Thermal sensitivity as a measure of spontaneous morphine withdrawal in mice

Opioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The following study describes a method for assessing increases in thermal sensitivity on the hotplate in a mouse model of spontaneous morphine withdrawal

A tail withdrawal procedure for assessing analgesic activity in rhesus monkeys

Rhesus monkeys were restrained in chairs from which their tails hung free so that their tails could be immersed into a thermos of water. Monkeys consistently kept their tails in 38-40[deg]C water for at least 20 sec, but withdrew them from 55[deg]C water in 1-4 sec. Tail withdrawal latencies from 55[deg]C water remained consistent over a period of 3 hr. Morphine produced dose-dependent increases in tail withdrawal latencies from 55[deg]C water, whereas pentobarbital, haloperidol, and phencyclidine did not increase tail withdrawal latencies except at doses that produced marked sedation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26151/1/0000228.pd

Chronic unpredictable stress enhances cocaine-conditioned place preference in type 1 cannabinoid receptor knockout mice

Cannabinoid signaling via the CB1 receptor modulates the effects of drugs of abuse and the response to exposure to stressors. In addition, exposure to stressors can alter the effects of drugs of abuse. The present study examined the effects of exposure to chronic unpredictable stress (CUS) in CB1 receptor knockout mice (CB1 KO) and their wild-type (WT) littermates, using cocaine conditioned place preference (CPP) to compare their response to cocaine. Mice were untreated or exposed to two weeks of CUS. Following this period, the acquisition of a cocaine CPP was examined with one of three doses (3.2, 10.0 or 17.0 mg/kg) of cocaine. Untreated CB1 KO and WT mice both acquired the cocaine CPP; however, exposure to CUS enhanced the acquisition of the cocaine CPP in CB1 KO mice, but did not significantly alter the effects of cocaine in WT mice. Taken together, these findings support previous evidence suggesting a role for the CB1 receptor in the response to stress as well as in the effects of cocaine

Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine

In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution prior to 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared to day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e., the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e., gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose

The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse

Cannabinoid CB1 antagonists decrease self-administration of palatable food and several abused drugs in animals and modulate extinction of conditioned fear responses. Less is known, however, about whether and how CB1 antagonists might modulate the extinction of appetitive behavior. Therefore, this study examined the effects of the CB1 receptor antagonist rimonabant (SR141716) during extinction of responding maintained either by cocaine or by palatable foods (corn oil or Ensure), as well as responding elicited by stimulus cues that had been paired with the presentation of cocaine (i.e., cue-induced reinstatement) or a prime (presentation of cocaine or food). The effect of rimonabant on high rate responding in water-deprived mice trained to self-administer water was also examined. In mice self-administering cocaine, rimonabant attenuated cue-induced reinstatement of cocaine self-administration, the initial burst of responding during cocaine extinction and responding during spontaneous recovery. In mice self-administering corn oil, rimonabant decreased responding during extinction and also attenuated responding that had been reinstated by a priming presentation of corn oil. Moreover, mice treated with rimonabant required fewer daily sessions to reach criterion for extinction of cocaine-maintained responding than vehicle treated mice. Also, rimonabant had no effect on rate of operant responding in mice trained to respond for water under an FR5 schedule of reinforcement. Taken together, these data suggest that in addition to attenuating the primary reinforcing effects of both palatable foods and drugs of abuse, CB1 receptor antagonism can attenuate context and cue reactivity during extinction learning and potentially enhance extinction learning in this way

Morphine Tolerance As A Function Of Ratio Schedule: Response Requirement Or Unit Price?

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price

Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: Interactive effects

CB1 cannabinoid (CB1) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB1/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB1 receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (zmix) with predicted additive potency (zadd). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (zadd = zmix), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (zadd > zmix). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations

Effects of morphine on pain-elicited and pain-suppressed behavior in CB1 knockout and wildtype mice

Pharmacological manipulations of the type 1 cannabinoid receptor (CB1) suggest a role for CB1 in morphine-induced antinociception, but studies utilizing CB1 knockout (KO) mice do not support this conclusion. Since studies using CB1 KO mice to study morphine’s antinociceptive effects have only examined thermal nociception, this study examines these interactions in models that employ a chemical stimulus

Developing Feasible and Effective School-Based Interventions for Children With ASD: A Case Study of the Iterative Development Process

Despite an emphasis on identifying evidence-based practices among researchers and using evidence-based practices among professionals in the field of education, there are still problems with uptake and implementation in real-world settings. This lack of diffusion of practices is evident in educational programming for children with autism spectrum disorder (ASD). One solution is to use an iterative process to develop interventions in which researchers work in collaboration with the end users to test and refine interventions. However, there are very few guidelines for developing feasible and effective interventions through these iterative processes. This article provides a description of the iterative process used to develop the Advancing Social-Communication and Play (ASAP) intervention, a supplemental program designed for public preschool classrooms serving students with ASD, and examples of how data from the sequence of iterative design studies shaped the intervention development. The research team offers guidelines for other researchers looking to engage in intervention development using an iterative process in the context of partnerships with end users, including suggestions for planning and executing an intervention development grant