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J H Woods

Publications and source records attributed to J H Woods.

At least 19 recordsLinked to original sources
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

Competitive and uncompetitive N-methyl-D-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine.

The purpose of the present studies was to examine representative uncompetitive and competitive NMDA antagonists, as well as the glycine/NMDA antagonist, HA 966, in pigeons trained to discriminate either PCP or CGS 19755 from saline. Separate groups of pigeons were trained to discriminate either the uncompetitive, phencyclidine (PCP; 0.32 and 1.0 mg/kg, IM), or the competitive, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid; 1.8 mg/kg, IM), NMDA antagonists from saline. Uncompetitive and competitive NMDA antagonists were examined in generalization studies, as were the racemate and the (+) and (-) stereoisomers of HA 966 (3-amino-1-hydroxypyrrolid-2-one). Dizocilpine (MK 801) was fully generalized to PCP but not to CGS 19755. All competitive NMDA antagonists tested were fully generalized to CGS 19755, but not to PCP. The competitive antagonists, however, produced > 50% PCP-appropriate responding. The (+) isomer of HA 966 was fully generalized by three of four pigeons discriminating PCP (1.0 mg/kg) or CGS 19755, whereas the racemate and the (-) isomer produced < 40% drug-appropriate responding in either group. Neither NMDA, morphine, nor pentobarbital produced > 10% drug-appropriate responding in either discrimination group. The competitive antagonists tended to produce peak drug-appropriate responding at times greater than 60 min after administration, whereas uncompetitive antagonists produced peak drug-appropriate responding at earlier times. HA 966 also had a relatively slow onset of action as compared to PCP. These results suggest that antagonists acting at different modulatory sites of the NMDA receptor complex produce similar, but not identical, discriminative stimuli.

Animals↗
PubMed1995

Current benzodiazepine issues.

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronically, and although this does not appear to result in dose escalation or other evidence of "psychological dependence," physiological dependence can result in patient discomfort if drug use is abruptly discontinued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.

Age Factors↗
PubMed1995

Receptor reserve and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding.

In order to quantitate the extent to which opioid agonist potencies obtained in behavioral assays are determined by the apparent in vivo affinity and efficacy of the agonist, the antinociceptive effects of the mu opioid agonists morphine, fentanyl, etonitazene, and NIH 10741 were assessed before and after administration of the insurmountable mu opioid antagonist clocinnamox (CCAM) in a 55 degrees C warm-water tail withdrawal test in Swiss albino mice. Under control conditions, all four mu opioid agonists produced a full antinociceptive response with the following ED50 values (in mg/kg): morphine, 12; fentanyl, 0.47; etonitazene, 0.039; NIH 10741, 0.0051. Analysis of CCAM's effects according to Black and Leff gave the following agonist efficacy or tau values: Morphine, 4; fentanyl 15, etonitazene, 7; and NIH 10741, 59. The respective KA values were (in mg/kg): morphine, 29; fentanyl, 7.3; etonitazene, 0.22; and NIH 10741, 0.30. The major determinant of the experimentally observed ED50 values seemed to be the apparent in vivo affinity of the respective agonist and not its efficacy. KA values (expressed as mol/kg) correlated with the Ki values (in mol/l) obtained with [3H]DAMGO radioligand binding (r = 0.96 for pKA vs. pKi), although being on average 11,000-fold higher. Values for q, the available receptor fraction as determined in the behavioral experiments, correlated strongly (r = 0.96) with the q values determined by ex vivo [3H]DAMGO- and [3H]naltrexone equilibrium binding (i.e., Bmax,clocinnamox/Bmax,control), the relationship approaching unity.

Analgesia↗
PubMed1995

Agonist and antagonist effects of dynorphin A-(1-13) in a thermal antinociception assay in rhesus monkeys.

