Delta-opioid receptor antagonist naltrindole reduces oxycodone addiction and constipation in mice

Yang, Pao-Pao; Yeh, Teng‐Kuang; Loh, Horace H.; Law, Peter K.; Wang, Yun; Tao, Pao‐Luh

doi:10.1016/j.ejphar.2019.04.009

Cited by 17 publications

(8 citation statements)

References 53 publications

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“…We investigated the effects of KK-103 on gastric motility since constipation is a common side effect of opioids. , MOR activation in the gastrointestinal tract reduces gastric motility, an effect that is also observed to a lesser degree with DOR activation . We performed a charcoal meal test to determine if KK-103 affects gastrointestinal transit, especially after observing the high radioactivity of [ 123 I]I-KK-103 in the small intestine (Figure A–C).…”

Section: Results and Discussionmentioning

confidence: 99%

“…67,68 MOR activation in the gastrointestinal tract reduces gastric motility, an effect that is also observed to a lesser degree with DOR activation. 69 We performed a charcoal meal test to determine if KK-103 affects gastrointestinal transit, especially after observing the high radioactivity of [ 123 I]I-KK-103 in the small intestine (Figure 2A−C). Charcoal passage through the small intestine was measured after s.c. injecting mice twice daily for 7 days with KK-103 (15 mg/kg, s.c.), morphine (10 mg/kg, s.c., positive control), or vehicle (10 mL/kg, negative control) (Figure 7A−C).…”

Section: Effect Of Kk-103 Treatment On Gastric Motility and Locomotor...mentioning

confidence: 99%

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A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Hohenwarter,

Puil,

Rouhollahi

et al. 2024

Mol. Pharmaceutics

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Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucineenkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptiveeffect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Effect Of Kk-103 Treatment On Gastric Motility and Locomotor...mentioning

confidence: 99%

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Hohenwarter,

Puil,

Rouhollahi

et al. 2024

Mol. Pharmaceutics

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“…Investigations in relation to the mechanism of opioid tolerance and dependence have shown an involvement of the delta and mμ receptors. Abdelhamid et al 20 , discovered that naltrindole was able to prevent morphine tolerance in male swisswebster mice. This establishes that delta receptor antagonism is able to attenuate opioid tolerance and could therefore be XA's mechanism of morphine tolerance attenuation.…”

Section: Discussionmentioning

confidence: 99%

Xylopic acid from Xylopia aethiopica (Annonaceae) inhibits morphine tolerance in rats

Mante¹,

Abakah-Ewusi²,

Mingle³

et al. 2022

Pharm Sci Asia

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Traditionally, Xylopia aethiopica is used to manage pain disorders such as neuralgia, colic pain, rheumatism and headache. Using animal models, this study aimed to investigate the ability of Xylopic Acid (XA), a kaurene diterpene obtained from Xylopia aethiopica, to cause tolerance when administered alone or combined with morphine. Development of withdrawal symptoms on discontinuation was also investigated. Tolerance to morphine was induced in rats through an 8-day regimen of chronic administration of morphine (10 mg/kg; twice daily). Effects of XA alone (100 mg/kg) or XA (10-100 mg/kg) on morphine tolerance and withdrawal syndrome precipitated with naloxone hydrochloride (3 mg/kg) were also assessed. XA's mechanism of action was then explored through drug-receptor binding.Chronic morphine administration in rats resulted in analgesic tolerance and morphine withdrawal syndrome. Chronic XA administration did not result in tolerance to XA's antinociceptive effect. Development of morphine withdrawal syndrome precipitated by naloxone and morphine tolerance was significantly (F(12, 60)=29.88, p<0.0001) inhibited by XA. Xylopic acid inhibited development of diarrhea, jumps and weight loss. Pretreatment with α-2-adrenoceptor antagonist, yohimbine, 5HT3 antagonist, ondansetron and muscarinic antagonist, atropine, significantly (p=0.0042) blocked the inhibitory effect of XA on withdrawal jumps. Pretreatment with naloxone produced similar effects on withdrawal jumps as XA alone. Drug-receptor binding assays revealed a lack of significant interaction of XA on alpha-2 adrenoceptors (A, B, C) but exhibited significant DOR-selective antagonism similar to naltrindole. This study reveals that xylopic acid significantly inhibits morphine antinociceptive tolerance and withdrawal in rats. This is the first report of xylopic acid's antagonism on delta opioidergic receptors and potential as an inhibitor of chronic morphine tolerance.

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“…In those rodent models, there is a clear pattern of increasing drug intake over time, accompanied by intensified drug-seeking behavior. Withdrawal symptoms are also a hallmark of drug dependence and upon withdrawal from opioids, both rats and mice exhibit allodynia (15–18), along with anxiety-like behaviors (19), and a spectrum of other withdrawal-related physical symptoms (20–23). These observations highlight the translational validity and value of such models in deepening our comprehension of the behavioral and physiological changes associated with OUD.…”

Section: Introductionmentioning

confidence: 99%

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Chen,

Xiao,

Kimbrough

2024

Preprint

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BackgroundThe rise in overdose deaths from synthetic opioids, especially fentanyl, necessitates the development of preclinical models to study fentanyl use disorder (FUD). While there has been progress with rodent models, additional translationally relevant models are needed to examine excessive fentanyl intake and withdrawal symptoms.MethodsThe study performed intravenous self-administration (IVSA) of fentanyl in male and female C57BL/6J mice for 14 days. Mechanical pain sensitivity during withdrawal was assessed using the von Frey test. Anxiety-like behavior was evaluated via the open field test one-week into abstinence and incubation of craving for fentanyl was assessed four weeks into abstinence.ResultsBoth male and female mice demonstrated a significant escalation in fentanyl intake over the 14 days of self-administration, with significant front-loading observed in the final days of self-administration. Increased mechanical pain sensitivity was present from 36- to 48-hour into withdrawal and increased anxiety-like behavior was found 1 week into abstinence. Four weeks into abstinence, mice showed significantly higher active lever pressing than the final self-administration session prior to abstinence.ConclusionsThe study establishes a translationally relevant mouse model of IVSA of fentanyl, effectively encapsulating critical aspects of FUD, including escalation of drug intake, front-loading behavior, withdrawal symptoms, and prolonged craving for drug into abstinence. This model offers a robust basis for further exploration into behavioral and neurobiological mechanisms involved in fentanyl dependence and potential therapeutic strategies.

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Delta-opioid receptor antagonist naltrindole reduces oxycodone addiction and constipation in mice

Cited by 17 publications

References 53 publications

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Xylopic acid from Xylopia aethiopica (Annonaceae) inhibits morphine tolerance in rats

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

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