Opioids and the skin – where do we stand?

Abstract

The common ectodermal origin of the skin and nervous systems can be expected to predict likely interactions in the adult. Over the last couple of decades much progress has been made to elucidate the nature of these interactions, which provide multidirectional controls between the centrally located brain and the peripherally located skin and immune system. The opioid system is an excellent example of such an interaction and there is growing evidence that opioid receptors (OR) and their endogenous opioid agonists are functional in different skin structures, including peripheral nerve fibres, keratinocytes, melanocytes, hair follicles and immune cells. Greater knowledge of these skin-associated opioid interactions will be important for the treatment of chronic and acute pain and pruritus. Topical treatment of the skin with opioid ligands is particularly attractive as they are active with few side effects, especially if they cannot cross the blood-brain barrier. Moreover, cutaneous activation of the opioid system (e.g. by peripheral nerves, cutaneous and immune cells, especially in inflamed and damaged skin) can influence cell differentiation and apoptosis, and thus may be important for the repair of damaged skin. While many of the pieces of this intriguing puzzle remain to be found, we attempt in this review to weave a thread around available data to discuss how the peripheral opioid system may impact on different key players in skin physiology and pathology.Key words: differentiation -immune system -melanocytesopioids -pruritus -skin Opioid receptors: expression in the skinOpioids and their receptors in the skin comprise part of the endogenous opioid system and includes peptides, such as enkephalins, endorphins, dynorphins and endomorphins, and three opioid receptors: l-(MOR ⁄ Oprm1), d-(KOR ⁄ Oprd1) and j-(KOR ⁄ Oprk1) receptors (16). OR are G protein-coupled receptors (GCPRs) that mediate the effects not only of the endogenous opioid peptides but also of the exogenous opiate alkaloids like morphine.We first reported MOR protein expression in human skin more than a decade ago, followed by further reports on MOR (2-4,6,8), DOR (7) and KOR (5) and the endogenous ligands, b-endorphin (8-11,17), enkephalins (18-21) and dynorphins (5), in the epidermis and peripheral nerve fibres. Noticeably, DOR and KOR are highly upregulated in the skin of fibromyalgia patients (22). While OR and peptide ligands are highly expressed in the CNS where they modulate pain, analgesia, emotional state, addiction, cognition, energy balance and autonomous functions (23), they are expressed at a lower density in the skin and immune cells. Using realtime PCR, we measured mRNA levels of DOR and MOR in skin epidermal keratinocytes, fibroblasts and epidermal melanocytes (EMs) (Fig. 1). Cell culture studies indicated that ectoderm-derived cells (e.g. brain cells, keratinocytes and melanocytes) express higher levels of MOR than of DOR. By contrast, mesoderm-derived fibroblasts express higher levels of DOR than of MOR. MOR expression in ...

Molecular Pharmacology ofδ-Opioid Receptors

“…Consistent with these observations, organotypic skin cultures containing DOPr-overexpressing keratinocytes displayed KRT10 repression and reduced epidermal thickness . Conversely, DOPrdeficient mice exhibited markedly increased expression of KRT10, hypertrophic wound edges, and delayed wound healing (Bigliardi-Qi et al, 2006;Bigliardi et al, 2009). Although the therapeutic potential of this type of response is undeniable, DOPr effects in the human skin were opposite to those described just above , underscoring the need for a better understanding of the human neuroendocrine skin system (Slominski, 2015) before any treatment strategy in wound healing can be envisioned.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…However, depending on the chronicity of the wound and the stage of the healing process, some groups reported retarding effects in models of excisional wounds (Rook et al, 2008) and corneal abrasions (Sassani et al, 2003). Several comprehensive reviews summarized these findings and mostly concluded that topically applied opioids have the potential to improve wound healing and pain, and that -, ␦-, and -opioids may have differential effects (Sassani et al, 2003;Tegeder and Geisslinger, 2004;Schmelz and Paus, 2007;Chen et al, 2008;Bigliardi et al, 2009;LeBon et al, 2009;.…”

“…Analgesia after local (topical) opioid administration has been amply demonstrated in patients with various types of acute (e.g., orthopedic, dental, abdominal, urological, and eye surgery) and chronic pain (e.g., rheumatoid and osteoarthritis, oral mucositis, complex regional pain syndrome) (Azad et al, 2000;Dionne et al, 2001;Stein et al, 2003;Faktorovich and Basbaum, 2010). Several comprehensive reviews summarized these findings and mostly concluded that topically applied opioids have a potential to improve pain, albeit many clinical trials are small (Sawynok, 2003;Kopf et al, 2006;Bigliardi et al, 2009;LeBon et al, 2009).…”

“…In addition, opioids have mitogenic properties in the regeneration of mucosa (Cho et al, 2003), promote reepithelialization and keratinocyte migration (Szabo et al, 2001;Bigliardi et al, 2002;Kü chler et al, 2010), and up-regulate cytokeratin and transforming growth factor-␤ receptors, both important components in wound healing (Tegeder and Geisslinger, 2004; for review, see Bigliardi et al, 2009). In ischemic wounds, locally applied opioids hastened wound closure increased granulation tissue and collagen formation, increased epidermal and dermal organization, and enhanced angiogenesis (Poonawala et al, 2005;Gross et al, 2009).…”

“…Apart from peripheral sensory neurons, opioid peptides and opioid receptors are expressed in immune cells (see II.4), fibroblasts, melanocytes, and keratinocytes (Tegeder and Geisslinger, 2004;Sharp, 2006;Chen et al, 2008; for review, see Bigliardi et al, 2009;Busch-Dienstfertig and Stein, 2010).…”