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Rationale: Opioid analgesics are the most effective medications used for the treatment of pain, however there are significant risks associated with repeated opioid use including opioid misuse and opioid use disorder development. Chronic pain affects millions of adults in the United States, and opioid misuse is often comorbid with pain conditions in individuals who are repeatedly treated with opioids. In addition to providing pain relief, opioids produce rewarding effects, but in chronic pain states, reward processing can become dysregulated. The conditioned place preference task is commonly used to measure the rewarding properties of opioids in rodents. During this task, opioid administration is paired with a distinct environment through repeated conditioning and the change in an animal's preference for the paired environment indicates whether the opioid is rewarding or not., Objectives: Rodent pain models can be combined with conditioned place preference to examine the effects of pain on opioid reward. The existing preclinical literature on pain effects on conditioned place preference is conflicting, where pain conditions have been reported to enhance, suppress, or have no effect on opioid reward. This review will discuss several factors that may contribute to these discordant findings including conditioning session duration and number, rodent strain differences in opioid sensitivity, analgesic properties of opioids at tested doses, locomotor effects at tested doses, and diurnal variation in pain sensitivity. Future studies should consider how these factors contribute to opioid conditioned place preference in both pain and pain-free animals to have a better understanding of the interactions between pain and opioid reward., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The co-occurrence of chronic pain and opioid misuse has led to numerous preclinical investigations of pain-opioid interactions to examine how pain manipulations alter the reinforcing properties of opioids. However, preclinical investigations of chronic pain effects on opioid drug self-administration have produced inconsistent results. Our previous work demonstrated that established fentanyl self-administration is resistant to change by induction of chronic inflammatory pain (Complete Freund's Adjuvant; CFA) in male and female rats, while other laboratories have shown that CFA increased fentanyl self-administration in male but not female rats when pain induction precedes self-administration, which may be a critical factor in determining the effects of chronic pain on self-administration. The present study was designed similarly to Higginbotham et al. (2022) to test the effects of CFA on fentanyl self-administration in rats that underwent pain prior to acquisition of fentanyl self-administration. Male and female rats treated with hindpaw CFA or saline were trained to intravenously self-administer (IVSA) fentanyl for 3 weeks under limited access to fentanyl (2 h per day) conditions. After 3 weeks of fentanyl IVSA acquisition, we tested motivation to take fentanyl using progressive ratio testing and dose-response testing. CFA male and female rats self-administered less fentanyl than saline-treated controls during week 1 of acquisition, but not during weeks 2-3 of acquisition. Intra-session analysis of week 1 data demonstrated that chronic inflammatory pain suppressed fentanyl intake towards the end of week 1 and at the end of each operant session. We also report no effects of chronic inflammatory pain on motivation to take fentanyl. We discuss potential methodological explanations for differences between these results and prior reports. Our findings demonstrate that CFA temporarily suppresses fentanyl IVSA in animals without changing motivation to take fentanyl or promoting escalation of opioid use, suggesting that chronic inflammatory pain is unlikely to promote long-term risk of opioid misuse., (Published by Elsevier Inc.)

