Biomedical subjects

S S Negus

Publications and source records attributed to S S Negus.

At least 55 records · Page 3Linked to original sources

PubMed1996

Acute and chronic effects of flupenthixol on the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys.

It has been proposed that the relatively nonselective dopamine receptor antagonist flupenthixol may be useful in the treatment of cocaine dependence. Drugs used in the treatment of cocaine dependence are administered chronically; however, most preclinical studies have examined only the acute effects of flupenthixol treatment on the effects of cocaine. Consequently, the purpose of the present study was to compare the effects of acute and chronic treatment with flupenthixol (0.0032-0.032 mg/kg) on the discriminative stimulus and reinforcing effects to cocaine in rhesus monkeys. One group of six monkeys was trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced, drug discrimination procedure. A second group of four monkeys was trained to respond for 0.032 mg/kg/injection cocaine (i.v.) and 1-g banana-flavored food pellets during alternating daily cycles of cocaine and food availability. Neither acute nor chronic treatment with a low dose of flupenthixol (0.0032 mg/kg) significantly altered the discriminative stimulus or reinforcing effects of cocaine. Higher doses of flupenthixol (0.01-0.032 mg/kg) produced a surmountable blockade of both the discriminative stimulus and reinforcing effects of cocaine, shifting the dose-effect curves for both cocaine discrimination and cocaine self-administration up to 0.5 log unit to the right. However, doses of flupenthixol that altered cocaine discrimination also decreased response rates. Similarly, doses of flupenthixol that decreased cocaine self-administration also often decreased rates of food-maintained responding. Consequently, nonselective behavioral effects of flupenthixol may have contributed to its effects on cocaine discrimination and self-administration. Moreover, the effects of flupenthixol on cocaine discrimination and self-administration diminished over time. After only 3 to 5 days of chronic treatment, flupenthixol did not consistently shift the cocaine discrimination dose-effect curve to the right. Similarly, rates of cocaine self-administration that were initially decreased by flupenthixol often recovered partially or completely during a 10-day regimen of chronic flupenthixol treatment. These results suggest that flupenthixol may have limited utility in the long-term treatment of cocaine dependence.

Animals↗

PubMed1996

Effects of the structurally novel opioid 14 alpha, 14' beta-[dithiobis [(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinone) on schedule-controlled behavior and thermal nociception in rhesus monkeys.

The in vivo pharmacology of the structurally novel opioid 14 alpha, 14' beta-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinon e) (TAMO) was examined in rhesus monkeys with assays of schedule-controlled behavior and thermal nociception. TAMO (0.032-1.8 mg/kg) produced dose-dependent decreases in response rates maintained under a fixed-ratio 30 schedule of food delivery (n = 3) and increases in tail-withdrawal latencies in a warm-water tail-withdrawal procedure (n = 3). Both the rate-decreasing and antinociceptive effects of TAMO (1.0 mg/kg) were maximal after 40 to 80 min and lasted at least 160 min. Pretreatment with the mu-selective opioid antagonist quadazocine (0.001-0.1 mg/kg) antagonized the effects of TAMO and shifted the TAMO dose-effect curves to the right. Schild analysis yielded in vivo apparent pA2 values (mean +/- S.E.M.) of 8.8 +/- 0.072 and 8.7 +/- 0.40 for quadazocine antagonism of the rate-decreasing and antinociceptive effects, respectively, of TAMO, which suggests that the effects of TAMO were mediated by mu-opioid receptors. In addition, quadazocine (0.1-1.0 mg/kg) reversed the behavioral effects of TAMO (1.0 mg/kg) when quadazocine was administered immediately after TAMO had attained its maximal effect. Twenty-four-hour pretreatment with 1.0 mg/kg TAMO did not significantly after the rate-decreasing or antinociceptive effects of fentanyl or the rate-decreasing effects of morphine. The dose-effect curve for morphine antinociception was shifted 4-fold to the right 24 hr after pretreatment with 1.0 mg/kg TAMO. However, 24-hr pretreatment with an equiactive dose of morphine (10.0 mg/kg) also produced a small (2-fold) but significant rightward shift in the dose-effect curve for morphine antinociception. Twenty-four-hour pretreatment with 1.8 mg/kg TAMO had no effect on the antinociceptive effects of U69,593 (0.0032-0.1 mg/kg). These results suggest that TAMO acts as a reversible mu agonist with a relatively slow onset and a duration of action and relative efficacy similar to those of morphine in rhesus monkeys. Twenty-four hours after TAMO administration, the highest doses of TAMO that could be safely administered produced little or no mu antagonist effects and no kappa antagonist effects.

