Alcohol amplifies cingulate cortex signaling and facilitates immobilization-induced hyperalgesia in female rats

Cucinello-Ragland, Jessica A.; Mitchell-Cleveland, Roshaun; Trimble, W Bradley; Urbina, Amy P.; Yeh, Alice; Edwards, Kimberly N.; Molina, Patricia E.; Peter, Liz Simon; Edwards, Scott

doi:10.1016/j.neulet.2021.136119

Cited by 7 publications

(8 citation statements)

References 90 publications

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“…Little data is available showing mechanical sensitivity in female mice using any model of alcohol dependence, and we are the first to directly compare mechanical thresholds in male and female mice after repeated cycles of CIEV and withdrawal. In a rat model of CAWIP, one study showed decreased mechanical thresholds in female rats 1 week after discontinuation of a nine weeks of alcohol administration via liquid diet (Cucinello-Ragland et al, 2021). However, they did not test for mechanical sensitivity during the critical 24 – and 48 – hour withdrawal period where physiological signs of dependence are maximal.…”

Section: Discussionmentioning

confidence: 99%

Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration and Blood Alcohol Concentration in Mice

Brandner

Baratta

Richod

et al. 2022

Preprint

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Approximately half of patients with alcohol use disorder (AUD) report pain and this can be severe during withdrawal. However, many questions remain regarding the importance of sex, blood alcohol concentration (BAC), time course, and pain modality. To examine the impact of sex and BAC on the time course of the development of mechanical and heat hyperalgesia, we characterized a mouse model of Chronic Alcohol Withdrawal Induced Pain (CAWIP) in the presence or absence the alcohol dehydrogenase inhibitor, pyrazole. Male and female C57BL/6J mice underwent chronic intermittent ethanol vapor (CIEV) + or - pyrazole exposure for 4 weeks, 4 days/week to induce ethanol dependence. Hind paw sensitivity to the plantar application of mechanical (von Frey filaments) and radiant heat stimuli were measured during weekly observations at 1, 3, 5, 7, 24, and 48 hr after cessation of ethanol exposure. In the presence of pyrazole, males developed mechanical hyperalgesia after the first week of CIEV exposure, peaking at 48 hours after cessation of ethanol. By contrast, females did not develop mechanical hyperalgesia until the fourth week; this also required pyrazole and did not peak until 48 hours. Heat hyperalgesia was consistently observed only in females exposed to ethanol and pyrazole; this developed after the first weekly session and peaked at 1 hour. We conclude that CAWIP develops in a sex, time, and BAC dependent manner in C57BL/6J mice.

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Section: Discussionmentioning

confidence: 99%

Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration and Blood Alcohol Concentration in Mice

Brandner

Baratta

Richod

et al. 2022

Preprint

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“…Tissue homogenates were then heated to 90°C for 5 min, and total protein concentration was measured using a detergent‐compatible Lowry protein assay (Bio‐Rad). Samples were stored in 10 μ g/ μ L protein aliquots at −80°C until used for western blot analysis as previously described (Cucinello‐Ragland et al, 2021). Briefly, samples underwent SDS‐polyacrylamide gel electrophoresis on 10% acrylamide gels using a Tris/Glycine/SDS buffer system (Bio‐Rad), followed by overnight electrophoretic transfer to polyvinylidene difluoride membranes (ThermoFisher).…”

Section: Methodsmentioning

confidence: 99%

“…Immunoreactivity was quantified by densitometry using ImageJ (NIH), and protein densitometry values were normalized to the total protein densitometry values. Both ERK bands were quantified together, as previously described (Cucinello‐Ragland et al, 2021). Densitized phosphoprotein values were normalized to total protein densitometry values to generate phosphorylated: total protein ratio values.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, the periaqueductal gray (PAG) is a midbrain region that largely modulates somatic components of pain via integration of ascending and descending inputs (Hemington & Coulombe, 2015) and has been implicated in the aversive effects of alcohol (Le et al, 2020). Animal models of chronic pain and AUD separately produce increased glutamatergic activity and extracellular signal‐regulated kinase ERK 1/2 (ERK) signaling throughout these areas (Adrienne McGinn et al, 2020; Cucinello‐Ragland et al, 2021; Zamora‐Martinez & Edwards, 2014). However, less is known about the effects of acute alcohol exposure on these neuroadaptations in the context of persistent pain.…”