The agonist and antagonist effects of intravenously administered dynorphin A-(1-13) were characterized in the warm water (50 and 55 degrees C) tail withdrawal assay of antinociception in rhesus monkeys. The peptide dose-dependently elevated tail withdrawal latencies in 50 degrees C water, but was ineffective in 55 degrees C water. The antinociceptive effect of dynorphin was surmountably antagonized by quadazocine (0.1 mg/kg) and nor-binaltorphimine (3.2 mg/kg), but was not antagonized by clocinnamox (0.1 mg/kg); this pattern of antagonism is consistent with a kappa-opioid receptor mediated effect. Pretreatment with dynorphin A-(1-13) (0.032-3.2 mg/kg) antagonized the antinociceptive effects of U50,488 and U69,593 in 55 degrees C water, suggesting a low efficacy action of the peptide at the receptors activated by these kappa agonists. However, dynorphin A-(1-13) (3.2 mg/kg) did not antagonize other kappa agonists: bremazocine (0.018-0.056 mg/kg) and enadoline (0.0056-0.018 mg/kg). Taken together, these dynorphin A-(1-13) findings support the notion of functional kappa-opioid receptor subtypes, and it appears that dynorphin A-(1-13) has limited efficacy at one of these sites. Finally, dynorphin A-(1-13) (0.32 mg/kg) also antagonized the antinociceptive effects of the mu-agonist etonitazene (0.0018-0.01 mg/kg).

Analgesics↗
PubMed1995

Behavioral effects and receptor binding affinities of fentanyl derivatives in rhesus monkeys.

These studies examined the opioid receptor binding affinities and behavioral effects of several fentanyl derivatives in rhesus monkeys. OHM3295, OHM3296, OHM3326 and OHM3463 displayed high affinity for mu (IC50 = 7-66 nM) as compared to kappa (IC50 = 263-3255 nM) or delta (IC50 = 480-4500 nM) receptors as measured by their ability to displace [3H](D-Ala2-Me-Phe4,Glyol5)enkephalin, [3H](5,7,8[beta])-N-[2- (1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]benzeneacetamide and [3H](D-Pen2-D-Pen5)enkephalin, respectively. All four compounds maintained i.v. self-administration responding at rates above those maintained by the mu agonist alfentanil. In drug discrimination studies, OHM3463, OHM3326 and OHM3296 substituted completely for nalbuphine whereas OHM3295, and a related compound, mirfentanil, substituted partially for nalbuphine. In morphine-treated monkeys, OHM3295 substituted for naltrexone; in monkeys acutely deprived of morphine, only OHM3463 reversed naltrexone-lever responding. All four compounds had antinociceptive effects, although the extent to which these effects were accompanied by respiratory depression or modified by naltrexone, as well as the interactions between antinociceptive effects of fentanyl derivatives and alfentanil, varied markedly among compounds. Thus, OHM3463 shared effects with mu agonists (e.g., alfentanil) under all conditions; the other three compounds had opioid agonist effects under only a subset of conditions. Moreover, one of these compounds (OHM3295) antagonized the discriminative stimulus and antinociceptive effects of other mu agonists. Collectively, these compounds appear to vary on two dimensions: opioid efficacy and the contribution of nonopioid actions to their antinociceptive effects. Together with results obtained with other fentanyl derivatives (mirfentanil) under similar conditions, results of the current study suggest this chemical class might be especially fertile for the development of novel analgesics that might have reduced toxicity and abuse liability as compared to fentanyl and related compounds that are currently used in medicine.

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

Buprenorphine antagonism of mu opioids in the rhesus monkey tail-withdrawal procedure.

The apparent in vivo dissociation constant (KA) and relative efficacy values for alfentanil, etonitazene, morphine, and nalbuphine were determined by comparing the effects of these agonists in the presence of buprenorphine with the effects of these agonists alone in the rhesus monkey tail-withdrawal procedure. Initial time course studies of buprenorphine alone indicated that 3.2 and 10 mg/kg produced increases in tail-withdrawal latencies when studied with 48 degrees C water for 48 hr. No increases in tail-withdrawal latency were found with either dose studied with 55 degrees C water. Buprenorphine produced dose-dependent shifts to the right for the antinociceptive effects of alfentanil, etonitazene, morphine and nalbuphine 72 hr after administration and decreased the maximal effects of morphine in 48 degrees C water and those of alfentanil and etonitazene in 55 degrees C water. Buprenorphine administration decreased the receptors available for agonist interaction to approximately 2%. The average apparent in vivo dissociation constant (KA) values for alfentanil, etonitazene, morphine and nalbuphine were 3.3, 0.073, 60 and 31 mg/kg, respectively. High efficacy estimates were determined for alfentanil (149-203) and etonitazene (174-203), whereas lower efficacy estimates were determined for nalbuphine (57) and morphine (17). The apparent in vivo dissociation constant of a pseudoirreversible antagonist (KB) value for buprenorphine averaged 0.15 mg/kg across agonists, temperatures and buprenorphine doses. These data extend and emphasize the significance of in vivo estimates of affinity and relative efficacy for drug classification.

