The Pharmacological and Ultra High Dilution Esketamine (12cH) Prevent Morphine-Conditioned Place Preference and Reprogram Reward-Related Plasticity in Opioid-Exposed Offspring
Murilo Barboza Fontoura, Jessica Leandra Oliveira da Rosa, Paola Brivio, Arianna Palumbo, Francesca Calabrese, Marilise Escobar Burger, Emanuele Frozi, Ana Paula Silva E Souza
International Journal of High Dilution Research May 7, 2026 DOI: 10.51910/ijhdr.v27i1.1880 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Adolescent female offspring of mouse dams exposed to escalating morphine doses during the perinatal period |
| Interventions | Esketamine Morphine |
| Dose | 20 mg/kg (pharmacological esketamine); 12cH (ultra-high dilution) |
| Measures | Morphine-conditioned place preference (MORPH-CPP), Y-maze, elevated plus maze, qPCR gene expression |
| Topics | Esketamine |
| Key findings | Offspring of morphine-exposed mothers showed enhanced morphine-conditioned place preference and altered nucleus accumbens gene expression (activation of CREB, NR4A1, GAD65, DLG4 and RhoA; suppression of long BDNF). Both pharmacological esketamine (20 mg/kg) and homeopathic esketamine 12cH prevented the place preference and rebalanced these pathways, which the authors interpret as converging on epigenetically sensitive plasticity mechanisms underlying transgenerational opioid vulnerability. |
Abstract
Introduction: Intergenerational opioid exposure induces persistent maladaptive plasticity in the mesolimbic reward circuitry, increasing vulnerability to addiction. Transcriptional adaptations, including CREB-dependent signaling and neurotrophic dysregulation, contribute to relapse risk and may reflect epigenetically mediated alterations transmitted across generations. While pharmacological esketamine (ESK) modulates glutamatergic signaling, the regulatory effects of ultra-high diluted ESK (12cH) on addiction-related neuroplasticity remain unexplored [1-16].
Methods: We therefore investigated whether homeopathic ESK 12cH modulates behavioral and transcriptional signatures of morphine-conditioned place preference (MORPH-CPP) in female offspring of morphine-addicted mothers (Ethics Committee Approval: CEUA-UFSM: 2935220824). Adolescent female offspring of dams exposed to escalating morphine doses during the perinatal period were randomly allocated to treatment groups, and experiments were conducted under blinded conditions. Animals received pharmacological ESK (20 mg/kg; acute or subchronic) or ESK 12cH prior to MORPH-CPP induction. Behavioral assessments included MORPH-CPP, Y-maze, and elevated plus maze paradigms, and gene expression in the nucleus accumbens (NAc) was analyzed by qPCR.
Results: MORPH offspring displayed enhanced drug-seeking behavior accompanied by transcriptional activation of CREB (rCREB1AB), NR4A1, GAD65, DLG4 (PSD-95), and RhoA, alongside marked suppression of the BDNF long isoform in the NAc. Both pharmacological ESK and ESK 12cH prevented MORPH-CPP and rebalanced addiction-related molecular pathways. Treatments normalized CREB–NR4A1 signaling, reduced GABAergic and synaptic scaffolding markers, modulated cytoskeletal remodeling through RhoA regulation, and restored BDNF–TrkB signaling.
Discussion: These transcriptional effects are consistent with the modulation of epigenetically sensitive pathways implicated in plasticity of the reward circuitry and transgenerational opioid vulnerability.
Conclusion: These findings indicate that pharmacological and ultra-high-diluted esketamine converge on transcriptional and synaptic plasticity mechanisms within the mesolimbic circuitry, counteracting maladaptive neurobiological signatures associated with intergenerational opioid vulnerability.
Comparable studies
Other preclinical and animal studies on esketamine, most cited first.