Biology subjects

Natividad, L.

Publications and source records attributed to Natividad, L..

2 recordsLinked to original sources

bioRxiv2024

Chronic intermittent ethanol produces nociception through endocannabinoid-independent mechanisms in mice

Alcohol use disorder (AUD) affects millions of people and represents a significant health and economic burden. Pain represents a frequently under-treated aspect of hyperkatifeia during alcohol withdrawal, yet to date no drugs have received FDA approval for the treatment of this indication in AUD patients. This study aims to evaluate the potential of targeting bioactive lipid signaling pathways as a therapeutic approach for treating alcohol withdrawal-related pain. We utilized a chronic intermittent ethanol (CIE) vapor exposure model in C57BL/6J mice of both sexes to establish alcohol dependence, and demonstrated that CIE mice developed robust tactile allodynia and thermal hyperalgesia during withdrawal that was independent of prior blood alcohol levels. Next, we evaluated four drugs for their efficacy in reversing tactile allodynia during abstinence from CIE using a cross-over treatment design that included FDA-approved naltrexone as well as commercially available inhibitors targeting inflammatory lipid signaling enzymes including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and 15-Lipoxygenase (LOX). None of these compounds produced significant therapeutic benefit in reversing established CIE-induced tactile allodynia, despite attenuating pain-like behaviors at these doses in other chronic pain models. Additionally, we assessed plasma endocannabinoid levels in both sexes during withdrawal. We found that there is an inherent sex difference in the endogenous anti-inflammatory endocannabinoid tone in naive mice and CIE treatment affected endocannabinoids levels in female mice only. These findings underscore the need to better understand the driving causes of AUD induced pain and to develop novel therapeutic approaches to mitigate pain in AUD patients.

pharmacology and toxicology↗

bioRxiv2023

Striatal enkephalin supports maintenance of conditioned cocaine reward during extinction

Drug predictive cues and contexts exert powerful control over behavior and can incite drug seeking and taking. This association and the behavioral output are encoded within striatal circuits, and regulation of these circuits by G-protein coupled receptors affects cocaine-related behaviors. Here, we investigated how opioid peptides and G-protein coupled opioid receptors expressed in striatal medium spiny neurons (MSNs) regulate conditioned cocaine seeking. Augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP). In contrast, opioid receptor antagonists attenuate cocaine CPP and facilitate extinction of alcohol CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. We generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing MSNs (D2-PenkKO) and tested them for cocaine CPP. Low striatal enkephalin levels did not attenuate acquisition or expression of CPP; however, D2-PenkKOs showed faster extinction of cocaine CPP. Single administration of the non-selective opioid receptor antagonist naloxone prior to preference testing blocked expression of CPP selectively in females, but equally between genotypes. Repeated administration of naloxone during extinction did not facilitate extinction of cocaine CPP for either genotype, but rather prevented extinction in D2-PenkKO mice. We conclude that while striatal enkephalin is not necessary for acquisition of cocaine reward, it maintains the learned association between cocaine and its predictive cues during extinction learning. Further, sex and pre-existing low striatal enkephalin levels may be important considerations for use of naloxone in treating cocaine use disorder.

neuroscience↗