Accepted

Alcohol use disorder (AUD) is a chronic, relapsing disorder characterized by an escalation of drinking and the emergence of negative affective states over time. Within this framework, alcohol may be used in excessive amounts to alleviate withdrawal-related symptoms, such as hyperalgesia. Future effective therapeutics for AUD may need to exhibit the ability to reduce drinking as well as alleviate co-morbid conditions such as pain, as well as take mechanistic sex differences into consideration. Agmatine is an endogenous neuromodulator that has been previously implicated in the regulation of reward and pain processing. In the current set of studies, we examined the ability of agmatine to reduce escalated ethanol drinking in complementary models of AUD where adult male and female mice and rats were made dependent via chronic, intermittent ethanol vapor exposure (CIE). We also examined the ability of agmatine to modify thermal and mechanical sensitivity in alcohol-dependent male and female rats. Agmatine reduced alcohol drinking in a dose-dependent fashion, with somewhat greater selectivity in alcohol-dependent female mice (versus non-dependent female mice) but equivalent efficacy across male mice and both groups of male and female rats. In mice and female rats, this efficacy did not extend to sucrose drinking, indicating some selectivity for ethanol reinforcement. Female rats made dependent on alcohol demonstrated significant hyperalgesia symptoms, and agmatine produced dose-dependent antinociceptive effects across both sexes. While additional mechanistic studies into agmatine are necessary, these findings support the broad-based efficacy of agmatine to treat co-morbid excessive drinking and pain symptoms in the context of AUD.

Previous international mass-media campaigns for low back pain (LBP) have had conflicting impacts on the general population. The objective was to evaluate the impact of a national back pain campaign conducted between 2017 and 2019 on beliefs and behaviours of general practitioners and the general population in France.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics to treat inflammatory pain. Despite their efficacy, recent studies show that NSAID use in early acute pain can prolong pain and inflammation and delay their resolution. We suggest using analgesics without inflammation-related properties in early acute pain instead of NSAIDs.

Administration of a nitric oxide (NO) donor triggers migraine attacks but mechanisms by which this occurs are unknown. Reactive nitroxidative species, including NO and peroxynitrite (PN), have been implicated in nociceptive sensitization and neutralizing PN is anti-nociceptive. We determined whether PN contributes to nociceptive responses in two distinct models of migraine headache. Female and male mice were subjected to three consecutive days of restraint stress or to dural stimulation with the pro-inflammatory cytokine interleukin-6. Following resolution of the initial post-stimulus behavioral responses, animals were tested for hyperalgesic priming using a normally non-noxious dose of the NO donor sodium nitroprusside (SNP) or dural pH 7.0, respectively. We measured periorbital von Frey and grimace responses in both models and measured stress-induced changes in 3-nitrotyrosine (3-NT) expression (a marker for PN activity) and trigeminal ganglia (TG) mitochondrial function. Additionally, we recorded TG neuronal activity in response to the PN generator SIN-1. We then tested the effects of the PN decomposition catalysts, FeTMPyP and FeTPPS, or the PN scavenger MnTBAP against these behavioral, molecular, and neuronal changes. Neutralizing PN attenuated stress-induced periorbital hypersensitivity and priming to SNP, with no effect on priming to dural pH 7.0. These compounds also prevented stress-induced increases in 3-NT expression in both the TG and dura mater and attenuated TG neuronal hyperexcitability caused by SIN-1. Surprisingly, FeTMPyP attenuated changes in TG mitochondrial function caused by SNP in stressed males only. Together, these data strongly implicate PN in migraine mechanisms and highlight the therapeutic potential of targeting PN.Among the most reliable experimental triggers of migraine are nitric oxide donors. Mechanisms by which nitric oxide triggers attacks are unclear but may be due to reactive nitroxidative species such as peroxynitrite. Utilizing mouse models of migraine headache, we show that peroxynitrite-modulating compounds attenuate behavioral, neuronal, and molecular changes caused by repeated stress and nitric oxide donors (two of the most common triggers of migraine in humans). Additionally, our results show a sex-specific regulation of mitochondrial function by peroxynitrite following stress, providing novel insight into the ways in which peroxynitrite may contribute to migraine-related mechanisms. Critically, our data underscore the potential in targeting peroxynitrite formation as a novel therapeutic for the treatment of migraine headache.

Back pain is common among older adults resulting in high societal and economic burden of persistent pain and disability. Pain medications are frequently prescribed for back pain, especially among older patients, but the efficacy of analgesics on back pain in this patient population remains under debate. In the present study, we investigated the outcomes (i.e. pain intensity and disability) of pain medication use in older people with back pain participating in a prospective cohort study.

To summarize published studies evaluating productivity loss and productivity loss costs associated with cancer, chronic lung disease, depression, pain, and cardiometabolic disease among US employees.

The objective of this study was to assess women's healthcare providers' treatment practices for pregnant women with migraine.

The synthetic peptide ERα17p (sequence: PLMIKRSKKNSLALSLT), which corresponds to the 295-311 region of the human estrogen receptor α (ERα), induces apoptosis in breast cancer cells. In mice and at low doses, it promotes not only the decrease of the size of xenografted triple-negative human breast tumors, but also anti-inflammatory and anti-nociceptive effects. Recently, we have shown that these effects were due to its interaction with the seven-transmembrane G protein-coupled estrogen receptor GPER. Following modeling studies, the C-terminus of this peptide (sequence: NSLALSLT) remains compacted at the entrance of the GPER ligand-binding pocket, whereas its N-terminus (sequence: PLMI) engulfs in the depth of the same pocket. Thus, we have hypothesized that the PLMI motif could support the pharmacological actions of ERα17p. Here, we show that the PLMI peptide is, indeed, responsible for the GPER-dependent antiproliferative and anti-nociceptive effects of ERα17p. By using different biophysical approaches, we demonstrate that the NSLALSLT part of ERα17p is responsible for aggregation. Overall, the tetrapeptide PLMI, which supports the action of the parent peptide ERα17p, should be considered as a hit for the synthesis of new GPER modulators with dual antiproliferative and anti-nociceptive actions. This study highlights also the interest to modulate GPER for the control of pain.