Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD. METHODS: The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin. Breast milk proteomics was profiled using Olink inflammation panel. RESULTS: We analysed gut microbiota of 1034 faecal samples from 294 infants [80 born to mothers with and 214 to mothers without IBD]. Alpha diversity was driven by maternal IBD status and time point. The major influencers of the overall composition of the microbiota were mode of delivery, feeding, and maternal IBD status. Specific taxa were associated with these exposures, and maternal IBD was associated with a reduction in Bifidobacterium. In 312 breast milk samples [91 from mothers with IBD], mothers with IBD displayed lower abundance of proteins involved in immune regulation, such as thymic stromal lymphopoietin, interleukin-12 subunit beta, tumour necrosis factor-beta, and C-C motif chemokine 20, as compared with control mothers [adjusted p = 0.0016, 0.049, 0.049, and 0.049, respectively], with negative correlations with baby´s calprotectin, and microbiome at different time points. CONCLUSION: Maternal IBD diagnosis influences microbiota in their offspring during early life. The proteomic profile of breast milk of women with IBD differs from that of women without IBD, with distinct time-dependent associations with baby's gut microbiome and feacal calprotectin.

Jumping mechanisms and performance of pygmy mole crickets (Orthoptera, Tridactylidae).

Pygmy mole crickets live in burrows at the edge of water and jump powerfully to avoid predators such as the larvae and adults of tiger beetles that inhabit the same microhabitat. Adults are 5-6 mm long and weigh 8 mg. The hind legs are dominated by enormous femora containing the jumping muscles and are 131% longer than the body. The ratio of leg lengths is: 1:2.1:4.5 (front:middle:hind, respectively). The hind tarsi are reduced and their role is supplanted by two pairs of tibial spurs that can rotate through 180 deg. During horizontal walking the hind legs are normally held off the ground. Jumps are propelled by extension of the hind tibiae about the femora at angular velocities of 68,000 deg s(-1) in 2.2 ms, as revealed by images captured at rates of 5000 s(-1). The two hind legs usually move together but can move asynchronously, and many jumps are propelled by just one hind leg. The take-off angle is steep and once airborne the body rotates backwards about its transverse axis (pitch) at rates of 100 Hz or higher. The take-off velocity, used to define the best jumps, can reach 5.4 m s(-1), propelling the insect to heights of 700 mm and distances of 1420 mm with an acceleration of 306 g. The head and pronotum are jerked rapidly as the body is accelerated. Jumping on average uses 116 microJ of energy, requires a power output of 50 mW and exerts a force of 20 mN. In jumps powered by one hind leg the figures are about 40% less.

Corticotropin releasing factor-1 receptor antagonist, CP-154,526, blocks the expression of ethanol-induced behavioral sensitization in DBA/2J mice.

RATIONALE: Manipulation of glucocorticoid receptor signaling has been shown to alter the acquisition and expression of ethanol-induced locomotor sensitization in mice. It is unknown if other components of the hypothalamic-pituitary-adrenal (HPA)-axis modulate locomotor sensitization resulting from repeated ethanol administration. In the present investigation, we determined if pretreatment with an i.p. injection of CP-154,526, a selective corticotropin releasing factor (CRF) type-1 receptor antagonist, would block the acquisition and/or expression of ethanol-induced locomotor sensitization in male DBA/2J mice. METHODS: To assess the role of the CRF1 receptor in the acquisition of behavioral sensitization, mice were pretreated with an i.p. injection of CP-154,526 30 min before each of 10 sensitizing i.p. injections of ethanol. To determine the role of the CRF1 receptor in modulating the expression of ethanol-induced sensitization, mice that had previously been sensitized to the locomotor stimulant effects of ethanol were pretreated with CP-154,526 30 min before an i.p. injection of ethanol on the test day. In a third study, ethanol-naïve mice were pretreated with CP-154,526 30 min before an initial i.p. injection of ethanol to determine the combined effects of the CRF1 receptor antagonist and ethanol on locomotor activity. Blood ethanol concentrations were assessed at the termination of sensitization studies. RESULTS: Pretreatment with CP-154,526 blocked the expression of ethanol-induced locomotor sensitization in DBA/2J mice but did not prevent the acquisition of sensitization. The ability of CP-154,526 to block the expression of ethanol-induced locomotor sensitization was not attributable to alterations in blood ethanol levels or possible sedative effects produced by the combined administration of CP-154,526 and ethanol. CONCLUSIONS: These data provide novel evidence that CRF1 receptor signaling modulates the expression of ethanol-induced locomotor sensitization, and add to a growing literature suggesting a role for neurochemicals and hormones associated with the HPA-axis in behavioral sensitization resulting from repeated exposure to drugs of abuse.

Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization.

RATIONALE: Mutant mice lacking the RIIbeta subunit of protein kinase A (regulatory subunit II beta(-/-)) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIbeta(-/-) and littermate wild-type (RIIbeta(+/+)) mice on multiple genetic backgrounds. METHODS: Over three consecutive days, mice were given single i.p. saline injections and immediately placed in a locomotor activity apparatus to establish a composite baseline for locomotor activity. Next, mice maintained on a hybrid 129/SvEvxC57BL/6J or pure C57BL/6J genetic background were given 10 i.p. ethanol injections before being placed in the activity apparatus. Each ethanol injection was separated by 3-4 days. To determine if changes in behavior were specific to ethanol injection, naïve mice were tested following repeated daily saline injections. The effects of ethanol injection on locomotor behavior were also assessed using an alternate paradigm in which mice were given repeated ethanol injections in their home cage environment. RESULTS: Relative to RIIbeta(+/+) mice, RIIbeta(-/-) mice, regardless of genetic background, consistently showed significantly greater ethanol-induced locomotor activation. RIIbeta(-/-) mice also showed increased sensitivity to ethanol-induced locomotor sensitization resulting from repeated administration, an effect that was dependent on genetic background and testing paradigm. Increased locomotor activity by RIIbeta(-/-) mice was specific to ethanol injections, and was not related to altered blood ethanol levels. CONCLUSIONS: These data provide novel evidence implicating an influence of protein kinase A signaling on ethanol-induced locomotor activity and behavioral sensitization. The observation that RIIbeta(-/-) mice are more sensitive to the effects of repeated ethanol administration suggests that normal protein kinase A signaling limits, or is protective against, the stimulant effects of ethanol and the plastic alterations that underlie behavioral sensitization.

Gas exchange characteristics, metabolic rate and water loss of the Heelwalker, Karoophasma biedouwensis (Mantophasmatodea: Austrophasmatidae).

This study presents the first physiological information for a member of the wingless Mantophasmatodea, or Heelwalkers. This species shows cyclic gas exchange with no evidence of a Flutter period (more typical of discontinuous gas exchange in insects) and no indication that the spiracles are fully occluded during quiescent metabolism. Standard metabolic rate at 20 degrees C was 21.32+/-2.73 microl CO(2)h(-1) (mean+/-S.E.), with a Q(10) (10-25 degrees C) of 1.7. Increases in V()CO(2) associated with variation in mass and with trial temperature were modulated by an increase in burst period volume and a decline in cycle frequency. Total water loss rate, determined by infrared gas analysis, was 0.876+/-0.08 mg H(2)Oh(-1) (range 0.602-1.577, n=11) whilst cuticular water loss rate, estimated by linear regression of total water loss rate and metabolic rate, was 0.618+/-0.09 mg H(2)Oh(-1) (range 0.341-1.363, n=11). Respiratory water loss rate was therefore no more than 29% of the total rate of water loss. Both total water loss rate and estimated cuticular water loss rate were significantly repeatable, with intraclass correlation coefficients of 0.745 and 0.553, respectively.

Effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin on the delayed matching-to-sample performance of pigeons.

The effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin were examined in pigeons performing under a delayed matching-to-sample procedure. Clonazepam, valproic acid, ethosuximide, and phenytoin typically reduced the rate of responding to the sample stimulus, whereas phenobarbital usually increased response rates at high doses. Phenobarbital, clonazepam, and valproic acid produced generally dose-dependent decreases in accuracy; ethosuximide and phenytoin failed to do so. These results suggest that there are qualitative as well as quantitative differences in the effects of anticonvulsant drugs under the delayed matching-to-sample procedure.

