title: Inhibition of spinal 5-HT3R reverted diabetes-induced mechanical hypersensitivity in a GABAAR-mediated neurotransmission-dependent manner.
abstract: Spinal 5-HT3 receptor (5-HT3R) has been implicated in chronic pain development. The extent to which 5-HT3R contributes to spinal sensitization and diabetic neuropathic pain (DNP) remains elusive and the mechanisms subserving the effects of 5-HT3R activation on spinal pain processing during chronic pain are still unclear. In this study, we evaluated the contribution of spinal 5-HT3R to pain facilitation and spinal sensitization during DNP, exploiting the role of GABAAR-mediated neurotransmission and glial activation in the effects elicited by intrathecal administration of a 5-HT3R antagonist. Mechanical nociception was evaluated by paw pressure test in streptozotocin (STZ)-diabetic and control rats after intrathecal (i.t.) administration of a 5-HT3R antagonist (Y25130). The spinal activation of extracellular signal-regulated kinases (ERKs) pathway and the expression of 5-HT3R, glial fibrillary acidic protein (GFAP; marker of astroglia activation) and ionized calcium binding adaptor molecule 1 (IBA-1; marker of microglia activation) were evaluated at the peak maximum effect of Y25130. The involvement of GABAAR-mediated neurotransmission in the behavioral pain effect of Y25130, was assessed in STZ-diabetic animals receiving i.t. administrations of muscimol (GABAAR agonist). Intrathecal administration of Y25130 reverted mechanical hyperalgesia and decreased the activation of ERKs in STZ-diabetic rats, while no effects were observed in control animals. The spinal activation of GABAAR by i.t. administration of muscimol abolished Y25130-driven antinociception. The expression of IBA-1, GFAP and 5-HT3R was unaltered by treatment. These findings point to a GABA-mediated pronociceptive role of spinal 5-HT3R during DNP.
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Portugal; i3S - Instituto de Inovação e investigação em Saúde, Universidade do Porto, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Silva
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Portugal; i3S - Instituto de Inovação e investigação em Saúde, Universidade do Porto, Portugal.
authors.forename: D
authors.initials: D
authors.lastname: Martins
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Portugal; i3S - Instituto de Inovação e investigação em Saúde, Universidade do Porto, Portugal. Electronic address: isatav@med.up.pt.
authors.forename: I
authors.initials: I
authors.lastname: Tavares
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Portugal; i3S - Instituto de Inovação e investigação em Saúde, Universidade do Porto, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Morgado
keywords: 5-HT3 receptor; ERK1/2; GABA(A)R; diabetic neuropathic pain; pronociception