5-HT6 Receptor Inverse Agonists Modulate Diabetic Neuropathic Pain in Female Rats: Evidence for 5-HT6 Receptor Constitutive Activity

Painful neuropathy is one of the most common complications of diabetes. First-line therapeutic agents such as tricyclic antidepressants, dual serotonin/noradrenaline reuptake inhibitors, and alpha2-delta ligands of calcium channels (i.e., gabapentinoids) are poorly effective. New strategies targeting the serotonin type 6 receptor (5-HT₆R) and mechanistic Target Of Rapamycin (mTOR) signaling have recently emerged. Until a few years ago, preclinical studies of pain in rodents were more often carried out in males than in females, despite compelling evidence of sex-specific mechanisms in pain. Here, we investigated the role of 5−HT₆R/mTOR signaling in neuropathic pain in streptozocin (STZ)-induced type 1 diabetes (T1D) in female rats. Mechanical hyperalgesia was attenuated in female diabetic (STZ-D) rats by systemic injection of 5-HT₆-R inverse agonists. Further, administration of full (PZ-1386, SB258585) but not partial (PZ-1179) 5−HT₆R inverse agonists alleviated cognitive deficits in female STZ-D rats. Intrathecal administration of the mTOR inhibitor rapamycin or a cell-penetrating peptide that disrupts the physical interaction between the 5-HT₆R and mTOR also reduced pain and cognitive comorbidity in females. Together with previous data obtained in STZ-D male rats and in spinal nerve ligation (SNL) and oxaliplatin (OXA) models of neuropathic pain, these results suggest that the analgesic and procognitive effects of 5-HT₆R inverse agonists are sex-specific and dependent on the etiology of neuropathic pain, highlighting the importance of personalizing treatment that considers the patient's sex, etiology of neuropathy, and the presence or absence of comorbid cognitive symptoms.