Cross-tolerance and enhanced sensitivity to the response rate-decreasing effects of opioids with varying degrees of efficacy at the mu receptor.

The purpose of the present experiment was to determine whether the effects of opioids with varying degrees of efficacy at the mu receptor are differentially altered in morphine-tolerant pigeons. To this end, dose-effect curves were determined for high, intermediate, and low efficacy mu agonists in pigeons responding under a schedule of food presentation prior to, during, and after exposure to a regimen of chronic morphine administration. In pigeons treated with 56 mg/kg/daily morphine, the dose-effect curves for the rate-decreasing effects of the high-efficacy mu agonists morphine and fentanyl were shifted to the right of their prechronic positions (i.e., tolerance). A small degree of tolerance was also conferred to the intermediate-efficacy mu agonists (-)-pentazocine and (-)-metazocine, but not to nalbuphine or butorphanol. In contrast to the effects obtained with these mu agonists, the chronic morphine regimen shifted the dose-effects curves of the mu antagonist naloxone and the low-efficacy mu agonists nalorphine and levallorphan to the left of their prechronic positions (i.e., enhanced sensitivity). These findings demonstrate that morphine tolerance confers cross-tolerance to other high efficacy mu agonists, enhanced sensitivity to mu antagonists and low efficacy mu agonists, and little or no cross-tolerance to intermediate efficacy mu agonists. Disadvantages of using schedule-controlled responding to examine the effects of intermediate efficacy mu agonists are discussed.

Differential effects of opioid and nonopioid analgesics on conditional discriminations in pigeons.

Under the fixed-consecutive-number schedule (FCN), pigeons were reinforced for responding eight or more times on one response key (work key), and then responding once on a second response key. In one component of this schedule, an external stimulus signalled the completion of the response requirement on the work key (FCN 8-SD), whereas no stimulus change was programmed under the other (FCN 8). Across a range of doses, the mu opioid agonist morphine, the kappa opioid agonist U50,488 and the opioid antagonist naloxone had no consistent effect on accuracy under either FCN schedule. Naloxone and accuracy under either FCN schedule. Naloxone and U50,488 produced a general flattening of the conditional probability functions by decreasing the conditional probability of response runs exceeding the minimum response requirement of eight consecutive responses on the work key. The sigma agonists phencyclidine and (+)N-allylnormetazocine and the nonopioid analgesics clonidine and l-nantradol produced large decreases in accuracy under the FCN 8 and small decreases under the FCN 8-SD. With the exception of (+)N-allylnormetazocine, these drugs consistently increased the conditional probability of responses runs shorter than the minimum response requirement on the work key. These findings indicate that the accuracy-altering effects of some opioid and nonopioid analgesics depend in part on the type of discrimination task.

Dopaminergic activity and the discriminative stimulus effects of mu opioids in pigeons: importance of training dose and attenuation by the D3 agonist (+/-)-7-OH-DPAT.

The present investigation examined the effects of several dopaminergic compounds in pigeons trained to discriminate either a 0.1 (low) or 5.6 (high) mg/kg dose of the mu opioid butorphanol from saline. Various dopamine (DA) re-uptake inhibitors, releasers, a D1 agonist, a D2 agonist and a D3 agonist engendered partial substitution (50-79% butorphanol responding) for the butorphanol stimulus in the low-dose group. In the high-dose group, with a few exceptions, these compounds produced predominately saline responding. In the low-dose group, the opioid antagonist naloxone antagonized the stimulus effects produced by butorphanol, but failed to attenuate the butorphanol-like discriminative stimulus effects produced by the DA re-uptake inhibitors mazindol and cocaine. The D1 antagonist (+)-SCH 23390 and the D2 antagonist raclopride failed to attenuate the stimulus effects produced by either the low or high training dose of butorphanol. Doses of mazindol and cocaine that engendered between 16% and 70% butorphanol responding failed to alter the butorphanol dose-effect curve in either the low- or high-dose group, indicating a less than additive interaction. In the high-dose group, the D3 agonist (+/-)-7-hydroxy-dipropylaminotetralin [(+/-)-7-OH-DPAT] attenuated butorphanol's stimulus effects in a dose-dependent manner along with the butorphanol-like stimulus effects produced by nalbuphine and morphine. The present findings indicate that direct and indirect DA agonists share similar stimulus effects with a low but not high training dose of butorphanol, and in the high-training dose group, activation of the D3 receptor by (+/-)-7-OHDPAT results in the attenuation of the discriminative stimulus effects of mu opioids.

