Orexinergic descending inhibitory pathway mediates linalool odor-induced analgesia in mice

Linalool odor exposure induces an analgesic effect in mice. This effect disappeared in the anosmic model mice, indicating that olfactory input evoked by linalool odor triggered this effect. Furthermore, hypothalamic orexinergic neurons play a pivotal role in this effect. However, the neuronal circuit mechanisms underlying this effect have not been fully addressed. In this study, we focused on the descending orexinergic projection to the spinal cord and examined whether this pathway contributes to the effect. We assessed the effect of intrathecal administration of orexin receptor antagonists on linalool odor-induced analgesia in the tail capsaicin test. We found that the selective orexin type 1 receptor antagonist, but not the selective orexin type 2 receptor antagonist, prevented the odor-induced analgesic effect. Furthermore, immunohistochemical analyses of c-Fos expression induced by the capsaicin test revealed that neuronal activity of spinal cord neurons was suppressed by linalool odor exposure, which was prevented by intrathecal administration of the orexin 1 receptor antagonist. These results indicate that linalool odor exposure drives the orexinergic descending pathway and suppresses nociceptive information flow at the spinal level.

Presynaptic Glycine Receptors Increase GABAergic Neurotransmission in Rat Periaqueductal Gray Neurons

The periaqueductal gray (PAG) is involved in the central regulation of nociceptive transmission by affecting the descending inhibitory pathway. In the present study, we have addressed the functional role of presynaptic glycine receptors in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs) were recorded in mechanically dissociated rat PAG neurons using a conventional whole-cell patch recording technique under voltage-clamp conditions. The application of glycine (100 µM) significantly increased the frequency of sEPSCs, without affecting the amplitude of sEPSCs. The glycine-induced increase in sEPSC frequency was blocked by 1 µM strychnine, a specific glycine receptor antagonist. The results suggest that glycine acts on presynaptic glycine receptors to increase the probability of glutamate release from excitatory nerve terminals. The glycine-induced increase in sEPSC frequency completely disappeared either in the presence of tetrodotoxin or Cd2+, voltage-gated Na+, or Ca2+channel blockers, suggesting that the activation of presynaptic glycine receptors might depolarize excitatory nerve terminals. The present results suggest that presynaptic glycine receptors can regulate the excitability of PAG neurons by enhancing glutamatergic transmission and therefore play an important role in the regulation of various physiological functions mediated by the PAG.