Abstract
Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment. Opioid substitution and α2-adrenergic agonists are the current standard of pharmacotherapy for opioid use disorder in western medicine; however, each is associated with significant complications. Heantos-4 is a non-opioid botanical formulation used to facilitate opioid detoxification in Vietnam. While ongoing clinical use continues to validate its safety and effectiveness, a mechanism of action accounting for these promising effects remains to be specified. Here, we assess the effects of Heantos-4 in a rat model of morphine-dependence and present evidence that alleviation of naloxone-precipitated somatic withdrawal signs is related to an upregulation of mesolimbic dopamine activity and a consequent reversal of a hypodopaminergic state in the nucleus accumbens, a brain region implicated in opioid withdrawal. A central dopaminergic mechanism is further supported by the identification of l-tetrahydropalmatine as a key active ingredient in Heantos-4, which crosses the blood–brain barrier and shows a therapeutic efficacy comparable to its parent formulation in attenuating withdrawal signs. The anti-hypodopaminergic effects of l-tetrahydropalmatine may be related to antagonism of the dopamine autoreceptor, thus constituting a plausible mechanism contributing to the effectiveness of Heantos-4 in facilitating opioid detoxification.
Highlights
Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment
We examined whether the effects of intra-nucleus accumbens (NAc) l-THP on the DA autoreceptor could be replicated by a systemic route of administration (Fig. 4c)
The present findings indicate that a modest upregulation of mesolimbic DA activity, and a consequent reversal of a hypodopaminergic state in the NAc, underlies the ability of Heantos-4 to attenuate somatic signs of withdrawal in morphine-dependent rats
Summary
Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment. Withdrawal-associated reductions in firing rates of DA neurons in the midbrain along with attenuated DA efflux in the basal forebrain[18,19,20,21,22,23,24] Based on these data, normalization of hypodopaminergia has been proposed as a pharmacotherapeutic strategy to facilitate cessation of opioid u se[2,16,25]. Normalization of hypodopaminergia has been proposed as a pharmacotherapeutic strategy to facilitate cessation of opioid u se[2,16,25] This therapeutic rationale is consistent with the findings of our initial preclinical assessment of Heantos-4, which confirmed in morphine-dependent rats the alleviation of naloxone-induced hypodopaminergia and significant attenuation of somatic withdrawal measures[19]. Similar outcomes were observed with the α2-adrenergic agonist clonidine[18], suggesting that normalization of DA function may be achieved even by indirect effects on the DA system
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