Deletion of μ- and κ-Opioid Receptors in Mice Changes Epidermal Hypertrophy, Density of Peripheral Nerve Endings, and Itch Behavior

Abstract

The mu- (MOR) and kappa- (KOR) opioid receptors have been implicated in the regulation of homeostasis of non-neuronal cells, such as keratinocytes, and sensations like pain and chronic pruritus. Therefore, we have studied the phenotype of skin after deletion of MOR and KOR. In addition, we applied a dry skin model in these knockout mice and compared the different mice before and after induction of the dermatitis in terms of epidermal thickness, epidermal peripheral nerve ending distribution, dermal inflammatory infiltrate (mast cells, CD4 positive lymphocytes), and scratching behavior. MOR knockout mice reveal as phenotype a significantly thinner epidermis and a higher density of epidermal fiber staining by protein gene product 9.5 than the wild-type counterparts. Epidermal hypertrophy, induced by the dry skin dermatitis, was significantly less developed in MOR knockout than in wild-type mice. Neither mast cells nor CD4 T(h)-lymphocytes are involved in the changes of epidermal nerve endings and epidermal homeostasis. Finally, behavior experiments revealed that MOR and KOR knockout mice scratch less after induction of dry skin dermatitis than wild-type mice. These results indicate that MOR and KOR are important in skin homeostasis, epidermal nerve fiber regulation, and pathophysiology of itching.

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

“…The epidermis of MOR knockout mice is thinner than that of wild-type mice. 41 Selective loss of motor and sensory nerve after neuronal injury also results in epidermal thinning. 42 Therefore, down-regulation of MOR and reduction in innervation of the skin of mice expressing HbS, as observed by us, may contribute to thinning of the epidermis.…”

Neuroimmune interactions in allergic skin diseases

“…The expression of m-opioid and k-opioid receptors was detected at reduced levels in skin biopsies of atopic dermatitis patients due to its internalization in keratinocytes [69]. Interestingly, dry skin induction in mice with deleted cutaneous m-opioid receptor revealed that these mice scratch less often than their wild type counterparts, indicating an important role in itch sensation and skin homeostasis [70].…”

Opioid Antagonists Enhance Diabetic Wound Closure: A New Therapy

“…Enkephalins such as [Met 5 ] and [Leu 5 ]-enkephalin and the synthetic d-Ala-d-Leu-enkephalin have been reported to inhibit cell differentiation dose-dependently in human keratinocytes in vitro, while β-endorphin had no effect [38]. Deletion of the classical opioid receptors in mice resulted in a phenotype of thinner epidermis and higher expression of differentiation markers, whereas a burn wound healed significantly slower in these KO mice relative to wildtype mice [31,32]. Naloxone and naltrexone (NTX) are general opioid antagonists that are devoid of intrinsic biological actions [39] and block the interaction of three opioid peptide families (prodynorphin, proopiomelanocortin, proenkephalin) and classical (μ, δ, κ) as well as non-classical (OGFr) opioid receptors.…”

“…Several endogenous opioids (enkephalins, endorphins, dynorphins, endomorphins) and classical (μ/MOR/Oprm1, δ/DOR/Oprd1, κ/KOR/Oprk1) opioid receptors, as well as the nuclear-associated, non-classical OGFr are present and functioning in skin [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Enkephalins such as [Met 5 ] and [Leu 5 ]-enkephalin and the synthetic d-Ala-d-Leu-enkephalin have been reported to inhibit cell differentiation dose-dependently in human keratinocytes in vitro, while β-endorphin had no effect [38].…”

“…Moreover, topical NTX accelerates full thickness wound repair in diabetic animals [20,21,31,33]. Rats with streptozotocin-induced type 1 diabetes received topical applications of NTX (10 -4 -10 -6 M) or vehicle in a variety of carriers.…”