Production by Systemic Enkephalin of Hemodynamic Effects by Afferent Modulation of Autonomic Nervous System Tone

Abstract

In our conscious, chronically instrumented dog model, systemic administration of methionine-enkephalin (Met5-ENK) and leucine-enkephalin (Leu5-ENK), 10–100 μg/kg, produces dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR); responses typically begin within 10–15 s after injection, reach maximal values by 30 s, and then terminate by 150 s [21]. Similar responses have been reported in conscious rats, rabbits, cats, and adult ewes [15, 25, 26, 28]. More recently, we have demonstrated indentical hemodynamic responses in humans; in nine subjects, intravenous Met5-ENK produced a positive dose-effect relationship for HR, and systolic, diastolic, and mean systemic arterial pressure. Statistically significant increases in diastolic blood pressure occurred at Met5-ENK doses of 1 μg/kg [12]. In conscious dogs, intravenous Met5-ENK also increases minute ventilation, as a result of increases in both tidal volume and respiratory rate [6]. All of these hemodynamic changes are prevented by pretreatment with the opiate antagonist naloxone, indicating that the observed responses are mediated at specific opiate receptors [6, 21]. These excitatory enkephalin (ENK) responses in the conscious state are reversed by pretreatment with barbiturates and benzodiazepine, indicating the critical importance of conscious animal models [22, 23]. The simultaneous occurrrence of increases in HR and MAP indicates baroreceptor suppression, and thus suggests that circulating ENK may physiologically function as chemoreceptor agonists, and thus produce hemodynamic responses by modulating afferent autonomic nervous system input into the CNS.