Odors released by stressed rats produce opioid analgesia in unstressed rats.

When unstressed Sprague-Dawley or Long-Evans rats were placed in a chamber containing the odor of a conspecific that had received electric shock, they became analgesic as assessed by the formalin test. During the course of 4 experiments, the odors of nonstressed conspecifics and novel odors produced no such effect. This analgesia was reversed by naltrexone (1 ml/kg). Data suggest that naturalistic stimuli innately associated with aversive environmental events can activate endogenous pain control mechanisms. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Context as a conditional cue in operant discrimination reversal learning.

Five experiments with 68 pigeons investigated the conditions under which contextual stimuli gain conditional control in the discrimination reversal paradigm. In Exp I, Ss learned an operant discrimination in which the positive stimulus (S+) was 555 nm and the negative stimulus (S–) was 576 nm in one context (houselight off plus white noise [HLFN]) and then learned the reversal (S+ 576 nm; S– 555 nm) in another context (houselight on plus tone [HLNT]). Subsequent wavelength generalization testing revealed responding appropriate to each context: The gradients peaked at 555 nm in HLFN and at 576 nm in HLNT. In Exp II, separate groups experienced both visual and auditory context cues, only visual ones, or only auditory ones. The visual cues worked as well as the compound, but the auditory cues gained no conditional control. In Exp III, houselight illumination replaced by white light directly added to the colors serving as discriminative cues. Results suggest that houselight illumination does not gain conditional control by altering the brightness and saturation of the key colors. In Exp IV, HLNT and HLFN gained conditional control over discriminations based on different angles of a white line, but background key color did not. In Exp V, conditional control over a color discrimination was established by contexts consisting of black and white striped walls vs plain walls. Findings suggest that pigeons use diffuse visual cues to identify the place where food-reinforced learning has taken place. (16 ref) (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Strain and sex differences in mouse killing by rats.

Tendency to exhibit muricide was examined in 481 adult rats of 15 inbred strains. Marked strain differences were observed; frequency of mouse killing ranged from 0 to 91% among the males and from 0 to 68% among the females. Whether males and females differed in their propensity to kill mice also appeared to be strain-dependent. Overall, there was a significant correlation between the frequency of mouse killing by males of each strain and that of females. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to a cat produces opioid analgesia in rats.

Two experiments tested the prediction that rats should react with reduced sensitivity/reactivity to nociceptive stimulation in the presence of a cat. In Exp I, naloxone (110 mg/kg) or saline was administered intraperitoneally to 90 female Sprague-Dawley rats before they were exposed to no stimulus, a novel stimulus, or a cat. In Exp II, 50 male rats were administered saline or naltrexone (7 mg/kg) and were exposed to either no stimulus or a cat. In both experiments, rats tested in the presence of the cat showed a significant reduction in sensitivity/reactivity to a skin-irritating formalin injection. Naltrexone reversed this analgesia, while naloxone produced only a weak trend toward shorter latencies. Findings are discussed in relation to the perceptual-defensive-recuperative model presented by R. C. Bolles and the 2nd author (see record 1981-25138-001), which depicts fear and pain as competing motivational systems that serve different biological functions. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis

A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.     

Nitrous oxide analgesia: reversal by naloxone and development of tolerance

The objective of this study was to characterize further the nature of nitrous oxide analgesia and to establish if tolerance to nitrous oxide occurs. Methods for studying the analgesic action of a gas are described. In mice, nitrous oxide is analgesic in the phenylquinone and acetic acid abdominal constriction tests. Aspirin and very high doses of alcohol are also active in these tests; however, only nitrous oxide-induced analgesia is antagonized by narcotic antagonists. These data indicate the mechanism of action of nitrous oxide analgesia differs from that of the other two drugs. Nitrous oxide produced a dose-related analgesic response in rats (ED50, 67%) as measured by the tail-flick method. Naloxone, 5 to 30 mg/kg, also antagonized nitrous oxide analgesia in rats. Lower doses of the antagonist were not effective. Tolerance developed to the effects of nitrous oxide in both rats and mice after prolonged exposure. These data lend support to the hypothesis that nitrous oxide and opiates have a significant pharmacologic resemblance and may ultimately produce similar molecular events in the brain leading to the relief of pain.     