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids.

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The rate-decreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.

The mu opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the mu opioid receptor.

The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.

Tolerance and cross-tolerance to the rate-suppressing effects of opioids in butorphanol-treated rats: influence of maintenance dose and relative efficacy at the mu receptor.

The purpose of the present investigation was to examine the development of tolerance to the rate-suppressing effects of mu and kappa opioids in rats administered either 3.0 (low) or 30 (high) mg/kg per day of butorphanol, an opioid with low relative efficacy at the mu receptor. The mu opioids butorphanol, buprenorphine, morphine, fentanyl and sufentanil, and the kappa opioid U50,488 dose-dependently suppressed responding under all conditions examined. In rats administered the low maintenance dose of butorphanol, tolerance developed to the effects of butorphanol, buprenorphine and morphine, but not to fentanyl and sufentanil. In rats administered the high maintenance dose, tolerance developed to all of the mu opioids examined. In both treatment groups, the degree to which tolerance developed was greater for butorphanol and buprenorphine than for morphine, fentanyl and sufentanil; and the degree to which tolerance developed to these mu opioids was greater in rats administered the high maintenance dose of butorphanol. The tolerance that developed to morphine, fentanyl and sufentanil was not altered when tested at both 23 and 47 h following the previous maintenance dose of butorphanol, suggesting that these changes were not due to any acute pharmacological interactions between butorphanol and the test compound (i.e., antagonism). Tolerance was also conferred to the kappa opioid U50,488 in both groups of rats, and in rats administered the high maintenance dose, this effect was obtained when tested 23 and 47 h following the previous maintenance dose of butorphanol. Physical dependence developed in rats administered the high maintenance dose of butorphanol, as evidenced by the development of enhanced sensitivity to the rate-suppressing effects of naloxone, and the finding that 30 mg/kg naloxone decreased body weight in a time-dependent manner. No physical dependence was apparent in rats administered the low maintenance dose of butorphanol. These data suggest that during chronic treatment with butorphanol, (1) greater degrees of tolerance are conferred to drugs possessing low efficacy at the mu opioid receptor, (2) tolerance is enhanced as the maintenance dose of the toleragen is increased, and (3) mu-opioid tolerance may be observed under conditions that do not produce mu-opioid dependence.

Effects of clonazepam and ethosuximide on the responding of pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus.

The effects of the anticonvulsant drugs clonazepam and ethosuximide were examined in pigeons performing under a fixed-consecutive-number schedule with and without an added external discriminative stimulus. Under these schedules, food was delivered whenever subjects responded between and 8 and 12 times on one response key (work key), and then responded once on a second response key (reinforcement key). For one group, an external discriminative stimulus signalled completion of the response requirement on the work key, while no stimulus change was programmed for the other group. Clonazepam (0.06-0.75 mg/kg) produced dose-dependent decreases in percentage of reinforced runs and rate of responding for both groups. The magnitude of the accuracy-decreasing effect was generally greater in the group without the external discriminative stimulus. For this group, the higher doses of clonazepam produced pronounced increases in switching to the reinforcement key before completing the minimum requirement of eight consecutive responses on the work key. No consistent patterns of errors were evident for the subjects with the added external discriminative stimulus. Although ethosuximide (20-160 mg/kg) produced dose-dependent decreases in rate of responding, it had little effect on the percentage of reinforced runs or the run length distributions. These findings are consistent with previous reports indicating that clonazepam, but not ethosuximide, substantially disrupts performance under operant tasks requiring conditional discriminations. These data also suggest that the addition of an external discrimination stimulus attenuates the disruptive behavioral effects of clonazepam.

Discriminative stimulus properties of tripelennamine in the pigeon.

