Nitric oxide within periaqueductal gray modulates glutamatergic neurotransmission and cardiovascular responses during mechanical and thermal stimuli

We have previously reported that nitric oxide (NO) within the rostral ventrolateral medulla (RVLM) attenuates cardiovascular responses and extracellular concentrations of glutamate during thermal, but not during mechanical nociceptive stimulation (Ishide. T., Maher, T.J., Ally, A. 2003. Role of nitric oxide in the ventrolateral medulla on cardiovascular responses and glutamate neurotransmission during mechanical and thermal stimuli. Pharmacol. Res. 47, 59-68). In this study, we examined the role of nitric oxide within the dorsolateral periaqueductal gray matter (PAG), a higher center integrating nociceptive reflexes, on cardiovascular responses and glutamate release during both mechanical and thermal nociception using anesthetized Sprague-Dawley rats. Two types of stimuli were studied, both activating peripheral A(delta) and C fiber polymodal nociceptors. Noxious mechanical stimulus was given by applying a bilateral hindpaw pinch for 5 s. Mechanical stimulation of a hindlimb increased mean arterial pressure (MAP), heart rate (HR), and extracellular fluid glutamate within PAG by 20 ± 3 mmHg, 37 ± 6 bpm, and 1.7 ± 0.3 ng/5 μl, respectively (n = 10). Bilateral microdialysis of l-arginine (1.0 μM), a NO precursor, into the PAG significantly attenuated MAP, HR, and glutamate increases during a mechanical stimulation. Subsequent administration of NG-methyl-l-arginine (l-NMMA) (1.0 μM), a NO synthase inhibitor, into the PAG blocked the ability of NO within PAG to modulate the cardiovascular responses to mechanical stimulus. The noxious thermal stimulus was generated by immersing the metatarsus of a hindpaw in water-bath at a temperature of 52 °C for 5 s. Similar increases were observed following thermal stimulation: 35 ± 5 mmHg, 40 ± 6 bpm, and 1.14 ± 0.4 ng/5 μl (n = 10). l-Arginine attenuated both cardiovascular responses and glutamate increase during thermal nociception. These results demonstrate that NO within the dorsolateral PAG plays a role in modulating cardiovascular responses by altering glutamate concentrations during both thermal and mechanical nociception.