N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats

Ward, Price; Moss, Hunter G.; Brown, Truman R.; Kalivas, Peter W.; Jenkins, Dorothea

doi:10.1038/s41390-019-0728-6

Cited by 27 publications

(16 citation statements)

References 39 publications

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“…Alterations of specific physiological functions are responsible for the individual signs of withdrawal observed 21 . The withdrawal signs investigated were diarrhea, weight loss, mean number of jumps per 60 minutes, and mean number of abdominal contractions 14,[22][23][24] . Research provides evidence suggesting an association of the cholinergic system with biological activity of opiates 25 .…”

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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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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“…Although in vivo testing in human neonates is limited by ethical constraints (i.e., positron emission tomography scanning with radiotracers for opioid receptors), we may test salivary cortisol as a non-invasive measure of stress and measure oxidative stress in the brain via non-invasive magnetic resonance spectroscopy (Moss et al, 2018 ). While both of these markers are associated with opioid withdrawal (Ward et al, 2020 ), they are not direct measures of endogenous opioid release by tAN vs. another mechanism. Therefore, precise elucidation of mechanism relies on laboratory models of NOWS or pain models of neuromodulation of these cranial nerves.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Transcutaneous Auricular Neurostimulation (tAN): A Novel Adjuvant Treatment in Neonatal Opioid Withdrawal Syndrome

Jenkins

Khodaparast

O’Leary

et al. 2021

Front. Hum. Neurosci.

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Maternal opioid use during pregnancy is a growing national problem and can lead to newborns developing neonatal opioid withdrawal syndrome (NOWS) soon after birth. Recent data demonstrates that nearly every 15 min a baby is born in the United States suffering from NOWS. The primary treatment for NOWS is opioid replacement therapy, commonly oral morphine, which has neurotoxic effects on the developing brain. There is an urgent need for non-opioid treatments for NOWS. Transcutaneous auricular neurostimulation (tAN), a novel and non-invasive form of electrostimulation, may serve as a promising alternative to morphine. tAN is delivered via a multichannel earpiece electrode worn on and around the left ear, targeting two cranial nerves—the vagus and trigeminal nerves. Prior research suggests that auricular neurostimulation exerts an anxiolytic effect on the body by releasing endogenous opioids and reduces withdrawal symptoms in adults actively withdrawing from opioids. In this first-in-human prospective, open-label trial, we investigated tAN as an adjuvant to morphine therapy in eight infants >33 weeks gestational age suffering from NOWS and receiving oral morphine treatment. Infants received tAN for 30 min 1 h before receiving a morphine dose. tAN was delivered at 0.1 mA below perception intensity at two different nerve targets on the ear: Region 1, the auricular branch of the vagus nerve; and Region 2, the auriculotemporal nerve. tAN was delivered up to four times daily for a maximum of 12 days. The primary outcome measures were safety [heart rate monitoring, Neonatal Infant Pain Scale (NIPS), and skin irritation] and morphine length of treatment (LOT). tAN was well-tolerated and resulted in no unanticipated adverse events. Comparing to the national average of 23 days, the average oral morphine LOT was 13.3 days (median 9 days) and the average LOT after tAN initiation was 7 days (median 6 days). These preliminary data suggest that tAN is safe and may serve as a promising alternative adjuvant for treating NOWS and reducing the amount of time an infant receives oral morphine.

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“…Opioids and N-acetylcysteine NAC has been shown to produce positive outcomes in rodents for opioids (29), and a recent study in opioiddependent neonatal rats demonstrated that NAC mitigated behavioral withdrawal symptoms and oxidative stress (67). However, the efficacy of NAC in opioid dependence has not yet been tested in clinical populations (24), neither as a stand-alone treatment nor in addition to opioid-replacement therapies or behavioral treatment (3).…”

Section: Nicotine and N-acetylcysteinementioning

confidence: 99%

N-acetylcysteine in the treatment of substance use disorders

Evren¹

2020

Dusunen Adam

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N-acetylcysteine (NAC) is an agent best known for its clinical efficacy in bronchopulmonary disorders due to its mucolytic properties, and in the treatment of acetaminophen overdose. Given the strong clinical evidence from animal studies of its critical role in regulating glutamatergic receptors, NAC has also been the subject of research related to several psychiatric disorders as a promising treatment approach. This editorial is a brief discussion of the characteristics of NAC and its place in substance use disorders and other psychiatric disorders.

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N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats

Cited by 27 publications

References 39 publications

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

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

Transcutaneous Auricular Neurostimulation (tAN): A Novel Adjuvant Treatment in Neonatal Opioid Withdrawal Syndrome

N-acetylcysteine in the treatment of substance use disorders

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