Intradermal application of nociceptin increases vascular permeability in rats: the possible involvement of histamine release from mast cells

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Abstract

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-like1 (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.

Introduction

The heptadecapeptide nociceptin (or orphanin FQ) has been identified as an endogeneous ligand for the opioid-receptor-like1 (ORL1) receptor from rat (Menuier et al., 1995) and porcine brain (Reinscheid et al., 1995). The ORL1 receptor is coupled to a pertussis toxin-sensitive G protein Fukuda et al., 1994, Mollereau et al., 1994 and possesses high homology with other classes of opioid receptors Fukuda et al., 1994, Mollereau et al., 1994. ORL1 receptor protein and mRNA are abundantly localized in the brain as well as the spinal cord Bunzow et al., 1994, Fukuda et al., 1994, Wick et al., 1994, Lachowicz et al., 1995, thus suggesting a probable functional role in the central nervous system (CNS) (see review of Meunier, 1997).

ORL1 receptor mRNA is also located in several non-nervous system tissues and organs (e.g., intestine, skeletal muscle, vas deferens and spleen) (Wang et al., 1994), as well as various populations of immune cells Peluso et al., 1998, Pampusch et al., 1998. Thus, it is predicted that nociceptin will likely pharmacologically modulate features of ORL1-positive populations, including the immune system, although to date, only a few reports have addressed this possibility (see review of Meunier, 1997). Interestingly, earlier in vitro studies have demonstrated that antisense oligonucleotides against the ORL1 receptor inhibited polyclonal immunoglobulin production (Halford et al., 1995) and that the stimulation of human peripheral blood lymphocytes upregulates ORL1 receptor mRNA expression (Wick et al., 1995), suggesting that nociceptin likely plays certain roles in the functional regulation of the immune system.

In addition to these in vitro findings, Nemeth et al. (1998) have described immune system influences of nociceptin using an in vivo paradigm. They reported that intraperitoneal injection of nociceptin inhibited plasma extravasation in denerved hindpaw induced by subplantar application of histamine and mast-cell-degranulating peptide. These results suggest that nociceptin likely has an anti-inflammatory effect. However, they did not address the issue of which component(s) is(are) important for the change in the inflammatory response at the local site. Namely, is there a direct anti-inflammatory effect of nociceptin on immune components and/or is there an indirect effect mediated by nociceptin modulation of the release of various neuropeptides [e.g., substance P and calcitonin gene-related peptide (CGRP)]? Indeed, considering nociceptin has been shown to inhibit the release of substance P and CGRP induced by capsaicin and bradikinin from sensory neuronal afferents Helyes et al., 1997, Nemeth et al., 1998, and that it is possible that substance P and CGRP might work as pro-inflammatory factors Schaffer et al., 1998, Sirinek and O'Dorisio, 1991, Rameshwar, 1997, the anti-inflammatory capacity of nociceptin may potentially involve modulation of the release of these and/or other neuropeptides.

Accordingly, it was deemed important to evaluate more precisely the nature of nociceptin in immune system modulation. In this study, we thus attempted to investigate the in vivo effect of the topical application of nociceptin in rats. Moreover, we investigated the effect of nociceptin on histamine release from rat peritoneal mast cells. Our data suggest that nociceptin is critical to regulate the immune response at the local site.

Section snippets

Animals and drugs

Male Wistar rats (300–400 g) were purchased from Japan SLC (Hamamatsu, Japan). Animals were kept in a temperature (22–24°C)-, humidity (55±5%)- and light (12-h light–dark cycle, lights on at 07:00 h)-regulated room with food and water ad libitum for at least 3 days before surgery. The procedures involving animals and their care were conducted in accordance with “Guiding Principles for the Care and Use of Laboratory Animals” provided by Nagoya University, Japan. Nociceptin was purchased from

Results

As shown in Fig. 1(a), nociceptin (5 pmol/site–5 nmol/site) induced edema formation in rat skin in a dose-dependent manner, with an increase in vascular permeability of approximately 2.9-fold being associated with the highest nociceptin dose (Fig. 1(a)). In addition, nociceptin (5 nmol/site)-associated increased vascular permeability was significantly blocked by pyrilamine (50 pmol/site–5 nmol/site), a histamine H1 receptor antagonist, in a dose-dependent fashion (Fig. 1(b)).

Fig. 2 (inset)

Discussion

The ORL1 receptor is located on various immune cells including circulating lymphocytes and monocytes as well as T, B and monocytic cell lines (Peluso et al., 1998), suggesting the possible role of the ORL1 receptor in the immune system. Earlier in vitro studies have demonstrated that antisense oligonucleotides against the ORL1 receptor inhibit polyclonal immunoglobulin production (Halford et al., 1995) and that the stimulation of human peripheral blood lymphocytes upregulates ORL1-receptor mRNA

Acknowledgements

The authors would like to thank Professor Tetsuo Hayakawa for his encouragement throughout the study and Dr. Hiroshi Yoshida for the technical advice.

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