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Updated: Sep 12, 2025

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

Nazarine Mokhtar1, Marcin Drop2,3, Lauriane Delay1

  • 1Université Clermont Auvergne, INSERM, NEURO-DOL, Clermont-Ferrand, France.

Journal of Neurochemistry
|August 4, 2025
PubMed
Summary
This summary is machine-generated.

New research shows that targeting serotonin type 6 receptor (5-HT6R) and mTOR signaling can reduce neuropathic pain and cognitive issues in female diabetic rats. These effects are sex-specific, emphasizing personalized treatment approaches.

Keywords:
5‐HT6Rconstitutive activitydiabetesinverse agonistmTORneuropathic painsex dimorphismstreptozocin

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Endocrinology

Background:

  • Diabetic neuropathic pain is common and poorly managed by current therapies.
  • Emerging strategies target serotonin type 6 receptor (5-HT6R) and mechanistic Target Of Rapamycin (mTOR) signaling.
  • Preclinical pain research has historically underrepresented females, despite known sex-specific pain mechanisms.

Purpose of the Study:

  • To investigate the role of 5-HT6R/mTOR signaling in neuropathic pain in female rats with streptozocin (STZ)-induced type 1 diabetes (T1D).
  • To evaluate the efficacy of 5-HT6R inverse agonists and mTOR inhibition on pain and cognitive deficits in this model.
  • To compare findings with previous studies in male rats and other neuropathic pain models.

Main Methods:

  • Induced type 1 diabetes in female rats using streptozocin (STZ).
  • Administered systemic 5-HT6R inverse agonists (full and partial) and intrathecal mTOR inhibitor (rapamycin) or a 5-HT6R/mTOR disrupting peptide.
  • Assessed mechanical hyperalgesia and cognitive function.

Main Results:

  • Systemic 5-HT6R inverse agonists attenuated mechanical hyperalgesia in female STZ-diabetic rats.
  • Full, but not partial, 5-HT6R inverse agonists alleviated cognitive deficits in female STZ-diabetic rats.
  • Intrathecal rapamycin or the 5-HT6R/mTOR disrupting peptide reduced both pain and cognitive comorbidity.

Conclusions:

  • The 5-HT6R/mTOR pathway is implicated in neuropathic pain and cognitive dysfunction in female diabetic rats.
  • Analgesic and procognitive effects of 5-HT6R inverse agonists are sex-specific and etiology-dependent.
  • Results underscore the need for personalized treatment strategies considering patient sex and neuropathy cause.