Analgesics↗

PubMed1995

BW373U86, a delta-opioid receptor agonist, reverses bradykinin-induced thermal allodynia in rhesus monkeys.

The synthetic delta-opioid receptor agonist BW373U86 (0.18-0.56 mg/kg s.c.) was studied in rhesus monkeys with a warm-water, tail-withdrawal assay, designed to detect bradykinin (0.1 microgram) and prostaglandin E2 (5-15.8 micrograms)-induced thermal allodynia. BW373U86 dose-dependently reversed bradykinin allodynia, but was ineffective against prostaglandin E2 allodynia. The BW373U86 dose-effect curve was shifted to the right by the delta-opioid receptor-selective antagonist naltrindole (1.0 mg/kg) but not by the mu-opioid receptor-selective antagonist quadazocine (0.1 mg/kg). The present findings add to the conditions in which delta-opioid receptor-mediated behavioral effects have been detected in primates, and suggest that delta-opioid agonists may be of therapeutic interest in the treatment of some types of hyperalgesic conditions.

Animals↗

PubMed1995

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys.

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013-1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1-3 min post-cocaine) and offset (within 20-60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.

Animals↗

PubMed1995

A primate model of polydrug abuse: cocaine and heroin combinations.

Abuse of cocaine-opiate combinations ("speedballs") reported clinically was simulated in a rhesus monkey model of simultaneous cocaine and heroin self-administration. The reinforcing effects of nine cocaine-heroin combinations (cocaine [0.001, 0.01 and 0.10 mg/kg per injection i.v.] and heroin [0.0001, 0.001 and 0.01 mg/kg per injection i.v.]) were evaluated for 10 days on a second-order fixed ratio of 4 (variable ratio of 16:S) schedule and compared with self-administration of cocaine and heroin alone. Dose-effect curves for cocaine-heroin combinations usually were similar to those for cocaine and heroin alone, and intermediate doses maintained equivalent high levels of drug self-administration. No toxic effects were observed. In drug discrimination studies, cocaine (0.004-1.3 mg/kg) substitution resulted in a dose-dependent generalization to the training dose (0.4 mg/kg i.m.) in all five monkeys. Heroin substitution (0.01-1.0 mg/kg i.m.) resulted in dose-dependent and complete generalization to cocaine in three of five monkeys. Heroin pretreatment (0.1-0.18 mg/kg i.m.) did not change the cocaine discrimination dose-effect curve. Pretreatment with an opiate antagonist, quadazocine (0.1 mg/kg i.m.), had no effect on the discriminative stimulus effects of cocaine but antagonized the cocaine-like discriminative stimulus effects of heroin. Pretreatment with a dopamine antagonist, flupenthixol (0.018 mg/kg), antagonized the discriminative stimulus effects of cocaine but did not affect the cocaine-like effects of heroin. These findings demonstrate the feasibility of maintaining self-administration of cocaine-heroin combinations and suggest that cocaine and heroin have similar reinforcing and discriminative stimulus effects in rhesus monkeys.

Animals↗

PubMed1995

Effects of morphine and ketorolac on thermal allodynia induced by prostaglandin E2 and bradykinin in rhesus monkeys.

