Effects of endothelial NOS antagonism within the periaqueductal gray on cardiovascular responses and neurotransmission during mechanical, heat, and cold nociception

Nitric oxide (NO) is synthesized from l-arginine using NO synthase (NOS) enzyme that exists as 3 isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). We examined the role of eNOS within the dorsolateral periaqueductal gray mater (dlPAG) on cardiovascular responses along with glutamate and GABA concentrations during mechanical-, heat-, and cold-induced nociception in anesthetized rats. Mechanical stimulus was applied by a 10-second hindpaw pinch that increased mean arterial pressure (MAP) and heart rate (HR). Bilateral microdialysis of a selective eNOS antagonist, l-N(5)-(1-iminoethyl)ornithine (l-NIO; 10 μM), into the dlPAG had no effect on MAP or HR during a mechanical stimulation. Heat stimulus was generated by immersing a hindpaw metatarsus in a water-bath at 52 °C for 10 s which increased glutamate, GABA, MAP and HR. Administration of l-NIO into the dlPAG augmented cardiovascular responses and glutamate increase, but attenuated GABA changes during the heat stimulus. In contrast, application of a cold stimulus by immersing the hindpaw at 10 °C for 10 s resulted in decreases in MAP, HR, and glutamate. However, there was an increase in GABA concentration. Following microdialysis of l-NIO into the dlPAG, the responses to the cold stimulus was reversed i.e., the cold stimulus induced pressor and tachycardic responses, augmented glutamate, and attenuated GABA levels. These results demonstrate that eNOS within the dlPAG plays a differential role on the cardiovascular system during heat- and cold-mediated nociception via modulating glutamatergic/GABAergic neurotransmission. However, the mechanical stimulation had no effect on cardiovascular responses following eNOS antagonism within the dlPAG.