Sara Jane Ward

Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy

Paclitaxel (PAC) is associated with chemotherapy‐induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non‐psychoactive cannabinoid cannabidiol (CBD) prevents PAC‐induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy.

Effects of a Cannabinoid1 Receptor Antagonist and Serotonin2C Receptor Agonist Alone and in Combination on Motivation for Palatable Food: A Dose-Addition Analysis Study in Mice

The cannabinoid and serotonin systems modulate feeding behavior in humans and laboratory animals. The present study assessed whether a cannabinoid (CB)1 receptor antagonist and a serotonin (5-HT)2C receptor agonist alone and in combination attenuate motivation for the liquid nutritional drink Ensure as measured by a progressive ratio (PR) schedule of reinforcement in male C57BL/6 mice. Pretreatment (15 min i.p.) with either the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) (SR; Rimonabant or Acomplia) or the 5-HT2C receptor agonist m-chlorophenylpiperazine (mCPP) dose-dependently decreased the maximum ratio completed under the PR schedule (break point) in mice. ED25 values for SR and mCPP to decrease break point were determined, and the relative potency of each drug alone was quantified. Fixed dose-ratio pairs of SR/mCPP based on their relative potency were then administered. Dose-addition analysis comparing the experimentally determined potency for SR/mCPP combinations with their predicted additive potency revealed that SR/mCPP combinations in 1:1 and 2:1 ratios based on relative potency produced significant synergistic attenuation of break point for Ensure. The ED25 values for decreasing break point were consistently lower than ED25 values for decreasing response rate, and synergistic effects of SR/mCPP combinations on break point were seen independent of synergistic effects on response rate. These results indicate that cannabinoid CB1 and serotonin 5-HT2C receptors are involved in motivated feeding behavior in mice and that these compounds can synergistically modulate motivation for palatable food with the synergy dependent upon the ratio of SR/mCPP in the combination.

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

IntroductIon The endogenous cannabinoid (eCB) system plays a significant role in appetitive drive and feeding behavior. Therefore, antagonism of this receptor-mediated system was predicted to provide therapeutic benefit for the treatment of disorders associated with excess appetitive drive, such as obesity and substance abuse, as well as other disorders (1–3). Toward this end, cannabinoid receptor antagonists have been designed and investigated as pharmacotherapeutic agents. Rimonabant was the first-inclass of such compounds. Its biological activity is thought to be mediated by CB1 (cannabinoid receptor subtype 1) antagonist or inverse-agonist action, i.e., it acts as a functional antagonist in vivo. Rimonabant suppresses feeding in laboratory animals (4–6) and also shows efficacy at reducing body weight and improving cardiovascular and metabolic risk factors in nondiabetic and diabetic overweight and obese patients (7–10). However, concerns over psychiatric adverse effects such as depression, anxiety, and suicidal ideations, and other adverse effects (e.g., increased incidence of nausea, vomiting, and pruritis) led to the withdrawal of rimonabant from the market worldwide. The experience with rimonabant prompted the questioning of the CB1 antagonism approach. However, concern has now been expressed that the experience with one or two drugs might have potentially led to premature abandonment of an entire mechanism—a mechanism that might be valuable for treatment of several disorders that currently lack effective therapy (11–14). That is, the observed adverse effects might be related to the individual drug (a drug effect) rather than the mechanism of action (a class effect). Therefore, further understanding of the behavioral pharmacological, neurochemical, and cellular effects of rimonabant and of more recent novel CB1 receptor antagonists might shed some light on the therapeutic potential of such compounds. Specifically, (i) potential efficacy of peripherally restricted CB1 antagonists for obesity and type 2 diabetes and other disorders, (ii) the effects of CB1 neutral antagonists, as opposed to inverse agonists, on weight and mood disorders, (iii) the extent and mechanism(s) by which central CB1 receptor antagonism produces global effects on anhedonia or depressed mood, and (iv) whether combining lower doses of these agents with agents from other drug classes could improve or maintain efficacy while lessening adverse effects (see also Table 1 for a summary of points 1–3).

Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice

The taxane chemotherapeutic paclitaxel frequently produces peripheral neuropathy in humans. Rodent models to investigate mechanisms and treatments are largely restricted to male rats, whereas female mouse studies are lacking. We characterized a range of paclitaxel doses on cold and mechanical allodynia in male and female C57Bl/6 mice. Because the nonpsychoactive phytocannabinoid cannabidiol attenuates other forms of neuropathic pain, we assessed its effect on paclitaxel-induced allodynia. Paclitaxel produced allodynia that was largely dose independent and more robust in female mice, and this effect was prevented by treatment with cannabidiol. Our preliminary findings therefore indicate that cannabidiol may prevent the development of paclitaxel-induced allodynia in mice and therefore be effective at preventing dose-limiting paclitaxel-induced peripheral neuropathy in humans.

Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure ® and Corn-Oil Seeking in Mice

The cannabinoid CB1 receptor antagonist SR141716A decreases cue-induced reinstatement of sucrose and drug seeking in rats. Reinstatement behavior is not well characterized in C57Bl/6 mice, including CB1 receptor knockout mice generated on a C57Bl/6 background. In the present study, male C57Bl/6, CB1 knockout (CB1 KO), and wild-type littermate (WT) mice were trained to respond for the sweet reinforcer Ensure® or corn oil. Responding was maintained on a fixed ratio 1 (FR1) schedule of reinforcement for 10 days, and then extinguished by the removal of the reinforcer and associated cues. Subsequently, the effect of either pretreatment with SR141716A or CB1 receptor knockout on cue-induced reinstatement of Ensure® or corn-oil seeking was assessed. Both 1.0 and 3.0 mg/kg SR141716A decreased reinstatement of Ensure® seeking in C57Bl/6 mice. A tenfold higher dose of SR141716A (10.0 mg/kg) was required to attenuate reinstatement behavior in C57Bl/6 mice responding for corn oil, suggesting that CB1 receptors may be selectively involved in the neurobiology underlying reinstatement of responding for some food reinforcers but not others. Whereas CB1 receptor antagonism selectively attenuated reinstatement of responding for Ensure®, genetic deletion of the CB1 receptor produced only a trend in decreasing reinstatement of Ensure® seeking, and did not attenuate reinstatement of corn-oil seeking. Baseline differences in levels of operant responding were also observed in WT vs CB1 KO mice maintained by Ensure® and corn oil. This and other possible reasons for the observed discrepancy between pharmacological blockade vs genetic invalidation of the CB1 receptor on reinstatement of Ensure® seeking are discussed.

Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice.

No medication is approved to treat cocaine addiction, but mounting evidence suggests that glutamate-directed approaches may reduce cocaine dependence and relapse. We tested the hypotheses that the glutamate transporter subtype 1 activator, ceftriaxone, disrupts acquisition of cocaine self-administration, motivation to self-administer cocaine, and conditioned place preference in mice. Repeated ceftriaxone (200 mg/kg) reduced the ability of mice to acquire cocaine and the motivation to self-administer cocaine after successful acquisition without affecting acquisition of or motivation for sweet food. Repeated ceftriaxone had no effect on cocaine-conditioned place preference. These results suggest that a &bgr;-lactam antibiotic reduces the direct reinforcing strength of cocaine without producing nonspecific deficits in conditioned learning processes.

Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder

BACKGROUND Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry; therefore, the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing. METHODS Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacologic assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system. RESULTS Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared with control handling. Altered cocaine intake during extended access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities. CONCLUSIONS These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression.

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

CB(1) cannabinoid (CB(1)) 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 CB(1)/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 CB(1) 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 (z(mix)) with predicted additive potency (z(add)). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (z(add) = z(mix)), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (z(add) > z(mix)). 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.

Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality.

Sex and cannabinoid CB1 genotype differentiate palatable food and cocaine self-administration behaviors in mice.

Both cannabinoid CB1 receptor knockout and antagonism produce well-established attenuation of palatable food and drug self-administration behavior. Although cannabinoid drugs have received attention as pharmacotherapeutics for various disorders, including obesity and addiction, it is unclear whether these agents produce equivalent behavioral effects in females and males. In this study, acquisition of 32% corn oil or 10% Ensure self-administration, and maintenance of corn oil, Ensure, or 0.56 mg/kg/infusion cocaine self-administration under both fixed ratio (FR)-1 and progressive ratio (PR) schedule of reinforcement, was compared in male and female wild type (WT) and CB1 knockout (KO) mice. Furthermore, the effect of pretreatment with the CB1 antagonist SR141716 (0.3–3.0) on Ensure self-administration in male and female WT and CB1 KO mice was assessed. CB1 genotype and sex significantly interacted to produce an attenuation of acquisition and maintenance of Ensure self-administration and PR self-administration for both Ensure and cocaine in male CB1 KO mice. In contrast, male CB1 KO mice showed no deficit in acquisition and maintenance of FR-1 responding or in PR responding maintained by corn oil. Sex differences also arose within genotypes for responding maintained under all three reinforcers. Lastly, pretreatment with SR141716 attenuated Ensure self-administration in WT and CB1 KO mice but was approximately five-fold more potent in WT mice than in CB1 KOs. The present data add to a small but growing literature suggesting that the cannabinoid system may be differentially sensitive in its modulation of appetitive behavior in males versus females.