Alcohol use disorder (AUD) produces cognitive deficits, indicating a shift in prefrontal cortex (PFC) function. PFC glutamate neurotransmission is mostly mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic receptors (AMPARs); however preclinical studies have mostly focused on other receptor subtypes. Here we examined the impact of early withdrawal from chronic ethanol on AMPAR function in the mouse medial PFC (mPFC). Dependent male C57BL/6J mice were generated using the chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) paradigm. Non-dependent mice had access to water and ethanol bottles but did not receive ethanol vapor. Naïve mice had no ethanol exposure. We used patch-clamp electrophysiology to measure glutamate neurotransmission in layer 2/3 prelimbic mPFC pyramidal neurons. Since AMPAR function can be impacted by subunit composition or plasticity-related proteins, we probed their mPFC expression levels. Dependent mice had higher spontaneous excitatory postsynaptic current (sEPSC) amplitude and kinetics compared to the Naïve/Non-dependent mice. These effects were seen during intoxication and after 3-8 days withdrawal, and were action potential-independent, suggesting direct enhancement of AMPAR function. Surprisingly, 3 days withdrawal decreased expression of genes encoding AMPAR subunits ( Gria1/2 ) and synaptic plasticity proteins ( Dlg4 and Grip1 ) in Dependent mice. Further analysis within the Dependent group revealed a negative correlation between Gria1 mRNA levels and ethanol intake. Collectively, these data establish a role for mPFC AMPAR adaptations in the glutamatergic dysfunction associated with ethanol dependence. Future studies on the underlying AMPAR plasticity mechanisms that promote alcohol reinforcement, seeking, drinking and relapse behavior may help identify new targets for AUD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The current opioid epidemic is a national health crisis marked by skyrocketing reports of opioid misuse and overdose deaths. Despite the risks involved, prescription opioid analgesics are the most powerful and effective medications for treating pain. There is a clear need to investigate the risk of opioid misuse liability in male and female adults experiencing chronic pain. In the present study, we tested the hypothesis that chronic inflammatory pain would increase fentanyl intake, motivation to acquire fentanyl, and drug seeking in the absence of fentanyl in rats. Fentanyl intake, motivation for fentanyl, and drug seeking were tested under limited and extended access conditions using intravenous fentanyl self-administration. Fos activity in ventral tegmental area (VTA) dopamine neurons following intravenous fentanyl challenge (35 μg/kg) was examined using immunohistochemistry. Finally, we tested whether low-dose fentanyl supports development of conditioned place preference under an inflammatory pain state in rats. Contrary to our hypothesis, fentanyl self-administration and VTA Fos activity were unaffected by inflammatory pain status. During acquisition, males exhibited increased fentanyl intake compared to females. Animals given extended access to fentanyl escalated fentanyl intake over time, while animals given limited access did not. Males given extended access to fentanyl demonstrated a greater increase in fentanyl intake over time compared to females. During the dose-response test, females given limited access to fentanyl demonstrated increased motivation to acquire fentanyl compared to males. Both sexes displayed significant increases in responding for fentanyl as unit fentanyl doses were lowered. Following fentanyl challenge, females exhibited higher numbers of Fos-positive non-dopaminergic VTA neurons compared to males. Using conditioned place preference, we found that chronic inflammatory pain promotes fentanyl preference in males, but not females. These findings suggest that established fentanyl self-administration is resistant to change by inflammatory pain manipulation in both sexes, but chronic inflammatory pain increases the rewarding properties of low-dose fentanyl in males., Competing Interests: Declaration of competing interest NWG owns shares in Glauser Life Sciences, Inc, which is a start-up company with interest in the development of therapeutics for treatment of mental illness. The remaining authors declare no competing financial interests or potential conflicts of interest., (Published by Elsevier Ltd.)

