Intradermal application of nociceptin increases vascular permeability in rats: the possible involvement of 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.
References (51)
- et al.
Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type
FEBS Lett.
(1994) - et al.
PACAP-induced plasma extravasation in rat skin
Regul. Pept.
(1997) - et al.
Substance P-related inhibitors of mast cell exocytosis act on G-proteins or on the cell surface
Eur. J. Pharmacol.
(1998) - et al.
Nociceptin activation of the human ORL1 receptor expressed in Chinese hamster ovary cells: functional homology with opioid receptors
Eur. J. Pharmacol.
(1997) - et al.
cDNA cloning and regional distribution of a novel member of the opioid receptor family
FEBS Lett.
(1994) - et al.
Neuropeptide Y and truncated neuropeptide Y analogs evoke histamine release from rat peritoneal mast cells. A direct effect on G proteins?
Eur. J. Pharmacol.
(1994) - et al.
Functional role and sequence analysis of a lymphocyte orphan opioid receptor
J. Neuroimmunol.
(1995) - et al.
Regulation of Gi and Go by mastoparan, related amphiphilic peptides, and hydrophobic amines. Mechanism and structural determinants of activity
J. Biol. Chem.
(1990) - et al.
Procedures for immunochemical study of histamine release from leukocytes with small volume of blood
J. Allergy
(1970) Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor
Eur. J. Pharmacol.
(1997)