NLX-112, a highly selective 5-HT 1A receptor agonist, mediates analgesia and antidepressant-like activity in rats via spinal cord and prefrontal cortex 5-HT 1A receptors, respectively

Brain Res. 2018 Jun 1;1688:1-7. doi: 10.1016/j.brainres.2018.03.016. Epub 2018 Mar 16.


NLX-112 (a.k.a. F13640 or befiradol) possesses marked activity in a variety of animal models of pain and of neuropsychiatric disorders; it exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine1A (5-HT1A) receptors. Although NLX-112 has been shown to activate 5-HT1A postsynaptic heteroreceptors in the prefrontal cortex (PFC), a brain region involved in the control of depressive states, the influence of NLX-112 on spinal cord 5-HT1A receptors (implicated in the control of pain) has not been described. Here we report on the ability, in rats, of NLX-112 to elicit analgesia in the intraplantar formalin model of nociceptive pain following intrathecal (i.t.) administration, and its ability to produce antidepressant-like activity in the forced swim test (FST) following in situ PFC microinjection. NLX-112, injected i.t. (L5-L6 region) induced analgesic effects in the formalin model of tonic nociceptive pain. At 20 µg, it almost abolished the effect of formalin on both the paw licking and paw elevation measures, and in both the early (0-5 min after formalin administration, reflecting acute pain) and the late (22.5-27.5 min, reflecting inflammatory pain) phases. The effects of NLX-112 (20 µg i.t.) were reversed by co-administration of 20 µg i.t. of the 5-HT1A receptor antagonist, WAY100635. Furthermore, the analgesic effects of systemically administered NLX-112 (0.63 mg/kg i.p.) were reversed by i.t. administration of WAY100635 (20 µg), most notably on paw licking. Finally, microinjection of NLX-112, bilaterally in the PFC, dose-dependently (MED 4 µg) and markedly reduced immobility in the FST (circa 90% reduction at 32 µg). In conclusion, the present data demonstrate that activation of spinal cord-located 5-HT1A receptors is sufficient for NLX-112 to mediate its analgesic effects in a rat model of tonic nociceptive pain. The data also highlight the involvement of PFC 5-HT1A receptors in the antidepressant-like activity of NLX-112 in the FST. Overall, the study suggests that highly selective and high efficacy 5-HT1A receptors agonists, such as NLX-112, could be useful to treat painful conditions associated with depressive states, through activation of different sub-populations of 5-HT1A receptors.

Keywords: 5-HT(1A)receptors; Befiradol; Forced swim test; Formalin pain test; Prefrontal cortex; Spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods
  • Analgesics, Non-Narcotic / administration & dosage*
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Behavior, Animal / drug effects
  • Depression / complications
  • Depression / drug therapy
  • Dose-Response Relationship, Drug
  • Formaldehyde / administration & dosage
  • Male
  • Nociceptive Pain / chemically induced
  • Nociceptive Pain / drug therapy*
  • Pain Measurement
  • Piperidines / administration & dosage*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiopathology
  • Pyridines / administration & dosage*
  • Rats, Sprague-Dawley
  • Serotonin 5-HT1 Receptor Agonists / administration & dosage*
  • Spinal Cord / drug effects*
  • Spinal Cord / physiopathology


  • Analgesics, Non-Narcotic
  • Antidepressive Agents
  • Piperidines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Formaldehyde
  • befiradol