Peripheral opioid analgesia

doi:10.1016/S1471-4892(01)00005-4

Current Opinion in Pharmacology

Volume 1, Issue 1, 1 February 2001, Pages 62-65

https://doi.org/10.1016/S1471-4892(01)00005-4 Get rights and content

Abstract

Major recent findings in peripheral opioid analgesia include the relative lack of tolerance under inflammatory conditions, tetrapeptides as novel peripherally restricted compounds, the potent anti-inflammatory activity of μ and κ agonists and the identification of selectins as important molecules governing the homing of opioid cells to injured tissue. Clinical studies have now moved into the field of chronic arthritic pain, a problem of major relevance and prevalence.

Introduction

The mediation of opioid analgesic effects has long been thought to occur exclusively within the central nervous system (CNS). Around a decade ago, reports on the existence of opioid receptors outside the CNS and the generation of analgesia by these peripheral receptors began to accumulate. Such analgesic effects are particularly prominent in painful inflammatory conditions and have been demonstrated both in animals and in humans (reviewed in [1]). Opioid receptors are present on peripheral sensory nerves and are upregulated during the development of inflammation. Their endogenous ligands, opioid peptides, are expressed in resident immune cells within peripheral inflamed tissue. Environmental stimuli (stress) and releasing agents (corticotropin-releasing factor, cytokines) can liberate these opioid peptides to elicit local analgesia, whereas suppression of the immune system abolishes these effects. These findings have led to the concept that endogenous opioid peptides can be secreted from immunocytes, occupy opioid receptors on sensory nerves and produce analgesia by inhibiting the excitability of these nerves and/or the release of proinflammatory neuropeptides (reviewed in [2]). This article will focus on publications of the last two years that have extended this concept. In particular, recent studies have examined the development of tolerance, anti-inflammatory effects, novel peripherally selective agonists, inhibition of visceral pain, adhesion molecules governing the homing of opioid-containing immune cells to injured tissue, and novel therapeutic applications.

Section snippets

Peripheral opioid receptors

Anatomical, molecular and electrophysiological studies have shown that all three opioid receptors (μ, δ and κ) are expressed within sensory neurons (reviewed in [3 radical dot ]). They have been found on cell bodies in the dorsal root ganglia (DRG) and on peripheral terminals of primary afferent neurons in animals and in humans [3]. A recent study used an antibody against the cloned δ-opioid receptor (DOR) and showed this receptor on unmyelinated sensory fibers, but not on postganglionic sympathetic

Peripheral opioid receptors and inflammation

Peripheral opioid analgesic effects have been observed mainly under pathological conditions like inflammation, neuropathy, colonic distension or bone damage. Inflammation was induced using Freund's adjuvant, formalin, carrageenan or prostaglandin in subcutaneous tissue, viscera or joints (reviewed in [1], [10). During inflammation an increased axonal transport of receptors and receptor upregulation on peripheral nerve terminals is observed (for references, see [3 radical dot ]). In addition, the specific

Tolerance development

Central side effects typically associated with opioids (e.g. tolerance, dependence, respiratory depression) might be avoided by the peripherally restricted application of agonists. Tolerance, however, has also been observed in peripherally mediated opioid analgesia [11]; importantly though, the latter studies were performed in a model that does not entail inflammation. Opioid agonists were applied topically onto the uninjured skin of mouse tail and the reaction to heat stimuli (tail flick) was

Novel peripheral opioid agonists

Many conventional opioid agonists produce potent opioid receptor-mediated analgesia when adminstered locally at small, systemically inactive doses into injured tissue of rodents and humans (reviewed in [1]). Recent studies have confirmed these findings in nonhuman primates [17], [18]. Strategies to restrict the access of opioid agonists to the CNS include the incorporation of highly polar hydrophilic substituents [3 radical dot ]. Loperamide, an old drug originally developed as an antidiarrheal agent, was

Anti-inflammatory effects

An extremely intriguing feature of peripheral opioid agonists is their potential for disease-modifying anti-inflammatory activity. Evidence for such activity is accumulating in animal and human studies and the mechanisms underlying this have been examined extensively (reviewed in [3 radical dot ]). Opioids inhibit neurogenic inflammation by decreasing the release of substance P from peripheral terminals of primary afferent neurons and opioid receptors on immune cells can mediate suppression of lymphocyte

Peripheral endogenous opioid analgesia

Potent peripheral analgesia can be accomplished by the interaction of peripheral opioid receptors with opioid peptides released from immune cells [2], [3. In rat paw inflammation, mRNAs encoding pro-opiomelanocortin (POMC) and proenkephalin (PENK) and the respective opioid peptide products β-endorphin (END) and enkephalin are found in lymphocytes, monocytes and macrophages. Small amounts of dynorphin are also detectable [1], [2]. Recent studies indicate that END-producing immune cells home to

Clinical studies

Peripheral opioid actions are undoubtedly of clinical relevance. Opioid receptors on peripheral nerve terminals as well as opioid peptides have been demonstrated in human synovia [1]. A sizeable body of clinical literature has recently been reviewed and has demonstrated the analgesic efficacy of locally applied opioids in various clinical settings [35 radical dot ]. The most extensively studied clinical situation (over 50 papers in peer-reviewed journals) is the intra-articular application of opioid

Conclusions

In summary, we have discussed recent developments in the field of peripheral opioid analgesia, including localization, signaling pathways and tolerance development of peripheral opioid receptors, novel peripherally restricted agonists, anti-inflammatory effects, the migration of opioid-containing immune cells and clinical applications. Major recent findings are the localization of opioid receptors to primary afferent (but not sympathetic) neurons, the relative lack of tolerance under

Acknowledgements

The authors are supported by the Deutsche Forschungsgemeinschaft, the International Anesthesia Research Society and the National Institutes of Health. Current industrial collaborators include Ferring B.V. and EpiCept Corp.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest
of outstanding interest

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