prevention-allodynia-hyperalgesia-cannabidiol-rat-model-chemotherapy

Prevention of Allodynia and Hyperalgesia by Cannabidiol in a Rat Model of Chemotherapy-Induced Peripheral Neuropathy

This study demonstrates the utility of a rat model of chemotherapy-induced peripheral neuropathy (CIPN) to assess the ability of the non-psychoactive ...

The US geriatric population is growing and using more opioids than ever before. The purpose of this study was to determine whether aging influenced the reinforcing efficacy of morphine in male and female rats using a rodent intravenous self-administration paradigm. Male and female aged (20-24 months) and young (2-4 months) Wistar rats were tested at 2 doses of morphine (0.75 mg/kg/infusion and 0.25 mg/kg/infusion). During 10 days of self-administration, aged rats took significantly less morphine than their younger counterparts at the 0.25 mg/kg/infusion dose. Aged males also earned significantly fewer infusions on a progressive ration reinforcement schedule at this dose, suggesting that the reinforcing efficacy of morphine is decreased for this group at this dose. These effects dissipated when a separate group of animals had access to the 0.75 mg/kg/infusion dose for both sexes. Our results indicate that morphine is less reinforcing at lower doses in aged male, but not female rats. This research has potential clinical implications for the chronic treatments involving opioids in aged individuals.

Aging reduces the sensitivity to the reinforcing efficacy of morphine.

Parental drug use around or before conception can have adverse consequences for offspring. Historically, this research has focused on the effects of maternal substance use on future generations but less is known about the influence of the paternal lineage. This study focused on the impact of chronic paternal morphine exposure prior to conception on behavioral outcomes in male and female progeny.

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring.

Gadd45b: at the intersection of transcriptional and epigenetic changes associated with cocaine-related behaviors.

Parental history of opioid exposure is seldom considered when prescribing opioids for pain relief. To explore whether parental opioid exposure may affect sensitivity to morphine in offspring, we developed a "rat pain scale" with high-speed imaging, machine learning, and mathematical modeling in a multigenerational model of paternal morphine self-administration. We find that the most commonly used tool to measure mechanical sensitivity in rodents, the von Frey hair, is not painful in rats during baseline conditions. We also find that male progeny of morphine-treated sires had no baseline changes in mechanical pain sensitivity but were more sensitive to the pain-relieving effects of morphine. Using RNA sequencing across pain-relevant brain regions, we identify gene expression changes within the regulator of G protein signaling family of proteins that may underlie this multigenerational phenotype. Together, this rat pain scale revealed that paternal opioid exposure increases sensitivity to morphine's pain-relieving effects in male offspring.

Chronic paternal morphine exposure increases sensitivity to morphine-derived pain relief in male progeny.

Incubation of craving is a well-documented phenomenon referring to the intensification of drug craving over extended abstinence. The neural adaptations that occur during forced abstinence following chronic drug taking have been a topic of intense study. However, little is known about the transcriptomic changes occurring throughout this window of time. To define gene expression changes associated with morphine consumption and extended abstinence, male and female rats underwent 10 days of morphine self-administration. Separate drug-naive rats self-administered sucrose in order to compare opioid-induced changes from those associated with natural, non-drug rewards. After one or 30 days of forced abstinence, rats were tested for craving, or nucleus accumbens shell tissue was dissected for RNA sequencing. Morphine consumption was predictive of drug seeking after extended (30 days) but not brief (1 day) abstinence in both sexes. Extended abstinence was also associated with robust sex- and reinforcer-specific changes in gene expression, suggesting sex differences underlying incubation of morphine and sucrose seeking respectively. Importantly, these changes in gene expression occurred without re-exposure to drug-paired cues, indicating that chronic morphine causes long-lasting changes in gene expression that prime the system for increased craving. These findings lay the groundwork for identifying specific therapeutic targets for curbing opioid craving without impacting the natural reward system in males and females.

Transcriptomics in the nucleus accumbens shell reveal sex- and reinforcer-specific signatures associated with morphine and sucrose craving.

