Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity

Abstract

The involvement of the 5-HT(7) receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated. In the present study, we examined whether the 5-HT(7) receptor participates in some modulatory control of nerve injury-evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5-HT(7) receptors by systemic administration of the selective 5-HT(7) receptor agonist AS-19 (1 and 10mg/kg) exerted a clear-cut reduction of mechanical and thermal hypersensitivities that were reversed by co-administering the selective 5-HT(7) receptor antagonist SB-258719. Interestingly, blocking of 5-HT(7) receptors with SB-258719 (2.5 and 10mg/kg) enhanced mechanical (but not thermal) hypersensitivity in nerve-injured mice and induced mechanical hypersensitivity in sham-operated mice. Effectiveness of the treatment with a 5-HT(7) receptor agonist was maintained after repeated systemic administration: no tolerance to the antiallodynic and antihyperalgesic effects was developed following treatment with the selective 5-HT(7) receptor agonist E-57431 (10mg/kg) twice daily for 11 days. The 5-HT(7) receptor co-localized with GABAergic cells in the dorsal horn of the spinal cord, suggesting that the activation of spinal inhibitory GABAergic interneurons could contribute to the analgesic effects of 5-HT(7) receptor agonists. In addition, a significant increase of 5-HT(7) receptors was found by immunohistochemistry in the ipsilateral dorsal horn of the spinal cord after nerve injury, suggesting a "pain"-triggered regulation of receptor expression. These results support the idea that the 5-HT(7) receptor subtype is involved in the control of pain and point to a new potential use of 5-HT(7) receptor agonists for the treatment of neuropathic pain.

Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT7 ligands and role of the aromatic substituents in binding to the target receptor

“…nificantly inhibited mechanical hypersensitivity and thermal hyperalgesia in the neuropathic pain animal model. 15 These results suggest that the 5-HT 7 receptor antagonists and agonists can be used for treatment of depression and neuropathic pain, respectively. In the course of our ongoing efforts to discover novel 5-HT 7 modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group.…”

Inflammation and peripheral 5-HT7 receptors: The role of 5-HT7 receptors in carrageenan induced inflammation in rats

“…In line with our results, Brenchat et al demonstrated that pharmacological activation of 5-HT 7 receptors reduced "nerve injury" or "capsaicin" induced mechanical and thermal hypersensitivity in rat paws. This effect on mechanical and thermal hypersensitivity elicited by the 5-HT 7 agonist AS-19 in nerve-injured or capsaicin injected mice was significantly reduced when the agonist was co-administered with an antagonist; SB-258719 (Brenchat et al, 2010(Brenchat et al, , 2009). All of these data suggest that the 5-HT 7 receptor antagonist has pharmacologically reversed the anti-inflammatory effects exerted by the 5-HT7 receptor agonist.…”

“…Our finding that the agonist and antagonist decreased the levels of the 5-HT 7 receptor is consistent with some studies that demonstrated desensitization and down-regulation following agonist and antagonist exposure. This down-regulation is common among G protein-coupled receptors, but there is some discrepancy in this regard for 5-HT 7 receptors (Brenchat et al, 2010).…”

5-HT₇ Receptors and Tryptophan Hydroxylase in Lymphocytes of Rats: Mitogen Activation, Physical Restraint or Treatment with Reserpine

“…5-HT 7 receptors have previously been studied in the central nervous system using genetic, behavioral and pharmacological strategies and have been involved in sleep, mood, anxiety, thermoregulation, electricity of the brain, pain, memory and impulsivity testing, among others [12,13,14,17,21]. However, little has been done in the immune system.…”

“…In addition, 5-HT 7 receptor antagonists may function as analgesics in nerve injury pain states [13]. On the other hand, agonists possess analgesic properties in neuropathic pain [14]. Moreover, these receptors are related to memory consolidation [15], cognitive deficits, anxiety and depression [16].…”