Neuronal Nitric Oxide Synthase Modulation of Dorsal Horn Neuronal Responses in the Rat: A Developmental Study

Abstract

Nitric oxide (NO) is a diffusible chemical messenger functionally linked to N-methyl-D-aspartate (NMDA) receptor activity and has been shown to be involved in modulating numerous pathways in the central nervous system. In order to investigate the role of the neuronal NO synthase type I (nNOS)/NO system in the postnatal development of dorsal horn nociceptive pathways in rats, the specific nNOS inhibitor 7-nitroindazole sodium salt (7-NI) and the non-specific NOS inhibitor nitro-L-arginine methyl ester (L-NAME) were applied spinally at postnatal days (P) 14, 21, 28 and >56 (adult) and their effects on neuronal responses were compared. In response to a train of 16 noxious electrical stimuli, the wide dynamic range neurones in the deep dorsal horn showed a dose-dependent inhibition of C-fibre-evoked response, post-discharge and windup to both 7-NI and L-NAME. No difference between any age group was observed with either agent on these responses. However, the effect of both 7-NI and L-NAME on the primary evoked response, a measure of the events occurring pre-synaptic and intrinsic to the neurone recorded, was significantly different between the P14 and older age groups. nNOS is known to be expressed later in postnatal development than the NMDA receptor and from the results presented here, it is fully mature and functional from P14 onwards. The subtle differences in attenuation of the primary evoked response at P14 compared with older ages may reflect the immaturity of the dorsal horn and in particular the incomplete development of intrinsic and descending inhibitory controls.

Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity

“…A-fiber-evoked responses and input were unaffected by L-291. These selective inhibitory effects of spinal DDAH-1 antagonism on NMDA-mediated neuronal events suggest a predominantly postsynaptic effect and are similar to those produced by spinal inhibition of nNOS, 31 , 33 as well as drugs targeting spinal NMDA receptors. 6 , 7 Targeting DDAH-1 may be a novel way of modulating the NMDA-NO signaling pathway through manipulation of an endogenous control, which may allow physiopathological signaling to be selectively modulated and so potentially increasing tolerability over direct NMDA receptor blockers.…”

Monosynaptic reflexes, c-fos expression, and NADPH-diaphorase activity in the cat spinal cord: Changes induced by chronic muscle inflammation

“…Recent studies showed that endogenous nitric oxide (NO) can modulate the activity of high-threshold muscle afferents [12,13]. Nitric oxide synthase (NOS) is expressed in some spinal neurons; it can be activated in central neurons during the development of muscle fatigue [14].…”