When administered s.c. in the tail, both prostaglandin E2 (PGE2; 1.58-158.0 micrograms) and bradykinin (BK; 0.01-1.0 microgram) produced a dose-dependent allodynia in a warm-water tail-withdrawal assay in rhesus monkeys. PGE2 (A50 = 5.3 +/- 0.15 microgram) was 143-fold less potent than BK (A50 = 0.037 +/- 0.012 microgram) in producing allodynia at 42 degrees C. However, PGE2 (15.8 micrograms) was longer acting than an equieffective dose of BK (0.1 microgram), and the highest dose of PGE2 (158.0 micrograms) was the only treatment to produce allodynia when 38 degrees C water was used as the thermal stimulus, suggesting that PGE2 was a more efficacious allodynic agent than BK. Morphine (0.1-3.2 mg/kg) administered s.c. in the back completely blocked the allodynic effects of both BK (0.1 microgram) and PGE2 (15.8 micrograms), although morphine was more than twice as potent against BK (A50 = 0.26 +/- 0.085 mg/kg) than against PGE2 (A50 = 0.65 +/- 0.14 mg/kg). The effects of morphine were antagonized by the opioid antagonist quadazocine (0.1 mg/kg), indicating that morphine's effects were mediated by opioid receptors. The nonsteroidal anti-inflammatory drug ketorolac (0.32-10.0 mg/kg) administered s.c. in the back completely blocked the allodynic effects of BK (A50 = 0.60 +/- 0.095 mg/kg) but did not alter allodynia induced by PGE2. The antiallodynic effects of ketorolac against BK were not antagonized by quadazocine (1.0 mg/kg), indicating that these effects were not mediated by mu or kappa opioid receptors. Furthermore, relative to morphine, ketorolac displayed a slower onset and a longer duration of action. These findings suggest that the allodynic effects of BK in this procedure were mediated entirely by cyclooxygenase products of arachidonic acid metabolism, such as PGE2.

Analgesics, Non-Narcotic↗

PubMed1995

Role of delta opioid receptors in the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys.

The role of delta opioid receptors in the self-administration and discrimination of cocaine by rhesus monkeys was evaluated using the delta opioid antagonist naltrindole and the delta opioid agonist BW373U86 [(+/-)-4-((alpha R*)-alpha-((2S*,5R*)-4-Allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride]. In the self-administration studies, monkeys were trained to respond for food (1 g banana pellets) or cocaine (0.032 mg/kg/injection, i.v.) under a second-order FR4(VR16:S) schedule of reinforcement during multiple daily food and drug sessions. Substitution of saline or other unit doses of cocaine (0.001-0.1 mg/kg/injection) for the maintenance dose of cocaine yielded typical inverted-U shaped dose-effect curves relating unit dose of cocaine to the number of saline or drug injections per day. The unit dose of cocaine available during drug sessions had little effect on food-maintained responding. In the drug discrimination studies, monkeys were trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced drug discrimination task. Cumulative dosing with cocaine (0.004-1.3 mg/kg) produced a dose-dependent generalization to the training dose of cocaine without consistently altering response rates. Initial experiments with naltrindole (0.1-3.2 mg/kg, i.v. or i.m.) produced effects in some monkeys suggesting that naltrindole may have antagonized the effects of cocaine under both procedures. In the drug self-administration studies, treatment with at least one dose of naltrindole for 10 consecutive days decreased self-administration of a unit dose of cocaine at the peak of the ascending limb of the cocaine dose-effect curve (0.01 mg/kg/injection) in three of four monkeys. In the drug discrimination studies, treatment with at least one dose of naltrindole shifted the cocaine dose-effect curve 1/2 log unit to the right in two of four monkeys. However, naltrindole did not alter the effects of cocaine in all monkeys under either procedure. Furthermore, in the monkeys in which naltrindole was effective, the cocaine-antagonist actions of naltrindole were not replicable and were not monotonically related to dose. When the delta agonist BW373U86 (0.001-0.032 mg/kg/inj, i.v.) was substituted for cocaine in one monkey in which naltrindole decreased cocaine self-administration, BW373186 was not self-administered. In addition, BW373U86 (0.0032-0.32 mg/kg, i.m.) neither generalized to cocaine nor potentiated the effects of cocaine in the drug discrimination procedure. These results suggest that delta opioid receptors play, at best, a minor and inconsistent role in the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys.

Animals↗

PubMed1995

Antinociceptive effects of cocaine/opioid combinations in rhesus monkeys.