Alfentanil↗
PubMed1995

Repeated acquisition of behavioral chains in squirrel monkeys: comparisons of a mu, kappa and delta opioid agonist.

Responding by squirrel monkeys was maintained by food presentation under a repeated acquisition of behavioral chains procedure. Monkeys acquired a different three-response chain each session. Sequence completions were reinforced under a fixed-ratio 5 schedule, whereas errors produced a brief time out. Morphine (0.1-3.2 mg/kg) produced dose-related decreases in response rate at doses that had little or no effect on errors. U50488H ([trans]3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide methane sulfonate hydrate) (0.018-0.56 mg/kg) yielded a steep dose-effect curve, decreasing response rate only at high doses that also had little or no effect on errors. The delta opioid agonist BW373U86 (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (0.0056-0.32 mg/kg) produced dose-related decreases in response rate and increased errors. The delta opioid receptor antagonist naltrindole (0.056-18 mg/kg) alone had no effect on either the rate of responding or percent errors. The rate-decreasing and error-increasing effects produced by BW373U86 were antagonized by naltrindole. BW373U86 alone at doses of > or = 0.56 mg/kg produced brief tonic-clonic convulsions in all monkeys. Naltrindole (1 mg/kg) also antagonized the convulsant effects of BW373U86. At doses at which naltrindole was an effective antagonist of BW373U86, it failed to antagonize either morphine or U50488H. These results demonstrate that the delta opioid agonist BW373U86 produces effects on acquisition that differ dramatically from prototypical mu and kappa opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Butorphanol: characterization of agonist and antagonist effects in rhesus monkeys.

The effects of butorphanol were studied in assays of antinociception, respiratory depression, sedation, diuresis and reinforcing effects in rhesus monkeys, and opioid binding in monkey brain. Butorphanol (0.003-0.1 mg/kg s.c.) was effective in the warm-water tail withdrawal assay in 50 degrees C water but not in 55 degrees C. Over a similar dose range, butorphanol caused substantial respiratory depression, without an obvious plateau. Constrained quadazocine apparent pA2 analysis on the respiratory depressant and antinociceptive effects of butorphanol yielded different values between the two assays (respiratory depression pA2 = 6.61; antinociception pA2 = 8.26). Butorphanol (0.1 mg/kg) antagonized the antinociceptive effects of etonitazene in 55 degrees C water, but caused a nonparallel leftward shift in the U50,488 dose-effect curve; both effects were probably due to butorphanol's intermediate efficacy at mu receptors. Butorphanol (0.0001-0.003 mg/kg per injection i.v.) was self-administered; unlike other mu opioid agonists, its maximum effect was depressed after pretreatment with quadazocine (0.01-1.0 mg/kg). Butorphanol (0.003-0.32 mg/kg) was devoid of substantial sedative or muscle relaxant effects, as measured by observational rating scales. Butorphanol (0.01-0.1 mg/kg s.c.), unlike U50,488 (0.01-0.32 mg/kg) did not cause diuresis. Kappa agonist or antagonist effects of butorphanol were not detected in the present studies. This profile is consistent with butorphanol's binding characteristics in rhesus monkey brain which indicated 12-fold mu:kappa selectively and 34-fold mu:delta selectivity.

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

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↗
PubMed1994

Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice.

