Positive evolutionary pressure has preserved the ability to synthesize chemically authentic morphine, albeit in homeopathic concentrations, throughout animal phyla. The prototype catecholamine dopamine (DA) serves as an essential chemical intermediate in morphine biosynthesis both in plants and animals, thereby providing considerable insight into the roles reciprocal “morphinergic” and catecholamine regulation of diverse physiological processes. Primordial, multi-potential cell types, before the emergence of specialized plant and animal cells/organ systems, required selective mechanisms to limit their responsiveness to environmental noise. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule were provided with extremely positive evolutionary advantages. Endogenous “morphinergic” in concert with NO-coupled signaling systems have evolved as autocrine/paracrine regulators of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving “morphinergic”/NO-coupled regulation of cardiovascular mitochondrial function, with special emphasis on the interactive effects of ethanol, are discussed within the context of our review.

Previous work from our laboratory has established that cellular signaling processes of endogenous morphine are mediated by cognate G protein coupled receptor (GPCR) proteins, designated µ3 and µ4 opiate receptors. µ3 and µ4 opiate receptors are structurally unique “short” 6 transmembrane helical (TMH) domain GPCRs that are selectively responsive to endogenous morphine, not to families of endogenous opioid peptides, and are uniquely coupled to activation of constitutive nitric oxide synthase (cNOS). Based on high resolution predictive measures, it appears likely that domestic poultry express a µ opiate receptor mRNA encoding potentially two novel GPCRs with similar biochemical characteristics as described for µ3 and µ4 opiate receptors as well as traditional µ1 opioid receptors. The biological indications of these novel µ opiate receptors are discussed within the context of this short review.

Catecholamine signaling pathways in the peripheral and central nervous systems (PNS, CNS, respectively) utilize catechol-O-methyltransferase (COMT) as a major regulatory enzyme responsible for deactivation of dopamine (DA), norepinephrine (NE) and epinephrine (E). Accordingly, homeostasis of COMT gene expression is hypothesized to be functionally linked to regulation of autonomic control of normotensive vascular events. Recently, we demonstrated that morphine administration in vitro resulted in decreased cellular concentrations of COMT-encoding mRNA levels, as compared to control values. In contrast, cells treated with E up regulated their COMT gene expression. In sum, these observations indicate a potential reciprocal linkage between end product inhibition of COMT gene expression by E and morphine. Interestingly, the observed effects of administered E on COMT gene expression suggest an enhancement of its own catabolism or, reciprocally, a stimulation morphine biosynthesis.

Introduction

We have previously demonstrated that alcohol has the ability to release low levels of endogenously expressed, chemically authentic, morphine from neural tissues.

Material and methods

Presently, we demonstrate that chronic exposure of Mytilus edulis pedal ganglia tissues maintained in organotypic culture to very concentrations of 1 mM and 10 mM ethanol induces a time dependent increase in both endogenous morphine and dopamine (DA) levels.

Results

Chronic incubation of M. edulis pedal ganglia with 3 concentrations of DA resulted in statistically significant elevations of cellular morphine levels, thereby confirming previous studies from our laboratory establishing DA as an essential precursor in the morphine biosynthetic pathway.

Conclusions

By understanding multiple debilitating effects of alcohol on “morphinergic” signaling, we may understand the ravages of neural processes associated with alcohol abuse and how its treatment may be made more effective.

Stress can facilitate disease processes and causes strain on the health care budgets. It is responsible or involved in many human ailments of our time, such as cardiovascular illnesses, particularly related to the psychosocial stressors of daily life, including work. Besides pharmacological or clinical medical treatment options, behavioral stress reduction is much-needed. These latter approaches rely on an endogenous healing potential via life-style modification. Hence, research has suggested different ways and approaches to self-treat stress or buffer against stressors and their impacts. These self-care-centred approaches are sometimes referred to as mind-body medicine or multi-factorial stress management strategies. They consist of various cognitive behavioral techniques, as well as relaxation exercises and nutritional counselling. However, a critical and consistent element of modern effective stress reduction strategies are exercise practices. With regard to underlying neurobiological mechanisms of stress relief, reward and motivation circuitries that are imbedded in the limbic regions of the brain are responsible for the autoregulatory and endogenous processing of stress. Exercise techniques clearly have an impact upon these systems. Thereby, physical activities have a potential to increase mood, i.e., decrease psychological distress by pleasure induction. For doing so, neurobiological signalling molecules such as endogenous morphine and coupled nitric oxide pathways get activated and finely tuned. Evolutionarily, the various activities and autoregulatory pathways are linked together, which can also be demonstrated by the fact that dopamine is endogenously converted into morphine which itself leads to enhanced nitric oxide release by activation of constitutive nitric oxide synthase enzymes. These molecules and mechanisms are clearly stress-reducing.

Among the various non-neuronal cell types known to express and utilize neuropeptides, those of the immune system have received much attention in recent years. In particular, comparative studies in vertebrates and invertebrates have shown that endogenous opioid peptides are engaged in receptor mediated autoregulatory immune and neuroendocrine processes. The majority of these immune processes are stimulatory, as determined by their effects on conformational changes indicative of immunocyte activation, cellular motility, and phagocytosis. Endogenous opioid peptides form an effective network of messenger molecules in cooperation with cytokines, opiate alkaloids, and certain regulatory enzymes (neutral endopeptidase 24.11). Peptide-mediated immunostimulatory effects observed in this system are operationally counteracted by the inhibitory effects of morphine and related opiates. Opioid/opiate signaling processes are mediated by several types of receptors with different degrees of selectivity. Among them the recently identified, opioid insensitive µ3 receptor deserves attention on account of its specificity for opiate alkaloids.