Publisher Summary This chapter describes some of studies comparing the initial responses of plasma epinephrine and norepinephrine and the development of tolerance to intracerebroventricular (ICV) versus intra-arterial administration of nicotine in conscious rats. To determine whether alterations in sympathoadrenal sensitivity to nicotine might affect sympathoadrenal responses to other stimuli, the plasma catecholamine responses to a physiologic stress in two models is compared in which the animals were tolerant to nicotine. The responses to restraint in conscious rats tolerant to either systemic or ICV nicotine and to hypoglycemia in nicotine-tolerant, pentobarbital-anesthetized dogs is discussed. Finally, recent demonstration of endogenous opioid peptides colocalized with catecholamines in the adrenal medulla and in sympathetic nerve terminals has provided new impetus to study further the physiologic and pharmacologic regulation of sympathoadrenal secretion by nicotinic receptors. Thus, the chapter describes the differences between in vivo adrenal secretory responses of not only catecholamines but also Met-enkephalin to initial and subsequent systemic administration of nicotine.