The effects of the systemically active irreversible opioid receptor antagonist clocinnamox (C-CAM; 14 beta-(p-chlorocinnamoylamino)-7,8-dihydro-N- cyclopropylmethyl normorphinone mesylate) on mu receptor binding to cerebral membranes and on mu opioid analgesia were assessed using mice. After systemic administration, C-CAM produced a dose-dependent decrease in the Bmax values of both [3H]DAMGO ([D-Ala2, N-MePhe4, Gly5-ol][tyrosyl-3,5-3H]enkephalin) and [3H]naltrexone without affecting the Kd value of either ligand. After administration of 3.2 mg/kg of C-CAM, [3H]DAMGO binding recovered gradually, returning to control levels by 8 days. This time course of recovery was similar to that observed with 3.2 mg/kg of C-CAM against morphine analgesia in the warm-water tail-withdrawal assay. The analgesic effect of the mu agonist etonitazene also was assessed in the assay. C-CAM produced dose-dependent rightward and slight downward shifts of the etonitazene dose-effect curve. The analgesic activity of etonitazene had still not returned to base-line levels 12 days after administration of 32 mg/kg of C-CAM, a time at which [3H]DAMGO binding had returned to control levels. In addition, the apparent pA2 values of etonitazene with naltrexone in the tail-withdrawal assay were assessed at 4, 8 and 12 days after the administration of 32 mg/kg of C-CAM, and none were found to be different from the control pA2 value. These results support the notion that C-CAM is an irreversible mu receptor antagonist and suggest that post-treatment, perhaps newly synthesized, mu receptors are similar to mu receptors in control membranes.

Analgesia↗
PubMed1994

Antinociceptive and respiratory effects of nalbuphine in rhesus monkeys.

Antinociceptive and respiratory effects of nalbuphine and other opioids were studied in rhesus monkeys. In a thermal, tail withdrawal assay, the kappa agonist enadoline and the mu agonists alfentanil and fentanyl produced maximum antinociceptive effects in all subjects and over a wide range of temperatures, whereas nalbuphine produced antinociceptive effects in only some subjects and only when the water temperature was < or = 50 degrees C. Naltrexone antagonized the antinociceptive effects of nalbuphine, alfentanil and enadoline; however, the magnitude of antagonism was not equal among agonists. In subjects that did not show an antinociceptive response to nalbuphine, nalbuphine (3.2-10.0 mg/kg) antagonized the antinociceptive effects of fentanyl but not enadoline. The irreversible opioid antagonist clocinnamox produced a parallel shift to the right in the nalbuphine dose-effect curve 1 hr after administration and decreased the maximum effect produced by nalbuphine 24 and 48 hr after administration. Nalbuphine had modest respiratory-depressant effects in monkeys breathing air and attenuated hyperventilation produced by 5% CO2. In contrast, alfentanil had marked respiratory-depressant effects in monkeys breathing air or 5% CO2 in air and these effects were antagonized by nalbuphine. Taken together, these results suggest nalbuphine has low efficacy at mu opioid receptors; however, quantitative differences between alfentanil and nalbuphine indicate a second (non-enadoline sensitive) receptor might also be important for the antinociceptive effects of nalbuphine.

Alfentanil↗
PubMed1994

Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes.

The binding parameters of radiolabeled DAMGO (mu), DPDPE and pCl-DPDPE (delta) and 5 alpha, 7 alpha, 8 beta-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]benzeneacetamide (also known as U69593, kappa) and the affinity and selectivity profiles of various opioid agonists and antagonists at the three opioid receptor types were determined in membranes from brain cortex of rhesus monkey. Among the 10 opioids with established mu-selective actions, etonitazene inhibited the binding of [3H]DAMGO with a Ki of 0.02 nM (0.01 nM without sodium) and exhibited mu/delta and mu/kappa selectivities of 8800 and 11,650, respectively. DAMGO had a Ki of 1.23 nM and was about 500-fold more selective at mu receptors compared with delta and kappa sites. Other mu opioids with higher than 100-fold binding selectivity were fentanil and sufentanil. Highly selective delta opioids were DPDPE, deltorphin II and naltrindole. With the exception of N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, all investigated putative delta opioids bound to delta sites with low Kis, i.e., 0.04 nM, 0.13 nM and 1.4 nM for naltrindole, (+/-)-4-[(alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl) -3- hydroxybenzyl]-N,N-diethylbenzamide and DPDPE, respectively. In this series, the displacement of [3H]pCl-DPDPE yielded results similar to those obtained with [3H]DPDPE. With nanomolar Kis of 0.70, 0.89, 0.25 and 0.06, respectively, the highest kappa selectivity was displayed by (trans)-(+/-)-3,4-dichloro-N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide and U69593, followed by dynorphin 1-13 and norbinaltorphimine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

In vivo determination of mu opioid receptor turnover in rhesus monkeys after irreversible blockade with clocinnamox.

