PubMed · 9601599
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J Price. 1998. Burnaid.. https://doi.org/10.1016/s0305-4179(97)00097-1
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Intradermal application of nociceptin was used to investigate its in vivo effect on the inflammatory response in rats. Intradermal nociceptin (5 pmol/site-5 nmol/site) increased vascular permeability in a dose-dependent manner. The increased vascular permeability by nociceptin (5 nmol/site) was dose-dependently inhibited by the histamine H1 receptor antagonist pyrilamine (50 pmol/site-5 nmol/site). In rat peritoneal mast-cell preparation, nociceptin (10(-8)-10(-4) M) dose-dependently stimulated histamine release. The effect of nociceptin (10(-5) M) occurred rapidly (within 30 s) and was inhibited by pertussis toxin, Ca2+, but was not sensitive to naloxone, a classical opioid receptor antagonist. These characteristics are in agreement with features of the opioid-receptor-like 1 (ORL1) receptor, a non-classical opioid receptor linked to a pertussis toxin-sensitive G protein. Taken together, these data suggest that nociceptin, likely acting via the ORL1 receptor at the site of inflammation, might be critical for the enhancement of the inflammatory response by stimulating histamine release from mast cells.
Dendritic cells (DCs) exhibit considerable heterogeneity in their anatomical location, surface phenotype, and functional properties. In this study, we demonstrate that peripheral lymph nodes contain at least four major, functionally separable, and independently derived, DC subsets, which can be clearly demarcated by their CD11c, CD40, and CD8 expression pattern. Surprisingly, all DCs derived directly from the bone marrow, the myeloid- and the lymphoid-related subsets, turned over fast with t(1/2) of a couple of days. In contrast, DCs exported from the skin, both dermal and epidermal, accumulated 3- to 4-fold slower, turnover that is dramatically increased by cutaneous inflammation.
Antisense technology holds tremendous promise for therapeutic applications and the study of gene function. A broadly applicable route of administration that would provide for non-invasive, simple, and convenient delivery is highly desirable. Application of oligonucleotides to the skin may represent a solution to the delivery question for both local treatment of skin disease and for systemic delivery. The iontophoretic mode of delivery for phosphorothioate oligonucleotides across hairless mouse skin reveals the potential limitation in the delivery of sufficient oligonucleotide to provide for efficacy. A potential solution to this problem is the use of significantly more potent C-5 propyne base modifications in a phosphorothioate oligonucleotide. The combination of the iontophoretic delivery mode with potent oligonucleotides resulted in selective inhibition of the CYP3A2 gene expression in the rat liver. Alternatively, oligomers with neutral charge combined with passive modes of transdermal delivery may also be feasible and represent an even more broadly applicable technology. Future studies will focus on specific applications of local and systemic therapy of antisense oligonucleotide in animal models for the design of treatment regimens.