of rats to inescapable footshock produces an analgesic effect. To determine if endogenously released enkephalins play a role in this phenomenom, rats were treated with the enkephalinase inhibitor thiorphan (T), exposed to inescapable stress, and tested in the tail-flick test for antinociception. T (10-100 mg/kg sc) caused a dose-related potentiation of both the peak effect and the duration of the SIA. This effect was blocked by doses of naloxone (1 mg/kg sc) that did not affect baseline response latencies.

Antagonism of the analgesic effect of opioid and non-opioid agents by p-chlorophenylalanine (PCPA).

The ability of p-chlorophenylalanine (PCPA), an inhibitor of serotonin (5HT) biosynthesis to antagonize the antinociceptive effects of three classes of analgesics: opiates agonist (morphine), opiate agonist-antagonist (pentazocine) and non-steroid anti-inflammatory (aspirin and clonixin) were evaluated using the rat yeast paw test. The analgesic effect of equipotent doses of each of these drugs was abolished 48 h after PCPA (300 mg/kg i.p.) PCPA (150 mg/kg i.p.) reduced the relative potencies of morphine and aspirin to the same degree. The effect could not be attributed to a hyperalgesia or to an interaction with inflammatory mechanisms. PCPA did not alter the anti-edema activity of clonixin and it blocked morphine-induced increases in reaction times to pressure applied to the non-inflamed paw to the same extent as in the inflamed paw. The serotonin precursor 5-hydroxytryptophan (5HTP, 80 mg/kg i.p.) restored the antinociceptive activity of all four drugs. These results demonstrate serotonin can modulate sensitivity to analgesics with differing mechanisms of action.

Flunixin meglumine: a non-narcotic analgesic.

The N-methyl-d-glucamine salt of flunixin (flunixin meglumine) is a potent non-narcotic analgesic agent after parenteral administration in mice, rats and monkeys. It is significantly more potent than pentazocine, meperidine and codeine in the rat yeast paw test after subcutaneous administration in saline. Activity on intramuscular administration is comparable to that after subcutaneous administration and is enhanced when dissolved in buffered saline as compared to nonbuffered saline. In addition, flunixin meglumine also had oral activity and differs from indomethacin in having more analgesic activity per unit of anti-inflammatory activity. In mice, flunixin meglumine is equipotent to pentazocine and more potent than meperidine and codeine in the abdominal constriction test. In primates, flunixin meglumine at 10 mg/kg i.m., produced a degree of analgesic efficacy comparable to that of a clinically effective dose of morphine (0.3 mg/kg). In contrast to codeine, tolerance to the analgesic action of flunixin meglumine was not observed. Furthermore, flunixin meglumine retained its activity in rats made tolerant to codeine. Unlike narcotics, the analgesic effect of flunixin meglumine is not antagonized by naloxone after acute administration in rats. These results indicate that flunixin meglumine is a parenterally and orally effective analgesic in animals and is unlikely to have narcotic or drug dependence liability.