Species differences in μ- and δ-opioid receptors

Yoburn, Byron C.; Lutfy, Kabir; Candido, Joseph

doi:10.1016/0014-2999(91)90207-7

Cited by 40 publications

(16 citation statements)

References 10 publications

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“…This lack of effect could be related to differences in short- or long-acting KOR antagonist-induced activation of c-Jun N-terminal kinase (JNK) signaling (Bruchas et al, 2007), although it is currently unknown whether altered JNK signaling contributes to the therapeutic efficacy of KOR antagonists in alcohol dependence. Differences in the functional potency of opioid ligands has been attributed to species differences in mu- and delta-opioid receptor binding capacity and affinity (Yoburn, Lutfy, & Candido, 1991), and it follows that putative genetic differences in KOR expression contribute to the observed differences in zyklophin potency. However, zyklophin did not attenuate alcohol self-administration in a KOR antagonist-predicted manner in rats, even when tested at 10× the effective dose in mice (Aldrich, Patkar, et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, zyklophin did not alter U50488-, DAMGO-, or DADLE-stimulated signaling in the rat tissue preparation, while demonstrating positive efficacy that suggests agonist effects. However, efficacy is not only a ligand-dependent entity and ligands can display multiple efficacies based on the system tested (Kenakin, 2002, 2011; Kenakin & Beek, 1980; Yoburn et al, 1991). Interestingly, a recent study reported strain-dependent off-target effects (KOR-independent) following zyklophin administration in mice (Dimattio, Yakovleva, Aldrich, Cowan, & Liu-Chen, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Sirohi

Aldrich

Walker

2016

Alcohol

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We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Sirohi

Aldrich

Walker

2016

Alcohol

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“…Here, a key player such as the opioid system is different between species; considering the major morphological and functional differences between brains of rodents and humans, it is to be expected that differences are quite distinct (Yoburn et al, 1991). Animal studies are based mainly on motor reflexes or behavioral responses, and data from such studies can be interpolated only partly to pain, which is a net result of complex sensory, affective, and cognitive processing.…”

Section: Animal Versus Human Pain Modelsmentioning

confidence: 99%

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

et al. 2012

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“…Rats require 10 times less morphine than mice for analgesia after correcting for size differences (46,47,73), even though mice have a higher density of opioid receptor ligand binding sites (86). Yet the opioid dose injected into RM that evokes respiratory changes in mice is comparable to that which evokes analgesia in rat.…”

Section: Discussionmentioning

confidence: 98%

Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats

Hellman¹,

Mendelson

Mendez-Duarte³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

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Species differences in μ- and δ-opioid receptors

Cited by 40 publications

References 10 publications

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Species differences in the effects of the κ-opioid receptor antagonist zyklophin

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats

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