The 5-HT 1A receptor selective agonist NLX-204 displays analgesic activity in the knee osteoarthritis and plantar incisional post-operative pain models in rats

ABSTRACT Background NLX-204 is a highly selective, high efficacy biased agonist at serotonin 5-HT1A receptors, which are well-established modulators of pain processing. Objective To evaluate the analgesic activity of NLX-204 in two rat models of nociceptive/inflammatory pain: the monoiodoacetate (MIA)-induced knee osteoarthritis (KOA) and the Brennan’s plantar incision model, using morphine as an active comparator, in both male and female rats. Methods KOA was induced by left intra-articular MIA injection. Analgesic 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’s 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 post-surgery. Results 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 anti-allodynic activity (VF filaments) from 0.3 mg/kg in males (acute and repeated) and from 1 mg/kg in females. In the Brennan’s model, NLX-204 reduced GB scores at 1 mg/kg (males) and 0.3-1 mg/kg (females), and showed anti-allodynic effects from 0.3 mg/kg in both sexes. Morphine was effective in both models under acute and repeated administration. Conclusions Oral NLX-204 demonstrates dose-dependent analgesic and anti-allodynic activity in two rat models of nociceptive/inflammatory pain, supporting the therapeutic potential of selective, high-efficacy 5-HT1A receptor agonists as a novel non-opioid strategy for pain management.