Michael A. Emery

Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors.

Oxycodone and hydrocodone are opioids which are widely used for pain management and are also commonly misused and abused. The exposure to opioid analgesics has been associated with altered responses of D2-like dopamine receptors (D2DRs). Our recent results suggest that various opioids will differentially modulate the responses of D2DRs. The D2DRs are known to be involved in the pathology of addiction and other mental illnesses, indicating the need to improve our understanding of the effects of opioid analgesics on the responses of the D2DRs. Thus, in this study, we first established equianalgesic oral doses of oxycodone, hydrocodone, and morphine using the tail withdrawal assay. Then, mice were orally administered (gavage) with the various opioids or saline once daily for 6 days. Twenty-four hours later, the mice were tested for their locomotor response to quinpirole, a D2/D3 dopamine receptor agonist. Mice pretreated with oxycodone showed significantly greater locomotor supersensitivity to quinpirole than did morphine-pretreated mice, while hydrocodone-pretreated mice showed sensitivity in between that of mice treated with morphine and oxycodone. This finding suggests that various opioids differentially modulate the responses of D2DRs. It provides further evidence supporting of the notion that various opioids carry differential risks to the dopamine reward system.

Social environment alters opioid-induced hyperalgesia and antinociceptive tolerance in adolescent mice.

Chronic opioid treatment is complicated by the development of tolerance and hyperalgesia. Social environment alters both opioid‐induced behaviours and nociceptive mechanisms. Our previous studies demonstrated that, in adolescent rodents, the susceptibility to acquire opioid dependence and reward is dependent on the nature of social housing conditions. Specifically, our previous studies demonstrate that housing morphine‐treated mice with drug‐naïve animals mitigates the abuse liability of opioids. Thus, this study tested the effect of social housing conditions on the development of adaptive processes to morphine antinociception.

Differential Effects of Oxycodone, Hydrocodone, and Morphine on Activation Levels of Signaling Molecules

BACKGROUND Opioids alter the responses of D2-like dopamine receptors (D2DRs), known to be involved in the pathology of addiction and other mental illnesses. Importantly, our recent results demonstrated that various opioids differentially modulate the behavioral responses of D2DRs. OBJECTIVE To examine the effect of various opioids on striatal activation levels of Akt and ERK1/2, as well as the signaling responses of D2DRs following opioid exposure. METHODS Mice were pre-treated with 20 mg/kg morphine, hydrocodone, oxycodone, or saline for 6 days. Twenty-four hours later, mice were injected with vehicle or a D2/D3 receptor agonist, quinpirole. Thirty minutes later, dorsal striatum was collected and analyzed using Western blot. RESULTS In morphine-pretreated animals, baseline Akt activation level was unchanged, but was reduced in response to quinpirole. In contrast, baseline Akt activation levels were reduced in mice pretreated with hydrocodone and oxycodone, but were unchanged in response to quinpirole. In mice pretreated with all opioids, baseline ERK2 activation levels were unchanged and increased in response to quinpirole. However, quinpirole-induced ERK2 activation was significantly higher than drug naïve animals only in the morphine-pretreated mice. CONCLUSIONS Various opioids differentially modulate the baseline activation levels of signaling molecules, which in turn results in ligand-selective effects on the responses to a D2/D3 dopamine receptor agonist. This demonstrates a complex interplay between opioid receptors and D2DRs, and supports the notion that various opioids carry differential risks to the dopamine reward system. This information should be considered when prescribing opioid pain medication, to balance effectiveness with minimal risk.

Social housing conditions influence morphine dependence and the extinction of morphine place preference in adolescent mice

BACKGROUND Adolescent opioid abuse is on the rise, and current treatments are not effective in reducing rates of relapse. Our previous studies demonstrated that social housing conditions alter the acquisition rate of morphine conditioned place preference (CPP) in adolescent mice. Specifically, the acquisition rate of morphine CPP is slower in morphine-treated animals housed with drug-naïve animals. Thus, here we tested the effect of social housing conditions on the development of morphine dependence and the extinction rate of an acquired morphine CPP. METHODS Adolescent male mice were group-housed in one of two housing conditions. They were injected for 6 days (PND 28-33) with 20 mg/kg morphine. Morphine only mice are animals where all four mice in the cage received morphine. Morphine cage-mate mice are morphine-injected animals housed with drug-naïve animals. Mice were individually tested for spontaneous withdrawal signs by quantifying jumping behavior 4, 8, 24, and 48 h after the final morphine injection. Then, mice were conditioned to acquire morphine CPP and were tested for the rate of extinction. RESULTS Morphine cage-mates express less jumping behavior during morphine withdrawal as compared to morphine only mice. As expected, morphine cage-mate animals acquired morphine CPP more slowly than the morphine only animals. Additionally, morphine cage-mates extinguished morphine CPP more readily than morphine only mice. CONCLUSIONS Social housing conditions modulate morphine dependence and the extinction rate of morphine CPP. Extinction testing is relevant to human addiction because rehabilitations like extinction therapy may be used to aid human addicts in maintaining abstinence from drug use.

