Involvement of Vanilloid- and Cannabinoid Receptors in the Anti-inflammatory Action of Nociceptin

Abstract

In the present study, we have examined the probable interactions of N/OFQ(1-13)NH 2 and its structural analogue [Orn 9 ]N/OFQ(1-13)NH 2 with cannabinoid CB 1 -receptors on acute carrageenan (CG)-induced inflammation in rat paw, as well as the mechanism of these interactions. The study also aims to find out whether the TRPV1-receptors (transient receptor potential vanilloid 1) take part in these processes. Our results showed that the simultaneous treatment of rats with CB 1 -receptor agonist HU-210 and the investigated peptides did not change the specific effects of the nociceptin and [Orn 9 ]N/OFQ(1-13)NH 2 . Applied after blockade of CB 1 -receptors, the peptides did not exert their anti-inflammatory effects. On the contrary, when the TRPV1-receptors were blocked, the anti-inflammatory effects of nociceptin (NOP)-receptor agonists as a whole remained unchanged.In conclusion, based on the results obtained, it might be suggested that N/OFQ(1-13)NH 2 and [Orn 9 ]N/OFQ(1-13)NH 2 influenced the peripheral inflammation by interactions with their own NOP-receptors located on the primary sensory neurons.We also suppose that there is a functional link between NOP-and cannabinoid CB 1 -receptors. It might be assumed that vacant or activated CB 1 -receptors are required for NOP-evoked inhibition of acute peripheral inflammation.Key words: nociceptin, rat-paw inflammation, CB 1 -receptorsThe paper is supported by the National Science Fund of the Ministry of Education, Youth and Science of Bulgaria (Grant L-1510/05). 273Introduction. In spite of the various investigations performed over the last years, the pathophysiology of acute peripheral inflammation still remains unclear. This interest is based on the fact that the inflammation usually accompanies many widespread diseases such as asthma, arthritis, colitis, gastritis, etc. The inflammation process is associated with release of many pro-inflammatory mediators by the cutaneous nerve endings, such as substance P (SP), calcitonin gene-related peptide (CGRP), neurokinin A, [ 1 ] usually followed by vasodilatation and increased vascular permeability, plasma extravasation, neutrophil infiltration, oedema, etc., in the area innervated by the stimulated nerve [ 2 ]. It has been found that nociceptive primary afferent neurons express both receptor types -NOP and CB 1 . Many data have shown that cannabinoids [ 3, 4 ] as well as nociceptin (N/OFQ) [ 5 ] reduce acute peripheral inflammation by suppressing the release of substance P and CGPR from the primary sensory neurons. Generally, cannabinoids reduce inflammation and hyperalgesia by activating the peripheral CB 1 -receptor. The effects of some CB 1 -agonists are mediated via the TRPV1-receptor [ 6,7 ]. On the other hand, it is worth mentioning that N/OFQ inhibits the effects of the activated 9,5 ].Taken together, literature data suggest common stages in the mechanisms of action of cannabinoids and nociceptin in inflamed tissues and also that the involvement of vanilloid receptors in them is very likely. Therefore, com...