This study characterized the antinociceptive effects of cocaine alone and in combination with mu, delta, and kappa opioids in rhesus monkeys. The shaved tails of four rhesus monkeys were exposed to warm water (42, 46, 50, 54, and 58 degrees C), and tail withdrawal latencies (20 sec maximum) from each temperature were determined. The temperature that produced a tail withdrawal latency of 10 sec (T10) was interpolated, and drug-induced changes in the T10 value (delta T10) were calculated. Dose-dependent increases in delta T10 were produced by cocaine (0.032-1.8 mg/kg), the high efficacy mu agonist fentanyl (0.001-0.1 mg/kg), the intermediate efficacy mu agonist morphine (0.1-18 mg/kg), the low efficacy mu agonist nalbuphine (1-32 mg/kg), and the kappa agonist U69,593 (0.0032-0.1 mg/kg). The delta agonist BW373U86 (0.56 mg/kg) produced no effect. Relative maximum effects, determined from the maximum delta T10 values produced by each drug, were fentanyl > or = (5,7,8 beta)-N-methyl-N[2-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8- yl]benzeneacetamide > morphine > nalbuphine > or = cocaine > BW373U86. When individual doses of cocaine (0.1-1.8 mg/kg) and morphine (0.32-10.0 mg/kg) were combined, cocaine produced a dose-dependent increase in the effects of each dose of morphine, and the antinociceptive effects of most cocaine/morphine combinations were significantly greater than the antinociceptive effects of either cocaine or morphine alone. Cocaine (1.8 mg/kg) was also combined with nalbuphine (1.0, 10 mg/kg), fentanyl (0.001, 0.032 mg/kg), BW373U86 (0.56 mg/kg) and U69,593 (0.0032-0.056 mg/kg). Cocaine/nalbuphine combinations produced effects markedly greater than either drug alone.

Analgesics, Opioid↗

PubMed1994

Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on kappa-opioid agonists in the mouse writhing assay.

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-dependently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kg beta-FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone.2+ off

Animals↗

PubMed1994

Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys.

l-Deprenyl and its stereoisomer d-deprenyl did not maintain intravenous self-administration behavior in rhesus monkeys. In contrast, l-methamphetamine, the major metabolite of l-deprenyl, as well as the baseline drug, cocaine, maintained high rates of intravenous self-administration behavior. Treatment with l-deprenyl doses up to 1.0 mg/kg before self-administration sessions failed to alter self-administration of either cocaine or l-methamphetamine. Thus l-deprenyl did not appear to have cocaine- or methamphetamine-like reinforcing properties in monkeys and was ineffective in altering established patterns of psychomotor-stimulant self-administration behavior. These results support clinical findings that despite long-term use of l-deprenyl for the treatment of Parkinson's disease by large numbers of patients, no instances of abuse have been documented. l-Deprenyl has recently been suggested as a potential medication for the treatment of various types of drug abuse, including cocaine abuse, but its failure to produce selective effects in decreasing cocaine or methamphetamine self-administration behavior in the present experiments makes such an application seem unlikely.

Animals↗

PubMed1994

Behavioral effects of the systemically active delta opioid agonist BW373U86 in rhesus monkeys.

The behavioral effects of (+-)-4-((alpha R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (BW373U86), a nonpeptidic, systemically active, delta opioid agonist, were examined in rhesus monkeys. BW373U86, the mu agonist alfentanil and the kappa agonist U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro- (4,5)dec-8-yl)benzeneacetamide] all produced a dose-dependent suppression of response rates maintained under a fixed ratio 30 schedule of food presentation. The rate-suppressing effects of BW373U86 lasted 1 to 2 hr and were no longer apparent after 4 hr. The selective delta antagonist naltrindole (NTI) antagonized the effects of BW373U86 with relatively high potency (pKB = 6.5) and the antagonist effects of NTI against BW373U86 lasted approximately 4 hr. NTI was less potent in antagonizing alfentanil (pKB = 5.1) and the highest dose of NTI examined (10.0 mg/kg) did not antagonize U69,593. BW373U86 did not generalize to the discriminative stimulus effects of the mu agonist alfentanil or the kappa agonist ethylketocyclazocine. BW373U86 also did not produce antinociceptive effects in the warm-water tail-withdrawal procedure, significant respiratory depressant effects in monkeys breathing either air or 5% CO2 or reinforcing effects in a self-administration procedure. The highest dose of BW373U86 examined (1.78 mg/kg) produced convulsions in one monkey. The high relative potency of NTI to antagonize the rate-suppressing effects of BW373U86 was consistent with the characterization of BW373U86 as a systemically active, delta-selective agonist in rhesus monkeys. Under the conditions evaluated in the present study, the delta receptors to which BW373U86 binds do not appear to mediate antinociceptive, respiratory depressant or reinforcing effects in monkeys.

