Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat

https://doi.org/10.1016/j.ejphar.2006.11.037Get rights and content

Abstract

Antinociception achieved after peripheral administration of opioids has opened a new approach to the treatment of severe and chronic pain. Additionally, opioid analgesics with restricted access to the central nervous system could improve safety of opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and neuropathic pain. Their antinociceptive activities were compared with those of morphine, the classical μ-opioid receptor agonist. Intraplantar administration of morphine and the 6-amino acid derivatives produced dose-dependent reduction of formalin-induced flinching of the inflamed paw, without significant effect on the paw edema. Local i.pl. administration of the new derivatives in rats with neuropathic pain induced by sciatic nerve ligation produced antiallodynic and antihyperalgesic effects; however, the antinociceptive activity was lower than that observed in inflammatory pain. In both models, the 6-amino acid derivatives and morphine at doses that produced analgesia after i.pl. administration were systemically (s.c.) much less active indicating that the antinociceptive action is due to a local effect. Moreover, the local opioid antinociceptive effects were significantly attenuated by naloxone methiodide, a peripherally acting opioid receptor antagonist, demonstrating that the effect was mediated by peripheral opioid receptors. The present data indicate that the peripherally restricted 6-amino acid conjugates of 14-O-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in neuropathic pain. Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting pain.

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.

References (36)

  • A. Pertovaara et al.

    Peripheral effects of morphine in neuropathic rats: role of sympathetic postganglionic nerve fibers

    Eur. J. Pharmacol.

    (2001)
  • R. Przewlocki et al.

    Opioids in chronic pain

    Eur. J. Pharmacol.

    (2001)
  • R. Przewlocki et al.

    Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception

    Neuroscience

    (1992)
  • W. Puehler et al.

    Rapid upregulation of mu opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction

    Neuroscience

    (2004)
  • P. Sacerdote et al.

    Involvement of beta-endorphin in the modulation of paw inflammatory edema in the rat

    Regul. Pept.

    (1996)
  • M. Spetea et al.

    In vitro opioid activity profiles of 6-amino acid substituted derivatives of 14-O-methyloxymorphone

    Eur. J. Pharmacol.

    (2004)
  • C. Stein et al.

    Peripheral opioid analgesia

    Curr. Opin. Pharmacol.

    (2001)
  • R. Amann et al.

    Effects of morphine on oedema and tissue concentration of nerve growth factor in experimental inflammation of the rat paw

    Pharmacology

    (2002)
  • Cited by (55)

    • Nerve trauma-caused downregulation of opioid receptors in primary afferent neurons: Molecular mechanisms and potential managements

      2021, Experimental Neurology
      Citation Excerpt :

      Time-dependent reductions of the ORs at both mRNA and protein levels were observed in nerve trauma-related DRG after unilateral fifth lumbar (L5) spinal nerve ligation (SNL), partial sciatic nerve ligation, axotomy, and chronic constriction injury (CCI) of unilateral sciatic nerve.( Kohno et al., 2005; Lee et al., 2011; Obara et al., 2007; Rashid et al., 2004; Zhang et al., 1998) The mechanisms by which the ORs are downregulated in these DRG neurons following peripheral nerve trauma are still elusive, but recent evidence indicates that this downregulation occurs at both transcriptional and translational levels involving distinct molecular mechanisms under neuropathic pain conditions. Exploring these molecular mechanisms may provide a new avenue for improving efficacy of OR agonists following peripheral nerve trauma.

    • Simultaneous targeting of MOR/DOR: A useful strategy for inflammatory pain modulation

      2019, European Journal of Pharmacology
      Citation Excerpt :

      Interestingly, an increased DOR expression on the neuronal plasma membrane is induced by inflammation (Wang and Wessendorf, 2001; Cahill et al., 2003) and DOR targeting to the cell surface is abolished in MOR-KO mice (Morinville et al., 2003) suggesting that, in conditions of persistent inflammation, MOR activation plays a crucial role in DOR trafficking. This functional co-operation, supported by DOR and MOR co-expression in certain subpopulations of small neurons in dorsal root ganglia (DRG) and in nociceptive afferents, has been proposed as the cellular basis for opioid receptors interactions in pain pathways (Obara et al., 2007; Araldi et al., 2018; Zhang et al., 2015). A functional MOR and DOR interaction is also supported by a growing body of evidence showing that multitarget MOR/DOR ligands have additive or synergic antinociceptive effects, together with an improved tolerability (Bender et al., 2014; Nastase et al., 2018).

    • Opioids, sensory systems and chronic pain

      2013, European Journal of Pharmacology
    View all citing articles on Scopus
    View full text