Pigeons trained under a two-key drug discrimination procedure eventually learned to discriminate the antihistaminic tripelennamine (5 mg/kg) from saline. When 0.63-7.5 mg/kg doses of tripelennamine were administered in generalization test sessions, the percentage of responses directed to the tripelennamine-appropriate key varied directly with dose. At certain doses, the discriminative stimulus properties of the antihistaminics, diphenhydramine and pyrilamine, clearly generalized to tripelennamine, whereas intermediate generalization was evident with the antihistaminics, chlorpheniramine and promethazine. Chlorpromazine, cimetidine, d-amphetamine, diazepam, morphine, pentazocine, phenobarbital, and sodium valproate failed to produce tripelennamine-like patterns of responding.

Discriminative stimulus properties of valproic acid in the pigeon.

Pigeons were successfully trained to discriminate 60 mg/kg valproic acid from saline using a two-key drug discrimination procedure. When 5-80 mg/kg doses of valproic acid were administered during generalization tests the percentage of responses directed to the valproic acid-appropriate key varied directly with dose. The effects of administering the training dose of valproic acid at presession injection intervals ranging from 15 to 120 min were described by an inverted U-shaped function; the 30-min interval used during discrimination training engendered the largest percentage of valproic acid-appropriate responses. The discriminative stimulus properties of valproic acid failed to generalize to the anticonvulsant compounds phenobarbital (10, 20 mg/kg), phenytoin (2.5, 5 mg/kg), and ethosuximide (40, 80 mg/kg), indicating that not all anticonvulsant compounds share similar discriminative properties. Clonazepam (0.25, 0.50 mg/kg) and diazepam (1, 2 mg/kg), two benzodiazepines with anticonvulsant properties, produced quite different effects. The stimulus properties of valproic acid generalized to all doses of clonazepam, whereas intermediate generalization was evident with diazepam. Pentylenetetrazol (10, 20 mg/kg), chlorpromazine (5, 10 mg/kg), tripelennamine (2.5, 5.0 mg/kg), d-amphetamine (0.5, 1.0 mg/kg), morphine (1.25, 2.50 mg/kg), and imipramine (2.5, 5.0 mg/kg) induced only saline-like patterns of responding. The concomitant administration of pentylenetetrazol failed to antagonize the discriminative stimulus properties exerted by the training dose of valproic acid.

Evaluation of the effects of opioid agonists and antagonists under a delayed matching-to-sample procedure in pigeons.

The effects of several opioid agonists and antagonists were examined in pigeons performing under a delayed matching-to-sample procedure. The mu agonists morphine and l-methadone, the kappa agonists U 50,488 and ethylketocyclazocine, and the opioid antagonist naloxone had no effect on the accuracy of responding. These drugs were, however, behaviorally active as evidenced by the dose-dependent decreases in rates of responding associated with their administration. In contrast, the sigma agonists (+) N-allylnormetazocine and phencyclidine decreased the accuracy of responding in a dose-dependent fashion. The relative magnitude of these drug-induced decreases in accuracy were similar across the no delay (0-s), short (2-s), and long (8-s) delay intervals. For these drugs, accuracy-decreasing effects were obtained only at doses that reduced rates of responding. The results of the present investigation parallel those reported in pigeons responding under drug discrimination tasks, in which the discriminative stimulus properties produced by the mu and kappa agonists are similar to each other but distinguishable from those produced by the sigma agonists.

Chronic effects of ethosuximide, phenytoin, clonazepam, and valproic acid on the delayed-matching-to-sample performance of pigeons.

Acute and chronic effects of ethosuximide (40, 80, and 120 mg/kg), phenytoin (2.5, 5, and 7.5 mg/kg), clonazepam (0.25, 0.5, and 0.75 mg/kg), and valproic acid (40, 80, and 120 mg/kg) were examined in pigeons performing under a delayed-matching-to-sample procedure. Acute administration of clonazepam or valproic acid produced generally dose-dependent decreases in accuracy; over 50 sessions of daily exposure, complete or nearly complete tolerance developed to the accuracy-reducing effects of these drugs. Whether administered acutely or chronically, ethosuximide and phenytoin failed to affect accuracy. When given acutely, all drugs typically reduced rate of responding to the sample stimulus. A degree of tolerance appeared to develop to the rate-decreasing effects of all of the drugs tested.

Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure.

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphine's discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.

Modulatory effects of dopamine D3/2 agonists on kappa opioid-induced antinociception and diuresis in the rat.

RATIONALE: The dopamine (DA) D3/2 agonist 7-OH-DPAT has been shown to attenuate the behavioral effects of the mu agonist morphine as well as the development of morphine tolerance. OBJECTIVES: To evaluate the effects of DA D3/2 agonists [7-OH-DPAT, (+)-PD128,907, quinelorane, (-)-quinpirole], a D1 agonist (SKF38393), a D1 antagonist [(+)-SCH23390], a DA antagonist (spiperone), and an indirect DA agonist (cocaine) on the antinociceptive effects of kappa agonists (spiradoline, U69,593, bremazocine) as well as the effects of D3/2 agonists on the diuretic effects of spiradoline. METHODS: Antinociception was determined using a warm water (50-55 degrees C) tail-withdrawal procedure and urine output was collected over a 2-h interval. RESULTS: The antinociceptive effects produced by the kappa agonists varied with the intensity of the nociceptive stimulus (water), as maximal or near maximal effects were obtained with spiradoline at 55 degrees C, U69,593 at 52 degrees C, and bremazocine at 50 degrees C water. 7-OH-DPAT produced a dose-dependent attenuation of the antinociceptive effects of spiradoline, U69,593, and bremazocine. Spiperone completely reversed the effects of 7-OH-DPAT on spiradoline antinociception. (+)-PD128,907 and quinelorane, but not (-)-quinpirole or the other DAergic agents examined, attenuated the antinociceptive effects of spiradoline in a dose- and time-dependent manner. The diuretic effects of spiradoline were attenuated by 7-OH-DPAT, (+)-PD128,907, quinelorane, and (-)-quinpirole, and this attenuation was reversed by spiperone. CONCLUSIONS: The present study demonstrated that some D3/2 agonists can modulate both the antinociceptive and diuretic effects of kappa agonists. These modulatory actions are similar to those obtained against the effects of mu agonists.

The dopamine D3/2 agonist 7-OH-DPAT attenuates the development of morphine tolerance but not physical dependence in rats.

RATIONALE: The dopamine (DA) D3/2 agonist 7-OH-DPAT attenuates the acute antinociceptive, discriminative stimulus, locomotor activating, and reinforcing effects of mu agonists (for example, morphine). OBJECTIVES: To examine the ability of 7-OH-DPAT to modulate the development of morphine tolerance and physical dependence in the rat. METHODS: Morphine antinociception was assessed using a warm water tail-withdrawal procedure before and following chronic treatment with morphine (15 mg/kg)/7-OH-DPAT (0.3-3.0 mg/kg). Physical dependence was assessed following naloxone-precipitated (1.0 mg/kg) withdrawal in rats treated chronically with morphine (15 and 7.5 mg/kg)/7-OH-DPAT (1.0-10 mg/kg). RESULTS: 7-OH-DPAT attenuated the antinociceptive effects of morphine in both morphine naive and tolerant rats. Additionally, morphine tolerance was attenuated by the coadministration of 7-OH-DPAT in a dose- and time-dependent manner. The magnitude of the attenuation obtained when morphine and 7-OH-DPAT were administered at the same time was similar to that obtained when administration of these drugs was separated by 6 h, indicating that 7-OH-DPAT did not alter morphine pharmacokinetics. In rats rendered tolerant to morphine, the subsequent coadministration of morphine/7-OH-DPAT failed to reverse morphine tolerance, but did attenuate its further development. The level of physical dependence (number and frequency of withdrawal signs) was greater in rats treated with 15 than 7.5 mg/kg morphine. Under both treatment conditions, physical dependence was not altered by 7-OH-DPAT. In morphine-dependent (15 mg/kg) rats, 7-OH-DPAT (3.0 and 10 mg/kg) failed to precipitate withdrawal. CONCLUSION: The D3/2 agonist 7-OH-DPAT can attenuate the antinociceptive effects of morphine in both acute and chronic preparations as well as the development of morphine tolerance. 7-OH-DPAT does not, however, alter morphine physical dependence.