Targeting 5-HT₇ Receptor with Biased Ligands to Alleviate Pain and Spinal Neuroinflammation

The serotonin 5-HT₇ receptor (5-HT₇R), a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs), is highly expressed in the central nervous system (CNS) and represents a promising target for treating CNS disorders such as sleep disturbances, migraine, neuropsychiatric conditions, and neuropathic pain. Because of its therapeutic potential, extensive efforts have focused on developing selective 5-HT₇R ligands. In the last decades, biased signaling has emerged as a key concept in GPCR pharmacology as biased ligands can stabilize specific active states of the receptor and trigger selective activation of downstream signaling pathways. In this context, we recently identified two biased 5-HT₇R ligands, Serodolin and MOA51, from different chemical series. Here, we aimed to compare the pharmacological and safety profiles of these ligands and assess their effect on pain-related behaviors and spinal neuroinflammation. In inflammatory pain models (acid acetic writhing, formalin, and CFA tests), both Serodolin and MOA51 effectively attenuated pain responses to a similar extent. Furthermore, in neuropathic pain models, spinal nerve injury (SNI) and the Cuff model, both ligands reversed mechanical allodynia. Interestingly, unlike pregabalin, a clinically used reference drug, neither Serodolin nor MOA51, induced apparent development of tolerance after 10 consecutive days of administration. Treatment with these 5-HT₇R ligands also reduced spinal microglial activity and attenuated neuronal hyperactivity in the spinal cord. Altogether, these findings highlight the potential of 5-HT₇R-biased ligands as promising analgesic candidates capable of modulating neuroinflammatory processes and mitigating both inflammatory and neuropathic pain.