Analgesics↗

PubMed1993

Effects of opioid agonists selective for mu, kappa and delta opioid receptors on schedule-controlled responding in rhesus monkeys: antagonism by quadazocine.

Rhesus monkeys were trained to respond under a fixed-ratio 30 schedule of food reinforcement. The mu opioid agonists alfentanil and fentanyl, the kappa opioid agonists ethylketocyclazocine (EKC) and U69,593, the delta opioid agonist BW373U86 [(+-)-4-((R*)-a-((2S*5R*)-4-allyl-2,5-dimethyl-1-piperazinal)-3-h ydroxy- benzyl)-N,N-diethylbenzamide dihydrochloride] and the nonopioid, noncompetitive N-methyl-D-aspartate antagonist ketamine all produced a dose-dependent decrease in rates of responding. Quadazocine (0.1-10 mg/kg) antagonized the rate-decreasing effects of all the opioid agonists, but not of ketamine. The in vivo apparent pA2 values (95% CL) for quadazocine in combination with each agonist were: alfentanil, 7.7 (7.6-7.8); fentanyl, 7.7 (7.6-7.8); EKC, 6.3 (5.9-6.7); U69,593, 6.5 (5.9-7.0); and BW373U86, 5.5 (5.3-5.8). Additionally, antagonist effects of individual doses of quadazocine in combination with each agonist were evaluated by using in vivo apparent pKB analysis, and pKB values were found to be similar to the more rigorously determined pA2 values. The relative pA2 and pKB values of quadazocine in antagonizing the rate-decreasing effects of mu, kappa and delta opioid agonists corresponded to the relative potency of quadazocine in displacing the specific binding of the mu agonist [3H]Tyr-D-Ala-Gly-(Me)-Phe-Gly-ol (IC50 = 0.080 nM), the kappa agonist [3H]U69,593 (IC50 = 0.52 nM) and the delta agonist [D-Pen2,D-Pen5]-[3H]enkephalin (IC50 = 4.6 nM) from binding sites in membranes from monkey brain cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1993

Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys.

The effects of subcutaneously administered nor-binaltorphimine (nor-BNI; 1.0 and 3.2 mg/kg) were examined in the warm-water (50 degrees C and 55 degrees C) tail-withdrawal assay in rhesus monkeys (n = 3). Nor-BNI alone produced variable antinociceptive effects in 50 degrees C water up to 3.5 hr after administration but was completely ineffective against the 55 degrees C stimulus. Pretreatment with nor-BNI under conditions where it was devoid of antinociceptive effects produced rightward shifts in dose-effect curves for the kappa opioid agonist U50,488 for as long as 14 and 21 days after 1.0 and 3.2 mg/kg of nor-BNI, respectively. Under conditions when U50,488 dose-effect curves were shifted, nor-BNI (3.2 mg/kg) also caused rightward shifts in the antinociceptive dose-effect curves of the kappa agonist U69,593 but not in those of the mu agonist alfentanil or the kappa agonists [5R-(5,7,8,beta)]N-methyl-N-[7- (1-pirrolidinyl)1-oxaspiro[4,5]dec-8-yl]4-benzofuranaceta mide, bremazocine, ethylketocyclazocine and Mr2033. It is concluded that under the present conditions, nor-BNI acts as a selective kappa opioid antagonist with an extremely long duration of action. These findings are also consistent with the notion that nor-BNI may antagonize only compounds acting at a subtype of kappa opioid receptor.

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

PubMed1993

Prostaglandin E2-induced thermal hyperalgesia and its reversal by morphine in the warm-water tail-withdrawal procedure in rhesus monkeys.

