Selective Serotonin-1A Receptor Activation Elicits Antinociceptive Activity in the Knee Osteoarthritis and Plantar...

NLX-204 is a high selectivity/high efficacy agonist at serotonin 5-HT_1A receptors, which are well-established modulators of pain processing. Here, we evaluated the analgesic activity of NLX-204 in two rat models of nociceptive/inflammatory pain: the monoiodoacetate (MIA)-induced knee osteoarthritis (KOA) and the Brennan plantar incision model, using morphine as active comparator, in both male and female rats. KOA was induced by left intra-articular MIA injection. Antinociceptive effects of NLX-204 (0.1-3 mg/kg p.o.) or morphine (6 mg/kg s.c.) were assessed on days 5 and 8 by measuring withdrawal threshold (WT) using von Frey filaments and dynamic weight bearing (DWB) on injured and contralateral limbs. In the Brennan model, the plantar surface of the left hind limb was incised with elevation and incision of the plantaris muscle. Mechanical allodynia (WT) and guarding behavior (GB) were assessed 24 h postsurgery. In the MIA-KOA model, NLX-204 significantly attenuated DWB imbalance in males at 1-3 mg/kg (acute) and 0.1-3 mg/kg (repeated dosing), and in females at 3 mg/kg (repeated dosing only). NLX-204 demonstrated antiallodynic activity (VF filaments) from 0.3 mg/kg in males (acute and repeated) and from 1 mg/kg in females. In the Brennan model, NLX-204 reduced GB scores at 1 mg/kg (males) and 0.3-1 mg/kg (females), and showed antiallodynic effects from 0.3 mg/kg in both sexes. Morphine was effective in both models under acute and repeated administration. Oral NLX-204 demonstrates dose-dependent antinociceptive and antiallodynic activity in two rat models of nociceptive/inflammatory pain, supporting the therapeutic potential of selective, high-efficacy 5-HT_1A receptor agonists as a novel nonopioid strategy for pain management.