Differential Modulation of Central Sensitization Pathways by Common Antipsychotics in a Paclitaxel-Induced...

Neuropathic pain is a chronic condition characterized by central sensitization (CS) and inadequacy of current treatments. Although antipsychotics are considered potential adjuvant treatments, they are generally treated as a homogeneous class, and their specific anti-nociceptive mechanisms remain unclear. This study challenges the assumption that antipsychotics exhibit a uniform class effect by comparing the effects of five commonly used antipsychotics on key central sensitization pathways. A paclitaxel-induced neuropathic pain model was established in rats. After model stabilization, antipsychotic treatments were administered orally for 14 days. Mechanical nociception was assessed with the Randall-Selitto test and locomotor activity with the open field test. Protein and mRNA expression of targeted pathways in the M1 cortex and spinal cord were examined by immunohistochemistry and in situ hybridization. All five antipsychotics significantly reduced mechanical hyperalgesia without causing sedation. However, each agent exhibited a distinct molecular "fingerprint": Quetiapine and chlorpromazine strongly suppressed the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated GluN2B (p-GluN2B) in both the cortex and spinal cord. Haloperidol and aripiprazole exerted their effects primarily by modulating the sigma-1 receptor in the spinal cord. Risperidone, despite exhibiting anti-hyperalgesic effects, had the weakest and most paradoxical effects on the pathways examined. Our findings reveal that antipsychotics exhibit significant mechanistic heterogeneity in neuropathic pain modulation. A "one-size-fits-all" approach is therefore inadequate for this drug class. Understanding each agent's unique mechanistic profile could inform the development of targeted and more effective treatment strategies tailored to the patient's pathophysiology.