Opioid addiction: Who are your real friends?

HighlightsOpioid addiction is a chronic and relapsing mental health disorder.An Individual’s social network influences the outcome after taking opioids.Here we review the rodent literature on the subject.Includes studies on isolation, enrichment, and housing with different cage‐mates.Improved understanding of the social influences on opioid addiction is needed. Abstract Opioid addiction is a chronic and relapsing mental health disorder. However, only some individuals exposed to opioids, either recreationally or during the course of pain management, will develop addiction. The reasons why some individuals develop addiction and some are spared are not fully understood. Studies indicate that it is likely a combination of genetic predispositions and environmental conditions. Given the role of environmental factors in human addiction, this review examines the role of social environments and social interactions in the development of opioid addictive‐like behaviors in rodent studies. To date, three major behavioral approaches have been used in these studies, namely social isolation, environmental enrichment, and social housing with a variety of cage‐mates that differ in their drug administration conditions. This review highlights the importance of an individual’s social network in influencing the outcomes of drug abuse and the need to further elucidate the molecular mechanisms underlying these effects. Better understanding is likely to contribute to the development of novel and more effective treatments for addiction disorders.

Burn injury decreases the antinociceptive effects of opioids.

Burn victim patients are frequently prescribed opioids at doses that are significantly higher than standard analgesic dosing guidelines, and, even despite an escalation in opioid dosing, many continue to experience pain. Thus, the aim of this study was to determine the effect of burn injury on opioid antinociception. Mice were examined for their baseline pain sensitivity thresholds using the von Frey filaments test. Then, they were subjected to burn or sham injury to the dorsal surface of the hindpaw and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 following the burn injury. The antinociceptive effects of the various drugs were analyzed by computing the daily difference between pain sensitivity threshold scores (in g) before and after treatment. This study showed that burn injury decreases opioid antinociception potency. A marked reduction was observed in the antinociceptive effectiveness of all opioids, and for both doses, in the burn-injured versus the sham animals. These results suggest that burn trauma limits the ability of opioids to be effective in reducing pain.

The role of the vasopressin system and dopamine D1 receptors in the effects of social housing condition on morphine reward

BACKGROUND The association with opioid-abusing individuals or even the perception of opioid abuse by peers are risk factors for the initiation and escalation of abuse. Similarly, we demonstrated that morphine-treated animals housed with only morphine-treated animals (referred to as morphine only) acquire morphine conditioned place-preference (CPP) more readily than morphine-treated animals housed with drug-naïve animals (referred to as morphine cage-mates). However, the molecular mechanisms underlying these effects are still elusive. METHODS Mice received repeated morphine or saline while housed as saline only, morphine only, or cage-mates. Then, they were examined for the expression levels of D1 dopamine receptor (D1DR), D2 dopamine receptor (D2DR), dopamine transporter (DAT), oxytocin, and Arginine-vasopressin (AVP) in the striatum using qPCR. Additionally, we examined the effects of the AVP-V1b receptor antagonist, SSR149415, on the acquisition of morphine conditioned place-preference (CPP). RESULTS Increased striatal expression of D1DR and AVP was observed in morphine only animals, but not morphine cage-mates. No significant effects were observed on the striatal expression of D2DR, DAT, or oxytocin. Antagonizing the AVP-V1b receptors decreased the acquisition of morphine CPP in the morphine only mice, but did not alter the acquisition of morphine CPP in the morphine cage-mate mice. CONCLUSIONS Housing with drug-naïve animals protects against the increase in striatal expression of D1DR and AVP elicited by morphine exposure. Moreover, our studies suggest that the protective effect of housing with drug-naïve animals on the acquisition of morphine reward might be, at least partially, mediated by AVP.

Hydrocodone is More Effective than Morphine or Oxycodone in Suppressing the Development of Burn-Induced Mechanical Allodynia

Background Pain is the most frequent complaint of burn-injured patients. Opioids are commonly used in the course of treatment. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain. Objective This study compared the ability of morphine, oxycodone, and hydrocodone to suppress the development of burn-induced mechanical allodynia and reduce pain sensitivity. Methods Mice were examined for their baseline pain sensitivity thresholds using the von Frey Filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn. Results In the sham animals, morphine produced significant opioid-induced hyperalgesia (OIH). Development of OIH was minimal for hydrocodone and was not observed for oxycodone. Secondary mechanical allodynia was observed beginning four days after the burn injury and intensified with time. All opioids produced comparable antinociceptive effects. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia and fully treated the burn-induced increase in pain sensitivity. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia and only partially treated the burn-induced increase in pain sensitivity. Conclusions This study demonstrated that hydrocodone is effective in suppressing the development of burn-induced mechanical allodynia, while both morphine and oxycodone had minimal effects. These findings underscore the need for additional studies on the differences among various opioids using clinically relevant pain models.