Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Abstract

Relapse to drug use is often cited as the major obstacle in overcoming a drug addiction. Whereas relapse can occur for a myriad of reasons, it is well established that complex neuroadaptations that occur over the course of addiction are major factors. Cocaine, as a potent dopamine transporter blocker, specifically induces alterations in the dopaminergic as well as other monoaminergic neurotransmissions, which lead to cocaine abuse and dependence. Evidence also suggests that adaptations in the endogenous opioids play important roles in pathophysiology of cocaine addiction. Following this evidence, we investigated a combination medication, levotetrahydropalmatine (L-THP) and low dose naltrexone (LDN), targeting primarily dopaminergic and endogenous opioid systems as a cocaine-relapse-prevention treatment. In the present study Wistar rats were used to assess the effects of L-THP and LDN on cocaine self-administration, drug-seeking behavior during cocaine reinstatement, spontaneous locomotion, and effects on the endogenous opioid system. We determined that the combination of L-THP and LDN reduces drug-seeking behavior during reinstatement more potently than L-THP alone. Additionally, the combination of L-THP and LDN attenuates the sedative locomotor effect induced by L-THP. Furthermore, we revealed that treatment with the combination of L-THP and LDN has an upregulatory effect on both plasma b-endorphin and hypothalamic POMC that was not observed in L-THP-treated groups. These results suggest that the combination of L-THP and LDN has great potential as an effective and well-tolerated medication for cocaine relapse prevention.

Transgenic increase in the β‐endorphin concentration in cerebrospinal fluid alleviates morphine‐primed relapse behavior through the μ opioid receptor in rats

“…Moreover, some studies have confirmed that the pathophysiology of opioid addiction can be altered by up‐ or downregulation of endogenous opioids. The Sarah team demonstrated a strong negative correlation between plasma β‐EP and reinstatement . Our results further showed specific β‐EP‐positive cells located in the lateral ventricle wall and paraplexus.…”

“…The Sarah team demonstrated a strong negative correlation between plasma β-EP and reinstatement. 37 Our results further showed specific β-EP-positive cells located in the lateral ventricle wall and paraplexus. Similar results from our previous work showed that ependymal cells transfected with the recombinant adenovirus Ad-NEP lined the lateral ventricle after icv injection.…”

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

“…Higher, sedation-inducing doses of l-THP may involve antagonism of postsynaptic D2 receptors as well as a non-dopaminergic (benzodiazepine-like) mechanisms via positive allosteric modulation of GABA-A receptors 64 . It is also noteworthy that non-sedative doses of l-THP (below 10 mg/kg in rodents) [65][66][67][68][69]77 , administered in combination with a low dose of a µ-opioid receptor antagonist naltrexone is more effective than l-THP alone in blocking cocaine-seeking by rats 70 . While the precise quantity of l-THP in the Heantos-4 formulation in relation to the threshold for inducing side-effects remains to be determined, our behavioral observation of Heantos-4-treated rats indicate that l-THP within the Heantos-4 formulation is well-tolerated, with no adverse side-effects aside from a mild state of somnolence (present study and ref.…”

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

“…Furthermore, the mechanism by which THP improves METH-induced behavioral phenotype is regulating brain-derived neurotrophic factor pathway, 5-HT neuronal activity, and dopamine D3 receptor (D 3 R) expression ( Yun, 2014 ; Liu et al, 2021b ). Meanwhile, THP combined with low-dose naltrexone (LDN) is used to treat cocaine relapse( Sushchyk et al, 2016 ). Combined treatment with THP and LDN can upregulate plasma β-endorphin and hypothalamic pro-opiomelanocortin.…”