In a warm-water tail withdrawal antinociception assay performed at 45, 50 and 55 degrees C in the rhesus monkey, the irreversible opioid antagonist clocinnamox at a dose of 0.1 mg/kg s.c. produced an acute rightward shift of the dose-response curves of the selective mu opioid agonists alfentanil and morphine at all tested temperatures. In addition, clocinnamox depressed the maxima of the dose-response curves for both agonists at 50 and 55 degrees C. Analysis of these data according to Furchgott as modified by Black and Leff showed that clocinnamox acutely decreased mu opioid receptors available for alfentanil by 88%; receptor numbers returned to control levels with a half-life of 6.3 days. Assessment of receptor population changes after clocinnamox administration with either alfentanil or morphine gave essentially identical results: 2 to 4 weeks after clocinnamox, the receptor population not only returned to preclocinnamox levels, but actually showed an overshoot. In contrast, apparent values of alfentanil affinity; its efficacy, e; the theoretically obtainable maximum effect of the mu opioid antinociceptive system, Em; and the stimulus-response transducing factor, n; did not change significantly over time. Alfentanil showed a 29-fold higher affinity than morphine, the respective KA values being 0.84 mg/kg for alfentanil and 24 mg/kg for morphine. The efficacy of alfentanil was always 2- to 3-fold higher than that of morphine for any temperature tested, the efficacies of both mu opioid agonists being higher at lower temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗
PubMed1994

Comparison of kappa opioids in rhesus monkeys: behavioral effects and receptor binding affinities.

Bremazocine, [5R-(5,7,8 beta)]-N-methyl-N-[7-(1-pyrrolidinyl)1-oxaspiro [4,5]dec-8-yl]-4-benzofuranacetamide (Cl-977), (+-)-trans-3,4-dichloro-N- methyl-(2-(pyrrolidin-1-yl)-5-methoxy-1,2,3,4-tetrahydronapth++ +-1-yl benzeneacetamide methanesulfonate (DUP 747), ethylketocyclazocine (EKC), nalorphine, (+/-)-trans-N-methyl-N-[2-(1- pyrrolidnyl)-cyclohexyl]benzo[b]thiophene-4-acetamide (PD117302), trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide (U-50,488), (5,7,8 beta)-N-methyl-N[2-(1- pyrrolidinyl), 1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U-69,593) and spiradoline were compared in rhesus monkeys for their discriminative stimulus, analgesic and respiratory effects. Selected compounds also were studied for their binding affinities at mu [[3H](D-Ala2-Me-Phe4,Glyol5)enkephalin], kappa ([3H]U-69,593) and delta [[3H](D-Pen2-D-Pen5) enkephalin], opioid receptors in monkey brain membranes. All compounds substituted completely (> or = 90%) for EKC in monkeys discriminating between EKC and saline, with the exception that DUP 747 produced a maximum of 74% EKC responding. None of the compounds reversed naltrexone responding in morphine-abstinent monkeys; all of the compounds substituted for naltrexone in morphine-treated monkeys discriminating between naltrexone and saline, with the exception that spiradoline produced a maximum of 68% naltrexone responding. Eight compounds produced maximum analgesic effects in a tail withdrawal procedure and quadazocine antagonized these effects; nalorphine did not have analgesic effects, but it antagonized analgesic effects of several other compounds. U-50,488 did not decrease respiratory function, whereas U-69,593 decreased frequency of respiration and volume of respiration to less than 40% of control values; Cl-977, DUP 747, PD117302 and spiradoline had limited effects on respiratory function. Larger doses of each compound increased both respiration and motor activity.

Analgesics↗