5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice

Abstract

This work aimed to evaluate the potential role of the 5-HT(7) receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT(7) receptor agonists: AS-19, MSD-5a, E-55888; 5-HT(7) receptor antagonists: SB-258719, SB-269970; 5-HT(1A) receptor agonist: F-13640; 5-HT(1A) receptor antagonist: WAY-100635) were assessed on capsaicin-induced mechanical hypersensitivity, a pain behavior involving hypersensitivity of dorsal horn neurons (central sensitization). For the 5-HT(7) receptor agonists used, binding profile and intrinsic efficacy to stimulate cAMP formation in HEK-293F cells expressing the human 5-HT(7) receptor were also evaluated. AS-19 and E-55888 were selective for 5-HT(7) receptors. E-55888 was a full agonist whereas AS-19 and MSD-5a behaved as partial agonists, with maximal effects corresponding to 77% and 61%, respectively, of the cAMP response evoked by the full agonist 5-HT. Our in vivo results revealed that systemic administration of 5-HT(7) receptor agonists exerted a clear-cut dose-dependent antinociceptive effect that was prevented by 5-HT(7) receptor antagonists, but not by the 5-HT(1A) receptor antagonist. The order of efficacy (E-55888>AS-19>MSD-5a) matched their in vitro efficacy as 5-HT(7) receptor agonists. Contrary to agonists, a dose-dependent promotion of mechanical hypersensitivity was observed after administration of 5-HT(7) receptor antagonists, substantiating the involvement of the 5-HT(7) receptor in the control of capsaicin-induced mechanical hypersensitivity. These findings suggest that serotonin exerts an inhibitory role in the control of nociception through activation of 5-HT(7) receptors, and point to a new potential therapeutic use of 5-HT(7) receptor agonists in the field of analgesia.

Central modulation of pain

“…Spinal administration of an antagonist of the inhibitory 5-HT7 receptor blocked the antinociceptive effect of morphine microinjected into the RVM, whereas pharmacological antagonism of the facilitatory 5-HT3 receptor blocked hyperalgesia induced by CCK administered into the RVM (79). Further, systemic administration of 5-HT7 agonists blocked capsaicin-induced hyperalgesia in mice, whereas 5-HT7 antagonists elicited mechanical hypersensitivity (83). The 5-HT7 receptor has been identified in the dorsal root ganglion and on central terminals of primary afferent fibers (84,85) as well as on GABAergic interneurons in the dorsal horn of the spinal cord (84), which is consistent with a role in pain modulation (83).…”

“…Further, systemic administration of 5-HT7 agonists blocked capsaicin-induced hyperalgesia in mice, whereas 5-HT7 antagonists elicited mechanical hypersensitivity (83). The 5-HT7 receptor has been identified in the dorsal root ganglion and on central terminals of primary afferent fibers (84,85) as well as on GABAergic interneurons in the dorsal horn of the spinal cord (84), which is consistent with a role in pain modulation (83). Although these observations indicate an important serotonergic role for pain modulation, the precise spinal mechanisms involved remain unclear.…”

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

“…Serotonin (5HT) is released from descending neurons into the DH, and one action occurs via 5HT 7 receptors to evoke an antinociceptive affect. Capsaicin-induced hypersensitivity was reversed in mice with the addition of a 5HT 7 agonist and promoted when combined with a 5HT 7 antagonist (Brenchat et al, 2009). This implies that 5HT is important in the development of mechanical hypersensitivity.…”

Serotonin Receptor 5-HT2BMediates Serotonin-Induced Mechanical Hyperalgesia

“…In addition, 5-HT 4 enhances the inflammatory pain signal (Doak and Sawynok, 1997). 5-HT 7 inhibits capsaicin-induced mechanical sensitivity (Brenchat et al, 2009).…”