Lack of tolerance in peripheral opioid analgesia in mice

We recently developed a sensitive peripheral analgesic test in mice. Bradykinin, a representative pain-producing substance, when given subcutaneously through a polyethylene tube into the plantar of the limb connected to a transducer, induced a flexor reflex response, in a dose dependent manner. When morphine, a mu-opioid receptor agonist, was added to the plantar through another polyethylene tube, bradykinin-induced responses were completely abolished in a naloxone-reversible manner. These peripheral analgesic effects were also observed with DAMGO, another mu-opioid receptor agonist, and U-69,593, a kappa-opioid receptor agonist, but not DSLET, a delta-opioid receptor agonist. When morphine was given subcutaneously to the back, a potent analgesia in the tail pinch test was observed. Repeated administrations of morphine once per day for 5 days showed a marked tolerance or reduction in morphine analgesia on the 6th day, while there was no significant reduction in the peripheral analgesia of morphine. These findings suggest that tolerance to morphine analgesia is mediated through synaptic plasticity in the central nervous system, but not through a receptor desensitization at the level of the single cell.     

Serial discrimination reversal learning in the pigeon: Potentiation of "pattern" by a conditional cue.

In 6 experiments 52 domestic pigeons were trained daily on a conditional serial discrimination reversal problem. In the standard training procedure, on odd-numbered days a vertical line was superimposed on a successive wavelength discrimination task. On even-numbered days a horizontal line was superimposed on the reverse wavelength discrimination task. Exps I, II, and III assessed the degree of control acquired by the compound conditional cues (lines plus "days") and by the component elements (lines or "days"). Only Ss trained with lines relevant mastered the reversal task. In testing, when the conditional line stimuli were present, they exerted strong control, and no day effect was noted. However, when tested in the absence of lines, Ss that had had training with the compound conditional cue demonstrated reversal performance controlled by day (i.e., the pattern of alternating reversals had been acquired). Exps IV, V, and VI tested alternate interpretations of the control exerted by the day cue. Results imply that the "potentiation" effect noted is due to separate storage of the wavelength discrimination problems and different retrieval processes elicited by presence vs absence of the line stimuli. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions

Studies of direct excitatory effects elicited by opioid agonists on various types of neurone have been confirmed and expanded in numerous laboratories following the initial findings reviewed previously by Stanley Crain and Ke-Fei Shen. However, the critical role of the endogenous glycolipid GM1 ganglioside in regulating Gs-coupled, excitatory opioid receptor functions has not been addressed in any of the recent reviews of opioid stimulatory mechanisms. This article by Stanley Crain and Ke-Fei Shen focuses on crucial evidence that the concentration of GM1 in neurones might, indeed, play a significant role in the modulation of opioid receptor-mediated analgesia, tolerance and dependence.     

The opioid/nonopioid nature of stress-induced analgesia and learned helplessness.

Investigated whether the same factors that activate the processes that produce escape interference might also activate processes leading to opioid stress-induced analgesia (SIA). Exposure to a variety of stressors produces a subsequent analgesic reaction that is sometimes opioid in nature (reversed by opiate antagonists and cross-tolerant with morphine) and sometimes nonopioid. In Exp I, 40 male albino rats were subjected to 20 min of intermittent footshock, 3 min of continuous footshock, tailshock on a VI schedule, or confinement only. Ss were given escape/avoidance training 24 hrs later. In Exp II, 36 Ss received SIA with a tail-flick apparatus. In Exp III, 40 Ss received inescapable tailshocks or confinement only. In Exp IV, 24 Ss received 2 sessions of footshock before tail-flick was assessed. Both of the opioids SIA procedures produced a learned helplessness effect as assessed by shuttlebox escape acquisition and an analgesia that was reinstatable 24 hrs later. The nonopioid procedures produced neither a learned helplessness effect nor a reinstatable analgesia. These data implicate the learning of uncontrollability in the activation of opioid systems. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Naloxone-induced supersensitivity of oxytocin neurones to opioid antagonists

Here we report that a single administration of naloxone to conscious rats produces no significant increase in oxytocin release, but when repeated 3-4 days later results in a large release of oxytocin. Plasma oxytocin concentrations were measured in conscious and urethane-anaesthetized rats pretreated with naloxone or isotonic saline on Day 1. On Days 2, 3 or 4, a second dose of naloxone was given, producing an increase in oxytocin secretion in naloxone-pretreated groups (P < 0.05 vs. controls) on Day 3 and 4, but not on Day 2. The specificity of the opioid antagonist supersensitivity was determined by injection of the kappa-antagonist nor-binaltorphimine (nor-BNI). Pretreated rats (naloxone, saline or nor-BNI, Day 1) received an additional acute nor-BNI injection (Day 4) which increased plasma oxytocin concentration in the three groups. However, this increase was higher in naloxone-pretreated rats with no differences between the nor-BNI- and saline-pretreated animals. Measurements of electrical activity of single supraoptic nucleus oxytocin neurons and of plasma oxytocin concentration (Day 4) showed that naloxone modestly enhanced the responsiveness of oxytocin neurons to cholecystokinin (CCK) in naloxone-pretreated rats (by comparison with saline-pretreated rats), but had only a small effect on basal firing rate that did not differ between naloxone-pretreated rats and saline-pretreated rats. To investigate whether naloxone-pretreatment modified the effect of morphine on CCK-induced oxytocin release, on Day 4 CCK was injected i.v. with or without morphine. Morphine at a dose of 0.1 mg/kg did not affect CCK-induced oxytocin release, whereas 1 mg/kg of morphine blocked this release in both saline- and naloxone-pretreated rats. The results suggest that naloxone induces opioid antagonist supersensitivity on oxytocin secretion, mainly by up-regulating kappa-opioid mechanisms on oxytocin nerve terminals in the posterior pituitary.     

