Maynard H. Makman

A catecholamine-sensitive adenylate cyclase system is present in homogenates of both calf and rat retinas. Dopamine is a more potent activator of the bovine enzyme than is norepinephrine or epinephrine. Cyclic AMP concentrations in intact bovine retina are increased by dopamine, as well as by other catecholamines, and by depolarizing agents. Studies with adrenergic blocking agents suggest that the stimulation of retinal adenylate cyclase by catecholamines cannot be clearly defined in terms of the characteristics of alpha or beta adrenergic receptors. Bovine retina also contains a protein kinase that is stimulated 20-fold by cyclic AMP. It is proposed that dopamine is the major activator of a retinal adenylate cyclase, and that this activation is related to its role as a neurotransmitter.

The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel delta, mu, and kappa receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel mu3, opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.

Unilateral radiofrequency lesions or chemical lesions with 6-hydroxydopamine were produced in the substantia nigra of rat brain in order to destroy dopaminergic innervations to caudate nucleus and thereby to produce functional denervation supersensitivity. Both types of lesions resulted in enhanced stimulation of caudate adenylate cyclase (EC 4.6.1.1) activity by dopamine at all dopamine concentrations tested, with more marked enhancement at the lower concentrations. Response to another dopamine agonist, 1-(3,4-dihydroxybenzyl)-4-(20pyrimidinyl) piperazine (S584) was also enhanced. 6-Hydroxydopamine lesions resulted in selective enhancement of the dopamine-stimulated component of adenylate cyclase, whereas radiofrequency lesions resulted also in a marked decrease in basal activity. It is postulated that the basal activity of caudate represents primarily an adenylate cyclase distinct from that stimulated by dopamine and destroyed only by the less selective radiofrequency lesion. The enhancement of dopamine-sensitive adenylate cyclase after lesions serves as indirect evidence for a significant role of this system in the transmitter function of dopamine and indicates, furthermore, that it is directly involved in dopamine receptor supersensitivity in vivo produced by denervation.

The presence of morphine-like and codeine-like substances was demonstrated in the pedal ganglia, hemolymph, and mantle tissues of the mollusc Mytilus edulis. The pharmacological activities of the endogenous morphine-like material resemble those of authentic morphine. Both substances were found to counteract, in a dose-dependent manner, the stimulatory effect of tumor necrosis factor alpha or interleukin 1 alpha on human monocytes and Mytilus immunocytes, when added simultaneously to the incubation medium. The immunosuppressive effect of this opiate material expresses itself in a lowering of chemotactic activity, cellular velocity, and adherence. Codeine mimics the activity of authentic morphine, but only at much higher concentrations. Specific high-affinity receptor sites (mu 3) for morphine have been identified on human monocytes and Mytilus immunocytes. In Mytilus recovering from experimentally induced stress, the return of "altered" immunocytes to a more inactive state appears to be due to a significant rise in the content of morphine-like material in the pedal ganglia and hemolymph at this time. Thus, morphine may have a role in calming or terminating the state of immune alertness.