Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat
Introduction
Antinociception induced by classical opioids, such as morphine, is mainly attributed to their effects within the central nervous system. The central site of action is a reason of numerous undesirable side effects of opioids (e.g. sedation, respiratory depression, tolerance) (MacPherson, 2002) and strongly limits their clinical use. A large number of studies have indicated an important role in antinociception of peripheral opioid receptors (Pertovaara and Wei, 2001, Janson and Stein, 2003, Truong et al., 2003, Obara et al., 2004). The mRNAs are localized in the cell bodies of primary afferent sensory neurons located in the dorsal root ganglia (Stein, 1995, Wang and Wessendorf, 2001) and their respective proteins are present on peripheral afferent axons of sensory neurons in rodents and humans (Coggeshall and Carlton, 1997, Wenk and Honda, 1999, Stein et al., 2001). In addition, endogenous ligands of these peripheral opioid receptors were identified in resident immune cells within peripheral inflamed tissues (Stein et al., 1990, Przewlocki et al., 1992).
It is well known that function, regulation and axonal transport of peripheral opioid receptors are changed under pathological conditions (Przewlocki et al., 1992, Hassan et al., 1993, Zhang et al., 1998, Mousa et al., 2001, Truong et al., 2003, Zöllner et al., 2003). Analgesic effects mediated by peripheral opioid receptors have been demonstrated after local application of low, systemically inactive doses of opioids directly into an injured peripheral tissue. The opioid antinociceptive effects were largely investigated in different animal models of inflammatory (Stein et al., 2001, Whiteside et al., 2005) and neuropathic pain (Pertovaara and Wei, 2001, Truong et al., 2003, Obara et al., 2004), as well as in patients with chronic inflammation, arthritis or after knee or dental surgery (Kalso et al., 1997, Dionne et al., 2001, Cerchietti et al., 2003, Likar et al., 2005, Platzer et al., 2005). In order to avoid the adverse actions of centrally acting opioids, antinociception can also be achieved by systemic administration of potent analgesics with limited access to the central nervous system (DeHaven-Hudkins and Dolle, 2004, Fürst et al., 2005, Bileviciute-Ljungar et al., 2006).
Recently, 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were described as μ-opioid receptor agonists with restricted penetration to the central nervous system (Schütz et al., 2003, Spetea et al., 2004). Our recently published pharmacological data (Fürst et al., 2005) demonstrated that such derivatives produce long-lasting antinociception in acute and inflammatory pain after subcutaneous (s.c.) administration, being more potent than morphine. It was also shown that morphine, a centrally acting μ-opioid agonist, exerts its analgesic effects by both central and peripheral mechanisms, while the new opioids interact primarily with peripheral opioid receptors. The aim of our present study was to assess the antinociceptive effects of the 6-amino acid conjugates (glycine and phenylalanine), α- or β-orientated, of 14-O-methyloxymorphone (Fig. 1), in rat models of inflammatory pain (induced by formalin injection) and neuropathic pain (produced by ligation of the sciatic nerve) after local, i.pl. administration directly into the injured hindpaw. We have evaluated their effects in relationship with those of the classical and clinically relevant opioid morphine. Dose–response, time-dependence and site of action responsible for the antinociceptive effects were determined after i.pl. administration of the opioid agonists. Furthermore, this study compared the effects on the attenuation in pain-related behavior in inflammatory and neuropathic pain after i.pl. application of the peripherally acting opioid agonists in rats.
Section snippets
Animals
Male Wistar rats (300–350 g) were housed in individual polycarbonate cages with sawdust bedding under a standard 12-h/12-h light/dark cycle (08:00–20:00 h) with food and water available ad libitum. All experiments were conducted during the light phase, between 9:00 and 14:00. All experiments were carried out according to the National Institutes of Health Guide for Care and Use of Laboratory Animals and recommendations of the IASP, and were approved by the Local Bioethics Committee (Institute of
Effect of morphine and 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in inflammatory pain
Formalin injection induces biphasic incidence of spontaneous flinches, shakes, and jerks of the formalin-injected paw. Intraplantar (i.pl.) administration of morphine and 6-amino acid-substituted derivatives of 14-O-methyloxymorphone, HS-730, HS-731, HS-937 and HS-938, produces a dose-dependent antinociceptive action, observed as a reduction of formalin-induced pain behavior, in both phases of the formalin test in rats (Fig. 2, Fig. 3). The strongest analgesic effect was obtained for HS-731
Discussion
In the present study, we have shown that the 6-amino acid (glycine and phenylalanine) conjugates of 14-O-methyloxymorphone produce potent antinociceptive effects in a dose-dependent manner in rat models of inflammatory and neuropathic pain after their local (i.pl.) peripheral administration. We also demonstrate that the effects were mediated via activation of opioid receptors located in the periphery. These findings add new knowledge about the antinociceptive properties of the 6-amino
Acknowledgements
This work was supported by a grant from the European Community, EPILA, QLK6-1999-02334, EPILA No 26/E-40/SPB/5.PR VE/DZ 417/2003-2004, statutory funds from the Ministry of Scientific Research and Information Technology (Warszawa, Poland), and the Austrian Science Foundation (P15481). The contribution of Foundation for Polish Science (FNP) to I. Obara is greatly acknowledged.
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