Opioid antagonists: indirect antagonism of morphine analgesia by spinal dynorphin A

Naloxone and norbinaltorphimine when given ICV to mice can antagonize IT morphine-induced analgesia indirectly by releasing spinal dynorphin A(1-17) (Dyn A). Dyn A produces an antianalgesic action against IT morphine. In the present study, drugs with varying amounts of opioid antagonist to agonist action (nalbuphine, levallorphan, naltrexone, and naltrindole) were given ICV to determine whether they antagonized IT morphine-induced inhibition of the tail-flick response as an indication of spinal Dyn A release. Additional pharmacological tests were used as criteria for Dyn A release: a) Small doses of the opioid antagonists naloxone and norbinaltorphimine administered IT inhibited the antagonistic action; b) dynorphin antiserum given IT blocked the action of Dyn A; c) desensitization to the effect of Dyn A was produced by 3-h pretreatment with morphine, 10 mg/kg SC, or by pretreatment with the agents themselves. When given ICV, nalbuphine, levallorphan, and naltrexone released Dyn A in the spinal cord to produce an antianalgesic effect. Naltrindole, a delta-receptor antagonist, did not release Dyn A. Dyn A release did not appear to involve delta-receptors. Thus, a number of opioid antagonists inhibit the analgesic action of opioid agonists indirectly through Dyn A release.     

Species-specific danger signals, endogenous opioid analgesia, and defensive behavior.

Examined the effects of handling stimuli and stress odors on species-specific defensive behavior and pain sensitivity with a total of 100 female Sprague-Dawley derived rats in 4 experiments. Ss not adapted to handling had longer jump latencies on the hotplate test of pain sensitivity than those with extensive handling experience. In a postshock freezing test in Exp II, naltrexone (7 mg/kg, intraperitoneally) enhanced defensive freezing relative to saline controls in nonadapted Ss. However, naltrexone produced no such effect in Ss that were adapted to handling. These 2 studies indicate that the handling procedure triggered an endogenous opioid analgesic response in Ss not adapted to handling. Exp III showed that a similar naltrexone-reversible opioid analgesia could be triggered by stress odors. Naltrexone, when compared to saline, enhanced postshock freezing in the presence of conspecific stress odors but not in their absence. In Exp IV, stress odors and nonadapted handling were able to activate defensive freezing directly when tested in compound but not in isolation. Results are consistent with the view that stress odors and handling stimuli are danger signals that activate endogenous opioid analgesia as well as defensive behavior, suggesting that analgesia is a component of the rat's defensive behavior system. (41 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Low efficacy opioids: Implications for sex differences in opioid antinociception.

It is becoming increasingly evident that the sex of an organism is a critical determinant of responsiveness to opioid analgesics. However, the factors that determine the magnitude and direction of sex differences in opioid antinociception have not been fully elucidated. One factor that has received attention is the relative efficacy of the opioid. This review summarizes recent findings in which opioid efficacy was systematically manipulated as an independent variable to probe underlying sex differences in opioid system function. Overall, in rodents and nonhuman primates, υ and κ opioids are generally more potent and effective in males than in females. The data indicate that although sex differences in the potency of high efficacy opioids such as morphine are generally less than 3.0-fold, sex differences with lower efficacy opioids can be greater than 90-fold. Moreover, that these drugs can function as full agonists in males while functioning as antagonists in females under identical conditions suggests some fundamental sex difference in opioid system function. In addition to efficacy, a number of other variables can affect the outcomes of these studies, including the drug history, genotype, and nociceptive stimulus modality, duration, and intensity. These factors may interact with opioid efficacy to determine the specific conditions under which sex differences are observed. The testing of low efficacy opioids by other laboratories and under other experimental conditions will determine the extent to which this variable affords a strategic research tool. The potential utility of low efficacy opioids in other domains of behavioral pharmacology is also discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mu/kappa opioid interactions in rhesus monkeys: Implications for analgesia and abuse liability.

