Alcohol-Induced Disorders, Nervous System

A team showed how both alcohol intake and alcohol withdrawal can lead to increased pain and hypersensitivity. Chronic alcohol consumption may make people more sensitive to pain through two different molecular mechanisms -- one driven by alcohol intake and one by alcohol withdrawal. That is one new conclusion by scientists at Scripps Research on the complex links between alcohol and pain. The research, published in the British Journal of Pharmacology on April 12, 2023, also suggests potential new drug targets for treating alcohol-associated chronic pain and hypersensitivity. "There is an urgent need to better understand the two-way street between chronic pain and alcohol dependence," says senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine, and a professor of neuroscience at Scripps Research. "Pain is both a widespread symptom in patients suffering from alcohol dependence, as well as a reason why people are driven to drink again." Alcohol use disorder (AUD), which encompasses the conditions commonly called alcohol abuse, alcohol dependence and alcohol addiction, affects 29.5 million people in the U.S. according to the 2021 National Survey on Drug Use and Health. Over time, AUD can trigger the development of numerous chronic diseases, including heart disease, stroke, liver disease and some cancers. Among the many impacts of long-term alcohol consumption is pain: more than half of people with AUD experience persistent pain of some type. This includes alcoholic neuropathy, which is nerve damage that causes chronic pain and other symptoms. Studies have also found that AUD is associated with changes in how the brain processes pain signals, as well as changes to how immune system activation occurs. In turn, this pain can lead to increased alcohol consumption. Moreover, during withdrawal, people with AUD can experience allodynia, in which a harmless stimulus is perceived as painful. Roberto and her colleagues were interested in learning the underlying causes of these different types of alcohol-related pain. In the new study, they compared three groups of adult mice: animals that were dependent on alcohol (excessive drinkers), animals that had limited access to alcohol and were not considered dependent (moderate drinkers), and those that had never been given alcohol. In dependent mice, allodynia developed during alcohol withdrawal, and subsequent alcohol access significantly decreased pain sensitivity. Separately, about half of the mice that were not dependent on alcohol also showed signs of increased pain sensitivity during alcohol withdrawal but, unlike the dependent mice, this neuropathy was not reversed by re-exposure to alcohol. When Roberto's group then measured levels of inflammatory proteins in the animals, they discovered that while inflammation pathways were elevated in both dependent and non-dependent animals, specific molecules were only increased in dependent mice. This indicates that different molecular mechanisms may drive the two types of pain. It also suggests which inflammatory proteins may be useful as drug targets to combat alcohol-related pain. "These two types of pain vary greatly, which is why it is important to be able to distinguish between them and develop different ways to treat each type," says first author Vittoria Borgonetti, PhD, a postdoctoral associate at Scripps Research. Roberto's group is continuing studies on how these molecules might be used to diagnose or treat alcohol-related chronic pain conditions. "Our goal is to unveil new potential molecular targets that can be used to distinguish these types of pain and potentially be used in the future for the development of therapies," says co-senior author Nicoletta Galeotti, PhD, associate professor of preclinical pharmacology at the University of Florence. In addition to Roberto, authors of the study, "Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: a predictive mice model of alcoholic neuropathy," include Amanda Roberts, Michal Bajo and Vittoria Borgonetti of Scripps Research; and Nicoletta Galeotti of University of Florence. This work was supported by funding from the National Institutes of Health (The Integrative Neuroscience Initiative on Alcoholism Consortium AA013498, AA027700, AA021491, AA017447, AA006420, and AA029841), The Schimmel Family Chair, The Pearson Center for Alcoholism and Addiction Research, and The Scripps Research Institute's Animal Models Core Facility.