Section: Introductionmentioning

confidence: 99%

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Sex‐specific biobehavioral regulation of persistent inflammatory pain by alcohol

Cucinello‐Ragland,

Alrashed,

Lee

et al. 2023

Alcohol: Clinical and Experimental Research

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Background Although a large percentage of chronic pain patients consume alcohol to manage their pain, there is a significant gap in knowledge regarding the mechanisms underlying the antinociceptive effects of alcohol. Methods To determine the longitudinal analgesic effects of alcohol, we utilized the complete Freund's adjuvant (CFA) model of inflammatory pain in adult female and male Wistar rats. Both somatic and negative motivational aspects of pain were measured using the electronic von Frey (mechanical nociception) system, thermal probe test (thermal nociception), and mechanical conflict avoidance task (pain avoidance‐like behavior). Tests were conducted at baseline and 1 and 3 weeks following intraplantar CFA or saline administration. At both time points post‐CFA, animals were treated with each of three doses of alcohol (intraperitoneal; 0, 0.5, and 1.0 g/kg) over separate days in a Latin square design. Results Alcohol produced dose‐dependent mechanical analgesia and antihyperalgesia in females but only antihyperalgesia in males. Although alcohol continued to attenuate CFA‐induced decreases in both thermal and mechanical nociceptive thresholds between 1 and 3 weeks post‐CFA, it appeared less effective at increasing thresholds 3 weeks after CFA induction. Conclusions These data suggest that individuals may develop tolerance to alcohol's ability to alleviate both somatic and negative motivational symptoms of chronic pain over time. We also discovered sex‐specific neuroadaptations in protein kinase A‐dependent phosphorylation of GluR1 subunits and extracellular signal‐regulated kinase (ERK 1/2) phosphorylation in nociceptive brain centers of animals receiving an alcohol challenge 1 week post‐CFA. Together, these findings illustrate a sex‐specific regulation of behavioral and neurobiological indices of persistent pain by alcohol.

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“…Alcohol use alters responses to innocuous and noxious stimuli in adolescents (8,9) and adults (7,16,17) as well as neural processing of and behaviors to noxious stimuli (nociception) (18)(19)(20)(21) and innocuous stimuli (allodynia) (22,23) in preclinical models. Alterations in neuropeptide and neurotransmitter systems have been implicated in alcohol-induced alterations to behavior including corticotropin releasing factor (CRF), neuropeptide Y, calcitonin gene related peptide, and opioids to name a few (4,15).…”

Section: Introductionmentioning

confidence: 99%

The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure

Sharfman

Gilpin

2021

Front. Psychiatry

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The global COVID-19 pandemic has shone a light on the rates and dangers of alcohol misuse in adults and adolescents in the US and globally. Alcohol exposure during adolescence causes persistent molecular, cellular, and behavioral changes that increase the risk of alcohol use disorder (AUD) into adulthood. It is established that alcohol abuse in adulthood increases the likelihood of pain hypersensitivity and the genesis of chronic pain, and humans report drinking alcohol to relieve pain symptoms. However, the longitudinal effects of alcohol exposure on pain and the underlying CNS signaling that mediates it are understudied. Specific brain regions mediate pain effects, alcohol effects, and pain-alcohol interactions, and neural signaling in those brain regions is modulated by neuropeptides. The CNS melanocortin system is sensitive to alcohol and modulates pain sensitivity, but this system is understudied in the context of pain-alcohol interactions. In this review, we focus on the role of melanocortin signaling in brain regions sensitive to alcohol and pain, in particular the amygdala. We also discuss interactions of melanocortins with other peptide systems, including the opioid system, as potential mediators of pain-alcohol interactions. Therapeutic strategies that target the melanocortin system may mitigate the negative consequences of alcohol misuse during adolescence and/or adulthood, including effects on pain-related outcomes.

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Alcohol amplifies cingulate cortex signaling and facilitates immobilization-induced hyperalgesia in female rats

Cited by 7 publications

References 90 publications

Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration and Blood Alcohol Concentration in Mice

Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration and Blood Alcohol Concentration in Mice

Sex‐specific biobehavioral regulation of persistent inflammatory pain by alcohol

The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure

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