Cutaneous biology and endogenous opioids: How the skin modulates pain and addiction

• Main Author: Robinson, Kathleen Clare
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2014
• Subjects: Biology; Neurosciences
• ISBN: 130372460X; 9781303724602

The Proopiomelanocortin gene, (POMC), produces many biologically active peptides including the endogenous opioid, β-endorphin, and the melanocortins: α-Melanocyte Stimulating Hormone, (αMSH), γMSH, βMSH and Adrenocorticotropic Hormone, (ACTH). βendorphin is released by the brain in response to stress or injury and is a potent analgesic. Melanocortins are well known for regulating pigmentation, metabolism, and cortisol levels. Additionally, opioids and melanocortins are known to have opposing actions in several settings including the regulation of pain and metabolism. The Melanocyte Stimulating Hormones are expressed in the skin where they bind the Melanocortin 1 Receptor on melanocytes and promote pigmentation. It has been reported that β-endorphin is also produced in the skin, however it was not believed to have a central effect. In this thesis I show that expression of these peptides in the skin is reflected in blood levels and affects nociception and behavior. In Chapter 2 I show that the increased nociceptive thresholds seen in red-haired mice are due to lower plasma levels of melanocortin peptides. Thus in red-haired mice the decreased levels of melanocortins result in decreased antagonism to endogenous opioids, causing a stronger opioid effect and higher nociceptive thresholds. These higher thresholds are sensitive to genetic and pharmacologic opioid receptor blockade in red-haired mice, and to pharmacologic melanocortin receptor agonists. In Chapter 3 I show that UV exposure results in elevated blood β-endorphin levels in mice and this causes analgesia and addiction. In Chapter 4 I show that Vitamin D levels and receptor activity regulate the expression of β-endorphin and melanocortins in the blood plasma. Vitamin D-deficient mice, as well as Vitamin D Receptor null mice, have lower plasma levels of β-endorphin and melanocortins, and higher thermal nociceptive thresholds. Finally, in Chapter 5 I show that Vitamin D regulates MITF, a master transcriptional regulator in melanocytes. In conclusion, melanocyte expression of POMC contributes significantly to blood plasma levels of melanocortins, and can be altered by both the red-hair allele and Vitamin D. We suggest that this could have been an evolutionary advantage in latitudes with low UV as Vitamin D-deficient individuals may experience a stronger positive reinforcement to UV tanning.