Four monkeys were seated in primate restraint chairs and the terminal 10 cm of their shaved tails were dipped into water maintained at a series of temperatures ranging from 38-54 degrees C. The latency to tail withdrawal from several temperatures was measured and temperature-effect curves for each monkey were generated. When administered s.c. into the tail, prostaglandin E2 (PGE2; 0, 1.58, 5.0 and 15.8 micrograms) produced a dose-dependent hyperalgesia manifested as dose-dependent leftward shifts in the temperature-effect curves. This hyperalgesia peaked 15 to 45 min after administration and lasted for approximately 2 hr. PGE2-induced hyperalgesia was mediated locally, because administration of 15.8 micrograms of PGE2 into the back had no effect on the temperature-effect curve. The hyperalgesic effects of PGE2 were reversed potently by morphine (0.32-3.2 mg/kg), and the effects of morphine were antagonized in a surmountable manner by both the opioid antagonist quadazocine (0.1 mg/kg) and by systemic administration of the charged opioid antagonist quaternary naltrexone (3.2 mg/kg). These results indicate that PGE2 produces thermal hyperalgesia in rhesus monkeys and also suggests that this hyperalgesia may be reversed by activation of peripheral opioid receptors. PGE2-induced hyperalgesia in the warm-water tail-withdrawal procedure may provide a useful assay for evaluating the effects of pharmacological and nonpharmacological treatments on hyperalgesia associated with inflammation in primates.

Animals↗

PubMed1993

Effect of antagonists selective for mu, delta and kappa opioid receptors on the reinforcing effects of heroin in rats.

Antagonists selective for mu, delta and kappa-opioid receptors were evaluated for their effects on responding maintained by i.v. injections of heroin (60.0 micrograms/kg/injection) in rats during daily 3-hr sessions. Under base-line conditions, rats self-administered 10 to 20 heroin injections during each session, and injections were separated by relatively constant interinjection intervals of about 10 to 20 min. The mu-selective antagonist beta-funaltrexamine (beta-FNA; 5.0-20.0 mg/kg, s.c.) produced a dose-dependent increase in responding for heroin, with some doses of beta-FNA producing an extinction-like pattern of responding. These results were qualitatively similar to the effect obtained by lowering the unit dose per injection of heroin. The mu 1-selective antagonist naloxonazine (NXZ; 7.5-30.0 mg/kg, i.v.) and the delta-selective antagonist naltrindole (1.0-17.0 mg/kg) also produced dose-dependent increases in heroin self-administration, but neither naloxonazine nor naltrindole produced extinction-like patterns of responding. The kappa-selective antagonist nor-binaltorphimine (nor-BNI; 5.0-10.0 mg/kg, s.c.) had no effect on heroin self-administration. These results indicate that mu receptors play an important role in mediating the reinforcing effects of heroin in the rat. Delta and mu 1 receptors, but not kappa receptors, may also be involved.

Animals↗

PubMed1993

Antagonist effects of beta-funaltrexamine and naloxonazine on alfentanil-induced antinociception and muscle rigidity in the rat.

Alfentanil is a potent and short-acting mu opioid agonist that produces both antinociceptive effects and muscle rigidity. In the present study, the susceptibility of alfentanil-induced antinociception and rigidity to antagonism by the selective mu antagonist beta-funaltrexamine and the selective mu-1 antagonist naloxonazine was examined. Alfentanil (37.7-150.0 micrograms/kg) produced a dose-dependent increase both in antinociception as measured by the warm-water tail-dip assay and in rigidity as measured by electromyographic recording of the gastrocnemius muscle. Both beta-funaltrexamine (10.0 and 20.0 mg/kg) and naloxonazine (7.5 and 15.0 mg/kg) produced dose-dependent and parallel rightward shifts in the alfentanil dose-effect curves for both antinociception and rigidity. Furthermore, the alfentanil dose-effect curves for antinociception and rigidity were shifted to the right to a similar degree by any given pretreatment. These results suggest that alfentanil-induced antinociception in the warm-water tail-dip test and rigidity are mediated by pharmacologically similar populations of opioid receptors. More specifically, these results suggest that mu-1 opioid receptors mediate both alfentanil-induced antinociception and rigidity.

