Neural bases for attenuation of morphine withdrawal by Heantos-4: role of l-tetrahydropalmatine

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.

A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine

“…Treatment with THP blocks the morphine-induced downregulation of dopamine D2 receptors (D 2 R) and upregulation of GluA1 AMPA receptors in the prefrontal cortex, hippocampus (Hip), and striatum. THP inhibits dopamine-induced dopamine D1 receptor (D 1 R) activity and dopamine autoreceptor activity ( Wu et al, 2018 ; Ahn et al, 2020 ). These results suggest that the possible mechanism may be linked to antagonizing morphine-induced changes in brain dopamine and glutamate transmission.…”

Differential patterns of basal and naloxone‐evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged‐intermittent exposure to morphine

“…Consistent with this view, earlier in vivo microdialysis studies conducted in opioid‐dependent animals demonstrated that naloxone induces somatic withdrawal signs and suppresses DA levels in the ventral striatum for several hours (Pothos et al, 1991; Rossetti et al, 1992; Spanagel et al, 1994; Stella et al, 2003; Zhou & Nyberg, 2002) (but see Silverstone et al, 1993), findings that were confirmed again by recent in vivo monitoring studies (Ahn et al, 2020; Dias et al, 2016; Fox et al, 2017). In contrast, a recent reanalysis of [ 11 C]raclopride‐positron emission tomography (PET) scans of chronic opioid users failed to detect a significant decrease (or increase) in DA release in the human ventral striatum following naloxone administration (Shokri‐Kojori et al, 2021), a finding that challenges existing preclinical evidence.…”

“…Specifically, attenuation of dopaminergic function, or hypodopaminergia , in the ventral striatum is hypothesized to contribute to the aversive state associated with opioid withdrawal (Kakko et al, 2019; Koob, 2021; Melis et al, 2005). Furthermore, a ‘reset’ of the hypodopaminergic state in the ventral striatum is proposed as a therapeutic approach for managing opioid withdrawal symptoms and facilitating detoxification from opioids (Ahn et al, 2020; Koob, 2021; Melis et al, 2005).…”

Ayahuasca in the treatment of bipolar disorder with psychotic features–A retrospective case study

“…Notable recent examples include the development of the opioid detoxification product Heantos-4 by a traditional Vietnamese herbalist, Tran Khuong Dan, who tested his method by addicting himself first to opium and then heroin, confirming the efficacy of his invention based on twelve non-toxic, non-addictive herbal components (Turkia, 2021). Tetrahydroprotoberberines were later identified as the most likely active ingredients (Ahn et al, 2020;Nesbit and Phillips, 2020).…”