Mu opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce mu agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of mu agonists. To evaluate this hypothesis, the present study examined interactions between the mu agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1, and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50 °C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug self-administration, rhesus monkeys responded for intravenous drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in rates of fentanyl self-administration. Moreover, addition of U69,593 increased the sensitivity of fentanyl self-administration to increases in the FR value. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective mu agonists administered alone. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine-6beta-glucuronide-induced hyperphagia: characterization of opioid action by selective antagonists and antisense mapping in rats

Copper/zinc superoxide dismutase (CuZn-SOD) is a key enzyme in the metabolism of oxygen free radicals. The gene encoding CuZn-SOD resides on human chromosome 21 and is overexpressed in Down syndrome (DS) patients. Overexpression of CuZn-SOD in transgenic (Tg) mice and cultured cells creates chronic oxidative stress leading to enhanced susceptibility to degeneration and apoptotic cell death. We have now found that three lines of Tg-CuZn-SOD mice, one of which also overexpresses S100beta, a glial calcium binding protein, are deficient in spatial memory. Furthermore, hippocampal slices taken from these mice have an apparently normal synaptic physiology, but are impaired in the ability to express long-term potentiation (LTP). This effect on hippocampal LTP was abrogated by treatment of slices with the H2O2 scavenger catalase or the antioxidant N-t-butyl-phenylnitrone (BPN). It is proposed that elevated CuZnSOD causes an increase in tetanic stimulation-evoked formation of H2O2 which leads to diminished LTP and cognitive deficits in these mice.     

Strain differences in patterns of drug-intake during prolonged access to cocaine self-administration.

The current study examined possible interactions between genetic factors and prolonged drug access by testing the Fischer (F344), Lewis (LEW), and Wistar rat strains in a prolonged access cocaine self-administration (SA) procedure. Before prolonged access, the strains did not differ in breakpoints for food or cocaine with progressive ratio (PR) testing. The LEW and Wistar rats acquired cocaine SA faster than the F344s. With prolonged access to cocaine SA, the LEW and Wistar rats showed comparable within-session patterns that were higher at the outset of each session and decreased to a stable baseline. Alternatively, the F344 rats began sessions with lower intake and increased their rate of intake during the session. The F344 and Wistar rats took more drug per session than the LEW rats but did not differ from each other. Following prolonged access, the strains did not differ in breakpoints for food, but the Wistar rats had higher breakpoints for cocaine than the F344 rats. Possible underpinnings for the observed strain differences are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The central representation of an aversive event maintains the opioid and nonopioid forms of analgesia.

Exposure to an aversive event, such as shock, can elicit either an opioid or nonopioid analgesia in rats. We suggest that the central representation of an aversive event in working memory activates both forms of analgesia. We formalize this basic hypothesis by coupling it with a current model of animal learning and memory, SOP (Wagner, 1981). SOP is designed to capture the standard operating procedures that govern memory systems. Our application of SOP suggests that manipulations which disrupt the maintenance of information in working memory should alter the magnitude and time course of analgesia. Three experiments are reported that support our proposal. Experiment 1 showed that analgesia decays more rapidly if the representation of the aversive event is displaced from working memory by presenting a postshock distractor. Experiment 2 demonstrated that the postshock distractor alters the magnitude and time course of both the opioid and nonopioid forms of analgesia. Experiment 3 demonstrated that pharmacologically disrupting working memory, by administering a high dose of pentobarbital, prevents mild shock from inducing a strong change in pain reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Supersensitivity of spinal opioid receptors to antagonists in intrathecal butorphanol and morphine dependence

The purpose of this investigation was to evaluate changes in the sensitivity of spinal opioid receptors to selective antagonists in rats rendered dependent on intrathecal (i.t.) butorphanol and morphine. Using quantitative autoradiography, competitive binding assays with selective opioid antagonists were performed in the spinal cord sections of i.t. butorphanol- and morphine-dependent rats in which withdrawal was precipitated by i.t. naloxone. In butorphanol-dependent rats, the spinal kappa-opioid receptor developed a greater degree of antagonist supersensitivity than the spinal delta- and mu-opioid receptors did. In contrast, the spinal mu-opioid receptor became more sensitive than the delta-opioid receptor in morphine-dependent rats. These results indicate that differential supersensitivity of spinal opioid receptors was induced after chronic i.t. infusions of butorphanol and morphine.