Alfentanil↗

PubMed1992

Elucidation of dose-effect relationships for different opiate effects using alfentanil in the spontaneously ventilating rat.

In addition to producing antinociception and mild sedation, opiates diminish spontaneous movement and produce muscle rigidity. Examination of the relationship between different opiate effects may lead to a better understanding of the mechanism and sites of action of opiate anesthesia. Previous studies have compared the dose-effect relationships for morphine and fentanyl between antinociception and loss of righting reflex. However, neither muscle rigidity nor lack of spontaneous movement (as measured by catalepsy) has been fully examined or directly compared with either antinociception or loss of righting reflex. This study, therefore, compared five clinically relevant opiate endpoints (antinociception, muscle rigidity, catalepsy, loss of righting reflex, and respiratory depression) using the mu-selective agonist alfentanil in the spontaneously ventilating rat. Rats were randomized to receive alfentanil (0-500 micrograms/kg) subcutaneously. For muscle rigidity, 59 rats had electromyographic activity measured with percutaneous hindlimb electrodes. After alfentanil injection, electromyographic data were recorded for 60 min. For antinociception and catalepsy, 49 rats were studied for 120 min after alfentanil. Catalepsy was measured from the time the rat's forelimbs were placed on a 10-cm-high bar until either limb was removed. Antinociception was studied by measuring tail-flick response to hot (55 degrees C) water. For righting reflex, 40 rats were studied for 120 min. Alfentanil-induced respiratory depression was assessed in 40 rats with indwelling tail arterial catheters. Alfentanil was administered after baseline arterial blood gas measurements, and then additional samples were obtained for 45 min. For each effect, data were converted into quantal responses and were then transformed to probit-log dose-response curves for analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗

PubMed1992

Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats.

The present study examined the effects of morphine, the intermediate efficacy mu opioids (-)-pentazocine, (-)-metazocine, proxorphan, levallorphan, (-)-NANMY (N-allylnormetazocine) and (-)-cyclazocine, and the mu antagonist naloxone 1) in rats responding under a FR (fixed-ratio) 30 schedule before, during and after a chronic morphine regimen, and 2) in rats trained to discriminate 10.0 [10-MS (morphine sulfate)] or 3.0 mg/kg (3-MS) of morphine from saline. Under the FR30 schedule, chronic administration of morphine produced tolerance to morphine's rate-decreasing effects and conferred cross-tolerance to (-)-metazocine, proxorphan and (-)-pentazocine. However, the effects of these intermediate efficacy mu opioids could be differentiated from those of morphine on the basis of their 1) shallow dose-effect curves, and 2) large differences in the degree to which tolerance developed in individual rats. In the drug discrimination procedure, (-)-metazocine, proxorphan and (-)-pentazocine produced high levels of substitution for the 3-MS stimulus and intermediate levels for the 10-MS stimulus. In contrast to the pattern of substitution observed with morphine in the 10-MS group, the effects of these drugs were characterized by 1) shallow dose-effect curves, 2) large individual differences in the lowest dose of each drug that substituted completely for the 10-MS stimulus and 3) the failure to obtain complete substitution for the 10-MS stimulus in all of the rats tested. The behavioral profile obtained with the intermediate efficacy mu opioids (-)-NANM, levallorphan and (-)-cyclazocine was indicative of opioids with intrinsic efficacy lower than that of (-)-pentazocine, (-)-metazocine and proxorphan. Under the FR30 schedule, chronic administration of morphine produced an enhanced sensitivity to the rate-decreasing effects of (-)-NANM and levallorphan but not (-)-cyclazocine. In the drug discrimination procedure, (-)-NANM, levallorphan and (-)-cyclazocine produced high levels of substitution for the 3-MS stimulus and low levels for the 10-MS stimulus. Like naloxone, these drugs produced a dose-related attenuation of the 10-MS stimulus. The results of the present study suggest that the relative order of intrinsic efficacy among the opioids tested is: morphine > (-)-metazocine = (-)-pentazocine = proxorphan > (-)-cyclazocine = levallorphan = (-)-NANM > naloxone.

Animals↗