Melanoma targeting by melanocortin peptides: current status and future perspectives

Abstract

The peripheral nervous system comprises the autonomic and sensory (afferent) nervous systems. Major advances in our understanding of the autonomic and sensory transmission and function include the recognition of the phenotypic expression of a variety of transmitters and modulators that often coexist in individual neurons, the concept of co-transmission and chemical coding, the evidence for local effector functions of primary afferent nerves, and the discovery of plasticity of both the autonomic and the sensory nervous system during development, aging, diseases states, and inflammation. Co-transmission or plurichemical transmission, which indicates the release of more than one chemical messenger from the same neuron, enables autonomic and sensory neurons to exert a fine and highly regulated control of various functions such as circulation and immune response. The concept of chemical coding, in which the combination of transmitters/modulators is established, allows the identification of functional classes of neurons with their projections and targets. In addition to transmitters and modulators, autonomic and sensory neurons express multiple receptors, including G-proteincoupled and ion-gated receptors, further supporting the complexity of autonomic and sensory transmission and function. Autonomic neurons regulate the internal environment and maintain multiple homeostatic functions, and sensory neurons act as receptive structures that activate their targets in response to stimulation but also exert effector functions including the control of blood flow and vascular permeability, maintenance of mineralized tissue, and regulation of gene expression. Neurophysiology of painThe nociceptive system supports two sensory functions, pain and itch. Itch has often been regarded as a minor form of pain. Recently, it has been shown, however, that the pruritic system is supported by its own peripheral and central neuronal pathways which are closely associated, although antagonistic in some POMC processing in human melanocytes has been widely documented, and the a-MSH/MC1R/cAMP cascade has been implicated in the control of pigmentation. Only very recently, a role of b-endorphin, one cleavage product of b-LPH, has been demonstrated to influence melanocyte growth, dendricity and melanin biosynthesis via the m-opiate receptor. However, much earlier, it was shown that b-MSH, the other cleavage product of b-LPH, controls melanogenesis and melanin transfer in amphibians. To date, a specific receptor for b-MSH has not been identified. Earlier POMC processing has been found in melanosomes. Therefore, an MC1R-independent role of a-MSH was postulated and demonstrated in control of 6-tetrahydrobiopterin (6BH 4 )inhibited tyrosinase. Utilizing the depigmentation disorder vitiligo, we were now able to follow the fate of epidermal POMC processing in the presence of mM levels of hydrogen peroxide (H 2 O 2 ). In vitiligo epidermal PC2 and 7B2 protein expression is increased, whereas a-MSH, b-MSH and b-endorphin are significantly decreased. Analys...