Modulation of cardiovascular responses and neurotransmission during peripheral nociception following nNOS antagonism within the periaqueductal gray

Nitric oxide (NO) within the dorsal periaqueductal gray matter (dPAG) attenuated cardiovascular responses and changes in the concentrations of glutamate during both mechanical and thermal nociceptive stimulation [Ishide, T., Amer, A., Maher, T.J., Ally, A., 2005. Nitric oxide within periaqueductal gray modulates glutamatergic neurotransmission and cardiovascular responses during mechanical and thermal stimuli. Neurosci. Res. 51, 93-103]. Nitric oxide is synthesized from l-arginine via the enzyme, NO synthase (NOS), which exists in 3 isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). In this study, we examined the role of nNOS within the dPAG on cardiovascular responses and extracellular glutamate and GABA concentrations during mechanical and thermal nociception in anesthetized rats. The noxious mechanical stimulus was applied by a bilateral hindpaw pinch for 5 s that increased mean arterial pressure (MAP) and heart rate (HR) by 24 ± 4 mm Hg and 41 ± 7 bpm, respectively (n = 10). Extracellular glutamate levels within the dPAG increased by 10.7 ± 1.3 ng/μl while GABA concentrations decreased by 1.9 ± 0.5 ng/μl. Bilateral microdialysis of a selective nNOS antagonist, 1-(2-trifluoromethylphenyl)-imidazole (TRIM; 10.0 μM), into the dPAG had no effect on MAP, HR, glutamate and GABA values (P > 0.05) during a mechanical stimulation. In a separate set of experiments, a noxious thermal stimulus was generated by immersing the metatarsus of a hindpaw in a water-bath at 52 °C for 5 s (n = 10). Glutamate, MAP, and HR increased by 14.6 ± 2 ng/μl, 45 ± 6 mm Hg, and 47 ± 7 bpm, while GABA decreased by 2.1 ± 0.6 ng/μl. Administration of TRIM into the dPAG significantly enhanced the cardiovascular responses and glutamate increases (P < 0.05) but further attenuated GABA changes (P < 0.05) during subsequent thermal nociception. These results demonstrate that nNOS within the dPAG plays a differential role in modulating cardiovascular responses and glutamatergic/GABAergic neurotransmission during thermal and mechanical nociception.