Selective 5-HT7 receptor agonists LP 44 and LP 211 elicit an analgesic effect on formalin-induced orofacial pain in mice

Abstract

The most recently identified serotonin (5-HT) receptor is the 5-HT7 receptor. The antinociceptive effects of a 5-HT7 receptor agonist have been shown in neuropathic and inflammatory animal models of pain. A recent study demonstrated the functional expression of 5-HT7 receptors in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis, which receives and processes orofacial nociceptive inputs. Objective To investigate the antinociceptive effects of pharmacological activation of 5-HT7 receptors on orofacial pain in mice.Material and Methods Nociception was evaluated by using an orofacial formalin test in male Balb-C mice. Selective 5-HT7 receptor agonists, LP 44 and LP 211 (1, 5, and 10 mg/kg), were given intraperitoneally 30 min prior to a formalin injection. A bolus of 10 µl of 4% subcutaneous formalin was injected into the upper lip of mice and facial grooming behaviors were monitored. The behavioral responses consisted of two distinct periods, the early phase corresponding to acute pain (Phase I: 0–12 min) and the late phase (Phase II: 12–30 min).Results LP 44 and LP 211 (1, 5, and 10 mg/kg) produced an analgesic effect with reductions in face rubbing time in both Phase I and Phase II of the formalin test.Conclusion Our results suggest that 5-HT7 receptor agonists may be promising analgesic drugs in the treatment of orofacial pain.

5-HT7 Receptors Regulate Excitatory-Inhibitory Balance in Mouse Spinal Cord Dorsal Horn

“…An anti-nociceptive action of 5-HT7Rs has been observed, for example, in models of pain hypersensitivity induced by capsaicin injection ( Brenchat et al, 2009 ), sciatic nerve ligation ( Brenchat et al, 2010 ), or chronic constriction injury ( Viguier et al, 2012 ). Similarly, in mice, 5-HT 7 agonists LP-211 and LP-44 induce analgesic effects on formalin-induced orofacial pain ( Demirkaya et al, 2016 ). GABAergic interneurons seem to be especially involved in 5-HT 7 -mediated anti-nociception since the intrathecal administration of the GABA A antagonist bicuculline prevented the anti-hyperalgesic effect of 5-HT 7 agonists in rats with the constriction injury of the sciatic nerve ( Viguier et al, 2012 , 2013 ).…”

“…Recently, more selective agonists for 5-HT 7 R have become available ( Blattner et al, 2019 ). Among these, the compound LP-211 has been tested in several studies, proving to be specific and effective in activating 5HT 7 Rs, both in vivo and in vitro ( Leopoldo et al, 2011 ; Costa et al, 2012 ; Demirkaya et al, 2016 ; Lippiello et al, 2016 ).…”

Psychotropic Drugs for the Management of Chronic Pain and Itch

“…Study of the analgesic effect of 5-HT7 receptor agonists is ongoing. It was found that the selective agonists of 5-HT7 receptor LP-44 and LP-211 reduced orofacial pain caused by the introduction of formalin in mice [126]. Since chronic pain and depression often accompany and reinforce each other, and the serotonin receptors are involved in the regulation of mood and emotions, the efforts of many scientists are aimed at finding the agonists that would reduce both pain and depression.…”

Central nervous system effects of 5-HT7 receptors: a potential target for neurodegenerative diseases

“…(10µL at 0.02–0.2 nM), cultures (300 nM) Godínez-Chaparro et al ( 2012 ), Samarajeewa et al ( 2014 ) LP-44 Selective full agonist i.p. (1,5 and 10 mg/kg) Demirkaya et al ( 2016 ) LP-211 Selective full agonist i.p. (1,5 and 10 mg/kg), i.p.…”

“…(0.003–0.3 mg/kg),i.c.v. (0.2 µL at 2–6 mM) Demirkaya et al ( 2016 ), Liu et al ( 2021 ), Norouzi-Javidan et al ( 2016 ), (Monti et al 2014 ) Methiothepin maleate Non-specific 5-HT 1/6/7 R agonist Culture (10 µM) Soga et al ( 2007 ) 8-OH-DPAT Non-specific 5-HT 1A/7 R agonist i.p. (02–0.4 mg/kg and 1.0 mg/kg) Cassaday and Thur ( 2019 ), Odland et al ( 2019 ) SB-269970 Competitive selective antagonist, quasi-full inverse agonist i.p.…”