Nitric oxide synthase (NOS) plays important roles within the cardiovascular system in physiological states as well as in pathophysiologic and specific cardiovascular (CV) disease states, such as hypertension (HTN), arteriosclerosis, and cerebrovascular accidents. This review discusses the roles of the endothelial NOS (eNOS) and its effect on cardiovascular responses that are induced by nociceptive stimuli. The roles of eNOS enzyme in modulating CV functions while experiencing pain will be discussed. Nociception, otherwise known as the subjective experience of pain through sensory receptors, termed "nociceptors", can be stimulated by various external or internal stimuli. In turn, events of various cascade pathways implicating eNOS contribute to a plethora of pathophysiological responses to the noxious pain stimuli. Nociception pathways involve various regions of the brain and spinal cord, including the dorsolateral periaqueductal gray matter (PAG), rostral ventrolateral medulla (RVLM), caudal ventrolateral medulla, and intermediolateral column of the spinal cord. These pathways can interrelate in nociceptive responses to pain stimuli. The alterations in CV responses that affect GABAergic and glutamatergic pathways will be discussed in relation to mechanical and thermal (heat and cold) stimuli. Overall, this paper will discuss the aggregate recent and past data regarding pain pathways and the CV system.