Incubation of craving refers to the intensification of drug-seeking behavior in response to reward-paired cues over the course of abstinence. In rodents, craving and drug-seeking behaviors have been measured by an increase in lever pressing in the absence of reinforcer availability in response to cue presentations. However, craving in rodents is difficult to define and little is known about the behavioral signatures that accompany increased drug-seeking behavior measured by lever pressing. The affective components of relapse are also important, but understudied in rodents. Hormonal fluctuations influence craving for psychostimulants, but little is known about the impact of the estrous cycle on opioid-seeking behavior. This study sought to delineate the behavioral and affective signatures associated with craving, and to examine the influence of the female estrous cycle on craving. Male and female rats underwent 10 d of intravenous opioid self-administration. Separate cohorts of control rats self-administered oral sucrose, a natural nondrug reward. Cue-induced seeking tests were conducted after 1 or 30d of forced abstinence. These sessions were recorded and scored for overall locomotion, instances of sniffing, grooming, or hyperactivity. Ultrasonic vocalizations (USVs) were also recorded to determine affective profiles that accompany opioid seeking. Although active lever presses and overall locomotion increased unanimously over extended abstinence from heroin and sucrose, a sex- and reinforcer-specific behavioral and affective signature of craving emerged. Furthermore, although the female estrous cycle did not affect taking or seeking, it appears to influence more granular behaviors.

Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats.

A growing body of preclinical studies report that preconceptional experiences can have a profound and long-lasting impact on adult offspring behavior and physiology. However, less is known about paternal drug exposure and its effects on reward sensitivity in the next generation.

Paternal morphine exposure enhances morphine self-administration and induces region-specific neural adaptations in reward-related brain regions of male offspring.

The ongoing opioid addiction crisis necessitates the identification of novel risk factors to improve prevention and treatment of opioid use disorder. Parental opioid exposure has recently emerged as a potential regulator of offspring vulnerability to opioid misuse, in addition to heritable genetic liability. An understudied aspect of this "missing heritability" is the developmental presentation of these cross-generational phenotypes. This is an especially relevant question in the context of inherited addiction-related phenotypes, given the prominent role of developmental processes in the etiology of psychiatric disorders. Paternal morphine self-administration was previously shown to alter the sensitivity to the reinforcing and antinociceptive properties of opioids in the next generation. Here, phenotyping was expanded to include the adolescent period, with a focus on endophenotypes related to opioid use disorders and pain. Paternal morphine exposure did not alter heroin or cocaine self-administration in male and female juvenile progeny. Further, baseline sensory reflexes related to pain were unaltered in morphine-sired adolescent rats of either sex. However, morphine-sired adolescent males exhibited a reduction in social play behavior. Our findings suggest that, in morphine-sired male offspring, paternal opioid exposure does not affect opioid intake during adolescence, suggesting that this phenotype does not emerge until later in life. Altered social behaviors in male morphine-sired adolescents indicate that the changes in drug-taking behavior in adults sired by morphine-exposed sires may be due to more complex factors not yet fully assessed.

Paternal morphine exposure in rats reduces social play in adolescent male progeny without affecting drug-taking behavior in juvenile males or female offspring.

Article	Year
Aging reduces the sensitivity to the reinforcing efficacy of morphine. Neurobiology of aging\| PubMed ID: 33120086	2021
Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring. Psychopharmacology\| PubMed ID: 31912193	2020
Gadd45b: at the intersection of transcriptional and epigenetic changes associated with cocaine-related behaviors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 33077898	2021
Chronic paternal morphine exposure increases sensitivity to morphine-derived pain relief in male progeny. Science advances\| PubMed ID: 35171664	2022
Transcriptomics in the nucleus accumbens shell reveal sex- and reinforcer-specific signatures associated with morphine and sucrose craving. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 35190706	2022
Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats. eNeuro\| PubMed ID: 35241453	2022
Paternal morphine exposure enhances morphine self-administration and induces region-specific neural adaptations in reward-related brain regions of male offspring. bioRxiv : the preprint server for biology\| PubMed ID: 36711571	2023
Paternal morphine exposure in rats reduces social play in adolescent male progeny without affecting drug-taking behavior in juvenile males or female offspring. Molecular and cellular neurosciences\| PubMed ID: 37385516	2023

Mathieu E. Wimmer

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