Biology subjects

Miliano, C.

Publications and source records attributed to Miliano, C..

4 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↗

bioRxiv2024

Medial prefrontal cortical neurotransmitters reactive to relapse-promoting and relapse-suppressing cues in rats trained to self-administer cocaine or alcohol

Environmental cues conditioned to signal drug availability (S+) or omission (S-) activate specific neurons (neuronal ensembles/engram cells) within the medial prefrontal cortex (mPFC) to promote and suppress drug relapse in rats. However, the neurochemical source of such cue-specific activation remains unknown. In this study, we determined extracellular neurotransmitter fluctuations reactive to S+ vs. S- in the infralimbic (IL) and prelimbic (PL) cortices of male rats trained to lever-press for cocaine or alcohol self-administration. In cocaine- or alcohol-trained rats exposed to S+, no significant neurotransmitter fluctuations were observed in IL or PL. In cocaine-trained rats exposed to S-, glutamate, serotonin, taurine and adenosine were increased in PL but not in IL. In alcohol-trained rats exposed to S-, glutamate was increased, while dopamine and GABA were decreased, in IL but not in PL. Although S+ reactive neurotransmitters driving neuronal activation in mPFC remains to be elucidated, glutamate is likely the source of such activation by S- in rats trained to self-administer cocaine or alcohol. While drugs used for self-administration and cue-conditioning appear to dictate the type and anatomical specificity of S- evoked neurotransmission within mPFC, glutamate may serve as a common therapeutic target to mimic relapse-suppression by S- across cocaine and alcohol use disorders (CUD and AUD). In contrast, serotonin, taurine and adenosine may serve as the targets in CUD, while dopamine and GABA may serve as the targets in AUD.

neuroscience↗

bioRxiv2024

12/15-Lipoxygenases mediate neuropathic-like pain hypersensitivity in female mice

It is estimated that chronic neuropathic pain conditions exhibit up to 10% prevalence in the general population, with increased incidence in females. However, nonsteroidal inflammatory drugs (NSAIDs) are ineffective, and currently indicated prescription treatments such as opioids, anticonvulsants, and antidepressants provide only limited therapeutic benefit. In the current work, we extended previous studies in male rats utilizing a paradigm of central Toll-like receptor 4 (TLR4)-dependent, NSAID-unresponsive neuropathic-like pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) LPS. In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and locomotor hyperactivity in response to IT LPS. Congruent with our previous observations in male rats, systemic inhibition of 12/15-Lipoxygenases (12/15-LOX) in female B6N mice with selective inhibitors - ML355 (targeting 12-LOX-p) and ML351 (targeting 15-LOX-1) - completely reversed allodynia and grip force deficits. We demonstrate here that 12/15-LOX enzymes also are expressed in mouse spinal cord and that 12/15-LOX metabolites produce tactile allodynia when administered spinally (IT) or peripherally (intraplantar in the paw, IPLT) in a hyperalgesic priming model, similar to others observations with the cyclooxygenase (COX) metabolite Prostaglandin E2 (PGE2). Surprisingly, we did not detect hyperalgesic priming following IT administration of LPS, indicating that this phenomenon likely requires peripheral activation of nociceptors. Collectively, these data suggest that 12/15-LOX enzymes contribute to neuropathic-like pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and non-reflexive outcome measures.

pharmacology and toxicology↗

bioRxiv2024

Examining Cognitive Performance in Mice using the Open-Source Operant Feeding Device FED3

Cognitive impairments are prevalent in various neurological disorders, including chronic pain conditions, and pose significant therapeutic challenges. Preclinical rodent models serve as valuable tools for investigating the underlying mechanisms of and treatments for cognitive dysfunction. However, factors such as stress, age, sex, and disease duration present challenges to reliably capturing cognitive deficits in rodents. Here, we present a comprehensive and high-throughput protocol utilizing the open-source operant Feeding Experimentation Device 3 (FED3) for assessing cognitive performance in mice. We developed a data pipeline to streamline data compilation and analysis, and established operating conditions for a six-test cognitive battery which can be completed in as few as 20 days. We validated our testing procedures using bilateral orbitofrontal cortical lesions to capture deficits in executive function, and demonstrated the feasibility of assessing cognitive function in aged mice of both sexes to identify genotypic and sex-specific effects. Overall, our findings demonstrate that the FED3 is a versatile tool for evaluating cognitive function in mice, offering a low-cost, high-throughput approach for preclinical studies of neurological disorders. We anticipate that this protocol will facilitate broader implementation of cognitive testing in rodent models and contribute to the understanding and treatment of cognitive dysfunction in neurological diseases.

neuroscience↗