NMDA glutamatergic receptor-signalling in the ventrolateral columns of the periaqueductal grey matter mediates riparin A-induced antinociception to noxious heat stimulation.

Riparin A, a synthetic form of natural riparins, has been shown to produce antinociception. However, little is known regarding the neural mechanisms and structures that mediate its pain-supressing effects. Glutamatergic neurons in the ventrolateral columns of the periaqueductal grey matter (vlPAG) are implicated in modulating spinally projecting pain inhibitory pathways. The aim of this work was to examine the antinociceptive effect of systemic treatment with riparin A at increasing doses and then investigate whether riparin A-induced antinociception is mediated by vlPAG glutamatergic NMDA receptors. Male Wistar Hannover rats were intraperitoneally treated with riparin A at different doses (5, 10 or 20 mg/kg), and after 60 min, they were submitted to either tail-flick or Hargreaves' plantar tests. After the specification of the most effective dose of riparin A (20 mg/kg), independent groups of animals were pretreated with the NMDA receptor selective antagonist LY235959 (0.1 nmol/0.2 μL) in vlPAG. Ten minutes later, these animals received intraperitoneal injections of riparin A, and after 60 min, they were subjected to the same nociceptive tests. Intraperitoneal injections of riparin A caused antinociception in all laboratory rats. In contrast, previous intra-vlPAG microinjections of the LY235959 decreased the analgesic effect produced by riparin A. Our findings suggest that NMDA receptor-signalling in the vlPAG is critical for the antinociceptive effect produced by riparin A.