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1β signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1β can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1β signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1β in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1β may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Opioids are commonly prescribed for pain despite growing evidence of their low efficacy in the treatment of chronic inflammatory pain and the high potential for misuse. There is a clear need to investigate non-opioid alternatives for the treatment of pain. In the present study, we tested the hypothesis that acute and repeated dopamine agonist treatment would attenuate mechanical hypersensitivity in male Long-Evans rats experiencing chronic inflammatory pain. We used two clinically available therapeutics, l-DOPA (precursor of dopamine biosynthesis) and pramipexole (dopamine D2/3 receptor agonist), to examine the functional role of dopamine signaling on mechanical hypersensitivity using an animal model of chronic inflammatory pain (complete Freund's adjuvant, CFA). We found that both acute and repeated pramipexole treatment attenuated hyperalgesia-like behavior in CFA-treated animals but exhibited no analgesic effects in control animals. In contrast, there was no effect of acute or repeated l-DOPA treatment on mechanical hypersensitivity in either CFA- or saline-treated animals. Notably, we discovered some extended effects of l-DOPA and pramipexole on decreasing pain-like behavior at three days and one week post-drug treatment. We also examined the effects of pramipexole treatment on glutamatergic and presynaptic signaling in pain- and reward-related brain regions including the nucleus accumbens (NAc), dorsal striatum (DS), ventral tegmental area (VTA), cingulate cortex (CC), central amygdala (CeA), and periaqueductal gray (PAG). We found that pramipexole treatment decreased AMPA receptor phosphorylation (pGluR1845) in the NAc and DS but increased pGluR1845 in the CC and CeA. A marker of presynaptic vesicle release, pSynapsin, was also increased in the DS, VTA, CC, CeA, and PAG following pramipexole treatment. Interestingly, pramipexole increased pSynapsin in the NAc of saline-treated animals, but not CFA-treated animals, suggesting blunted presynaptic vesicle release in the NAc of CFA-treated animals following pramipexole treatment. To examine the functional implications of impaired presynaptic signaling in the NAc of CFA animals, we used ex vivo electrophysiology to examine the effects of pramipexole treatment on the intrinsic excitability of NAc neurons in CFA- and saline-treated animals. We found that pramipexole treatment reduced NAc intrinsic excitability in saline-treated animals but produced no change in NAc intrinsic excitability in CFA-treated animals. These findings indicate alterations in dopamine D2/3 receptor signaling in the NAc of animals with a history of chronic pain in association with the anti-hyperalgesic effects of pramipexole treatment., (Copyright © 2022. Published by Elsevier Ltd.)

Opioids and alcohol are widely used to relieve pain, with their analgesic efficacy stemming from rapid actions on both spinal and supraspinal nociceptive centers. As an extension of these relationships, both substances can be misused in attempts to manage negative affective symptoms stemming from chronic pain. Moreover, excessive use of opioids or alcohol facilitates the development of substance use disorder (SUD) as well as hyperalgesia, or enhanced pain sensitivity. Shared neurobiological mechanisms that promote hyperalgesia development in the context of SUD represent viable candidates for therapeutic intervention, with the ideal strategy capable of reducing both excessive substance use as well as pain symptoms simultaneously. Neurocognitive symptoms associated with SUD, ranging from poor risk management to the affective dimension of pain, are likely mediated by altered activities of key anatomical elements that modulate executive and interoceptive functions, including contributions from key frontocortical regions. To aid future discoveries, novel and translationally valid animal models of chronic pain and SUD remain under intense development and continued refinement. With these tools, future research strategies targeting severe SUD should focus on the common neurobiology between negative reinforcement and affective elements of pain, possibly by reducing excessive stress hormone and neurotransmitter activity within shared circuitry., Competing Interests: Disclosures The authors declare no competing financial or nonfinancial interests.

Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disease characterized by the emergence of negative emotional states and the development of motivational deficits that manifest during alcohol withdrawal. Accordingly, alcohol may be sought after and taken in excessive amounts to alleviate withdrawal-related symptoms. To develop more effective treatments for AUD, it is necessary to identify potential molecular targets that underlie the transition from initial alcohol use to alcohol dependence, and our previous work has implicated a role for potentiated glucocorticoid receptor (GR) signaling in this regard. As a key negative regulator of GR-mediated signaling, the current study first measured c-Jun N-terminal kinase (JNK) phosphorylation in animals following an acute alcohol challenge. We found that JNK phosphorylation (pJNK) was significantly increased in the hippocampus, frontal cortical regions, and striatum of adult male Wistar rats following alcohol challenge, indicating that initial alcohol exposure increases JNK activity across several brain regions. A separate group of adult male Wistar rats were made dependent via chronic, intermittent ethanol vapor exposure and were trained to self-administer alcohol. We found that alcohol-dependent animals consumed significantly more alcohol and escalated their drinking over time compared to non-dependent animals. We then measured alterations in JNK phosphorylation in this alcohol-dependent group during acute withdrawal and found that pJNK was selectively decreased in the dorsal hippocampus, dorsomedial prefrontal cortex, and cingulate cortex. These findings demonstrate that withdrawal from chronic alcohol exposure leads to region-specific deficits in JNK phosphorylation. JNK signaling dysregulation may foster long-lasting behavioral and motivational impairments in alcohol dependence, either as a result of increased GR-mediated stress signaling or via other downstream mechanisms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In contrast to their analgesic properties, excessive use of either opioids or alcohol produces a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may promote increased use of opioids or alcohol drinking to manage worsening pain symptoms. Hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the motivational and affective dimensions of pain in a state of opioid/alcohol dependence and withdrawal, this unit describes the use of a non-reflex-based method for measuring pain avoidance-like behavior in dependent rats. In the mechanical conflict-avoidance task, rats run across probes of varying heights to avoid a bright aversive light and to reach a dark goal chamber. A longer latency to exit onto the nociceptive probes reflects increased pain avoidance-like behavior during withdrawal. Mechanical conflict-avoidance testing can be repeated to provide both baseline assessment of pain avoidance behavior and pain avoidance measures after the induction of dependence.© 2018 by John Wiley & Sons, Inc., (© 2018 John Wiley & Sons, Inc.)

Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of opioid dependence and withdrawal, we employed a recently developed non-reflex-based method for measuring pain avoidance-like behavior in animals (mechanical conflict avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline (control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

The prefrontal cortex (PFC) represents and executes the highest forms of goal-directed behavior, and has thereby attained a central neuroanatomical position in most pathophysiological conceptualizations of motivational disorders, including alcohol use disorder (AUD). Excessive, intermittent exposure to alcohol produces an allostatic dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis along with heightened forebrain glucocorticoid signaling that can damage PFC architecture and function. Negative affective states intimately associated with the transition to alcohol dependence result not only from a dysregulated HPA axis, but also from the inability of a damaged PFC to regulate subcortical stress and reinforcement centers, including the ventral striatum and amygdala. Several cognitive symptoms commonly associated with severe AUD, ranging from poor risk management to the cognitive/affective dimension of pain, are likely mediated by altered function of key anatomical elements that modulate PFC executive function, including contributions from the cingulate cortex and insula. Future therapeutic strategies for severe AUD should focus on attenuating the deleterious effects of excessive stress hormone activity on cognitive/affective and motivational behaviors gated by the PFC., Competing Interests: Statement All authors have no conflicts of interest to report.

An important new study by Kvarta, Bradbrook, Dantrassy, Bailey, and Thompson (J Neurophysiol 114: 1713-1724, 2015) examined the effects of persistent stress and excessive glucocorticoid levels on hippocampal function and emotional behavior in rodents. The authors specifically implicate the temporoammonic pathway as being susceptible to reductions in excitatory function in the context of chronic stress. We discuss the importance of this new finding in the broader context of medication development for major depressive disorder., (Copyright © 2017 the American Physiological Society.)

The dorsal hippocampus and dorsal striatum have dissociable roles in learning and memory that are related to region-specific changes in proteins necessary for neuronal plasticity and memory formation. There is additional evidence that the hippocampus and striatum can interact during memory formation. Phosphorylation of tyrosine receptor kinase B is important for memory formation in the hippocampus, but whether or not it has a role in striatum-dependent learning, or in interactions between the hippocampus and striatum, has not been examined. In the present study, we tested the hypothesis that response training increases pTrkB in the dorsal striatum, but decreases pTrkB in dorsal hippocampus, due to an interaction between the systems during memory formation. Results show a significant decrease in pTrkB levels in the dorsal hippocampus of rats trained on the response task compared with swim controls. Response training did not increase pTrkB levels in the dorsal striatum. Positive correlations were found between response learning and the total area of cells expressing pTrkB in the dorsal striatum, while no correlations were found in swim controls. Our results partially support our hypothesis and indicate that response learning is associated with a decrease in hippocampal pTrkB, while phosphorylation of TrkB in the dorsal striatum remains constant. This indicates that suppression of hippocampal pTrkB during response learning may be involved in striatum-dependent memory formation. Additionally, our findings suggest that activation of TrkB in a sparse arrangement of cells may be associated with faster acquisition of a response task. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)