July 15, 2015 By Mark Terry , BioSpace.com Breaking News Staff San Diego-based Zogenix, Inc. announced yesterday that after meeting with the U.S. Food and Drug Administration (FDA) , it would push back its Phase III clinical trial for ZX008 for a rare form of epilepsy by about three months. The company will enroll an additional 105 patients in both of the two planned Phase III clinical trials. The baseline observation period will last eight weeks, followed by a two-week titration period. In addition, Zogenix indicated it will hold an optional, long-term, open label extension study. ZX008 is designed to treat Dravet syndrome, a rare type of epilepsy that starts in infancy. Dravet syndrome is characterized by long, fever-related seizures that can be fatal. They do not respond to typical epilepsy medications. “We received feedback from the FDA that will help us to Our target is the end of the summer,” said Gail Farfel , head of development for Zogenix in a breakfast webcast meeting yesterday. “With regard to CMC, FDA has agreed with our starting material and our proposed synthetic pathway and have given us clear guidance in regard to stability and impurity testing. For our Phase III studies that we’re targeting to start in 2015, the drug substance is manufactured and our liquid-oral preparation is on stability currently.” “We have a slightly different trial design to the one we originally thought and we contemplated, which we talked about in the past,” said Stephen Farr , president and chief executive officer in yesterday’s breakfast meeting. “We’ve gone to a multi-dose power group, placebo-controlled trial with more patients involved. So we’re currently working with our selector to confirm the costs and we’ll provide some guidance on that. But we’re still confident we have sufficient cash through 2016 to complete the studies.” It’s estimated that the two studies will cost about $20 million. Analyst Annabel Samimy with Stifel Nicolaus speaking to Medical Daily said the change in schedule was not “dramatically different.” She indicated she thought the company’s investigational new drug (IND) application would be approved within 30 to 60 days. Nonetheless, Zacks changed Zogenix from “hold” to “sell” earlier this week. Its focus was on the company’s lead product candidate, ZX002, an oral controlled-release formulation of hydrocodone used to treat moderate to severe chronic pain. In a research note on June 26, TheStreet analysts upgraded Zogenix from “sell” to “hold.” Brean Capital analysts held a “buy” rating and set a $2.50 price target on June 15. Oppenheimer analysts held an “outperform” rating and also set $2.50 as the price target on May 12. Piper Jaffray analysts set an “overweight” rating and also set a price target of $2.50. Zogenix stock recently took a big jump from $13.35 on July 7 to currently trade for $19.41. It’s been somewhat volatile over the last year, trading for $8.84 on Dec. 16, 2014, rising on Mar. 6, 2015 to $15.04, then dropping back to $9.76 on Mar. 11, 2015. As New Jersey Biotech Booms, Will It Overtake Other States As Prime Location? A week after Celgene Corporation announced it is officially the mystery buyer of Merck & Co. ’s former 1 million-square-foot R&D site in Summit, N.J., it quickly became our most popular story last week. The company announced last Wednesday that it is buying the space, ending months of speculation about what Big Pharma company might move into the neighborhood. The Summit, N.J. site is zoned research/office. The New Jersey site would put operations closer to some of the major biotech and pharmaceutical hubs on the East Coast. But, by far, the most tempting part of doing business in the state remains New Jersey’s operating tax credit, which allows companies to sell their net operating losses to the New Jersey Treasury. One of the state’s most recognizable biotechs, Celgene, used the program until it became profitable, which was key to it staying in the state, said local officials. That has BioSpace is wondering if New Jersey is becoming the new face of biotech . What do you think? Can the Garden State compete with other longtime stalwarts like California or Boston? var _polldaddy = [] || _polldaddy; _polldaddy.push( { type: "iframe", auto: "1", domain: "biospace.polldaddy.com/s/", id: "as-new-jersey-biotech-booms-will-it-overtake-other-states-as-prime-location", placeholder: "pd_1436372551" } ); (function(d,c,j){if(!document.getElementById(j)){var pd=d.createElement(c),s;pd.id=j;pd.src=(' '==document.location.protocol)?' ':' ';s=document.getElementsByTagName(c)[0];s.parentNode.insertBefore(pd,s);}}(document,'script','pd-embed'));