The Opioid Receptor Independent Actions of Kappa Receptor Agonists in the Cardiovascular System

It is not well known but the actions of opioid receptor agonist and antagonist drugs have not been well characterized in the heart and cardiovascular system. Under normal physiological conditions, opioid receptors have a limited role in the regulation of the cardiovascular system. Instead the primary focus of opioid receptor research, for many years, relates to the characterization of the actions as analgesics in the central nervous system (CNS). Recently, however a series of studies suggest that in particular the arylacetamide class of kappa (k) opioid receptor agonist drugs have significant opioid receptor independent actions on the heart and cardiovascular system. Some of the actions of these molecules may indeed be mediated by activation of peripheral opioid receptors; however, these new studies provide pharmacological evidence to the contrary and show using many different in vitro and in vivo animal models that these ‘non-opioid’ actions result from direct or opioid receptor-independent actions on cardiac tissue. This article will outline the molecular mechanism(s) that are responsible for the cardiovascular and cardiac actions these arylacetamide k opioid receptor agonists and characterize the role that these opioid receptors have in ischaemic arrhythmogenesis. In many instances it would appear that the effects of opioid agonists (and antagonists) in cardiovascular disease models of ischaemia may be mediated by opioid receptor-independent actions of these drugs.