Newman-Tancredi A, Bardin L, Auclair A, Colpaert F, Depoortère R, Varney M A
Neurolixis Inc., 34145 Pacific Coast Highway #504, Dana Point, CA 92629, USA.
Pierre Fabre Laboratories, 81100 Castres, France.
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-HT) receptors. Although NLX-112 has been shown to activate 5-HT 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-HT 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-HT 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-HT 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-HT receptors in the antidepressant-like activity of NLX-112 in the FST. Overall, the study suggests that highly selective and high efficacy 5-HT 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-HT receptors.
NLX - 112（又名F13640或贝非拉朵）在多种疼痛和神经精神疾病动物模型中具有显著活性；它在5 - 羟色胺1A（5 - HT）受体上表现出纳摩尔亲和力、卓越的选择性和高激动剂效力。尽管NLX - 112已被证明可激活前额叶皮质（PFC）中的5 - HT突触后异受体，PFC是参与抑郁状态控制的脑区，但NLX - 112对脊髓5 - HT受体（与疼痛控制有关）的影响尚未见报道。在此我们报告，在大鼠中，鞘内（i.t.）注射NLX - 112在伤害性疼痛的足底注射福尔马林模型中引发镇痛的能力，以及原位PFC微量注射后在强迫游泳试验（FST）中产生抗抑郁样活性的能力。鞘内（L5 - L6区域）注射NLX - 112在福尔马林持续性伤害性疼痛模型中诱导出镇痛作用。在20μg时，它几乎消除了福尔马林对舔爪和抬爪测量的影响，且在早期（福尔马林给药后0 - 5分钟，反映急性疼痛）和晚期（22.5 - 27.5分钟，反映炎性疼痛）阶段均如此。鞘内注射20μg 5 - HT受体拮抗剂WAY100635可逆转NLX - 112（20μg i.t.）的作用。此外，鞘内注射WAY100635（20μg）可逆转全身给药NLX - 112（0.63mg/kg腹腔注射）的镇痛作用，最显著的是对舔爪的影响。最后，双侧PFC微量注射NLX - 112剂量依赖性地（最小有效剂量4μg）且显著降低了FST中的不动时间（在32μg时约降低90%）。总之，目前的数据表明激活脊髓定位的5 - HT受体足以使NLX - 112在持续性伤害性疼痛大鼠模型中介导其镇痛作用。数据还突出了PFC 5 - HT受体参与NLX - 112在FST中的抗抑郁样活性。总体而言，该研究表明高选择性和高效力的5 - HT受体激动剂，如NLX - 112，可能通过激活不同亚群的5 - HT受体来治疗与抑郁状态相关的疼痛病症。
