N-methyl-D-aspartate Receptor Nitric Oxide Research Articles

Nicotine Facilitates Facial Stimulation-Evoked Mossy Fiber-Granule Cell Long-Term Potentiation in vivo in Mice.

Nicotine is a psychoactive component of tobacco that plays critical roles in the regulation of neuronal circuit function and neuroplasticity and contributes to the improvement of working memory performance and motor learning function via nicotinic acetylcholine receptors (nAChRs). Under in vivo conditions, nicotine enhances facial stimulation-evoked mossy fiber-granule cell (MF-GrC) synaptic transmission, which suggests that nicotine regulates MF-GrC synaptic plasticity in the mouse cerebellar cortex. In this study, we investigated the effects of nicotine on facial stimulation-induced long-term potentiation (LTP) of MF-GrC synaptic transmission in urethane-anesthetized mice. Our results showed that facial stimulation at 20 Hz induced an MF-GrC LTP in the mouse cerebellar granular layer that was significantly enhanced by the application of nicotine (1 μM). Blockade of α4β2 nAChRs, but not α7 nAChRs, during delivery of 20 Hz facial stimulation prevented the nicotine-induced facilitation of MF-GrC LTP. Notably, the facial stimulation-induced MF-GrC LTP was abolished by an N-methyl-D-aspartate (NMDA) receptor antagonist, but it was restored by additional application of nicotine during delivery of 20 Hz facial stimulation. Furthermore, antagonism of α4β2 nAChRs, but not α7 nAChRs, during delivery of 20 Hz facial stimulation prevented nicotine-induced MF-GrC LTP. Moreover, inhibition of nitric oxide synthase (NOS) abolished the facial stimulation-induced MF-GrC LTP, as well as the effect of nicotine on it. Our results indicated that 20 Hz facial stimulation induced MF-GrC LTP via an NMDA receptor/nitric oxide (NO) cascade, but MF-GrC LTP was enhanced by nicotine through the α4β2 AChR/NO signaling pathway. These results suggest that nicotine-induced facilitation of MF-GrC LTP may play a critical role in the improvement of working memory performance and motor learning function.

Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw

Nitric oxide synthase is expressed abundantly in the spinal cord, and nitric oxide (NO) has been shown to play important roles in the central mechanism of inflammatory hyperalgesia. However, the expression and function of the NO receptor, soluble guanylate cyclase, is not fully understood in this processing at the spinal cord level. In the present study, we report that the soluble guanylate cyclase α 1 subunit but not the β 1 subunit was expressed in rat spinal cord, particularly in the dorsal horn. We showed that intrathecal administration of a selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, produced a significant anti-nociception demonstrated by the decrease in the number of flinches and shakes in the formalin-induced inflammatory pain model. This was accompanied by a marked reduction in formalin-induced c-fos expression in the spinal cord. During formalin-induced long-lasting inflammation, we found that the expression of the α 1 subunit of soluble guanylate cyclase was dramatically increased in the lumbar spinal cord on the second and fourth days after formalin injection into the dorsal side of a hind paw. Intraperitoneal pretreatment with an N-methyl- D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and a neuronal NO synthase inhibitor, 7-nitroindazole, not only significantly blocked formalin-induced secondary thermal hyperalgesia but also suppressed formalin-produced increase in the α 1 subunit of soluble guanylate cyclase in the spinal cord. The present results indicate that peripheral inflammation not only initially activates but also later up-regulates soluble guanylate cyclase expression via the NMDA receptor–NO signaling pathway, suggesting that soluble guanylate cyclase might be involved in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.

Possible involvement of tachykinin NK 1 and NMDA receptors in histamine-induced hyperalgesia in mice

Intrathecal (i.t.) injection of histamine elicited a significant hyperalgesic response as assayed by the tail-flick test. This hyperalgesic effect peaked at 15 min following i.t. administration of histamine (800 pmol) and returned to control level with 30 min. Hyperalgesia produced by histamine was inhibited dose-dependently by i.t. co-administration of the histamine H 1 receptor antagonist, d-chlorpheniramine, but not the histamine H 2 receptor antagonist, ranitidine. The tachykinin NK 1 receptor antagonists, (+)-[(2 S,3 S)-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine] (CP-99,994), and [Tyr 6, d-Phe 7, d-His 9]substance P-(6–11) (sendide), inhibited histamine-induced hyperalgesic response in a dose-dependent manner. A significant antagonistic effect of [ d-Phe 7, d-His 9]substance P-(6–11), a selective antagonist for substance P receptors, was observed against histamine-induced hyperalgesic response. The tachykinin NK 2 receptor antagonist, Asp-Tyr- d-Trp-Val- d-Trp- d-Trp-Lys-NH 2 (MEN-10,376), had no effect on hyperalgesia elicited by histamine. The competitive N-methyl- d-aspartate (NMDA) receptor antagonists, and d-(−)-2-amino-5-phosphonovaleric acid ( d-APV), (±)-3-(2-carboxypiperazin-yl)propyl-1-phosphoric acid (CPP), the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), and l- N G-nitro arginine methyl ester ( l-NAME), a nitric oxide (NO) synthase inhibitor, markedly inhibited histamine-induced hyperalgesic response. The present results suggest that hyperalgesic response induced by i.t. injection of histamine may be mediated by tachykinin NK 1 receptors, but not NK 2 receptors in the spinal cord. In addition, spinal NMDA receptor–NO system may also contribute to elicitation of hyperalgesia following i.t. injection of histamine.