University Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group), Division of Anaesthesia, Critical Care and Pain Management, LRI, Leicester LE1 5WW, UK
* Corresponding author. E-mail: dgl3{at}le.ac.uk
In 1998, this journal published an editorial exploring the connection between opioids and the immune system.1 In the intervening 6 yr, our understanding of the peripheral actions of the neuroimmune system has progressed markedly.2 3 The group of Christoph Stein at the Freie Universität, Berlin has been instrumental in the use of basic science approaches to produce a working mechanistic model for potential evaluation in man. Using an inflammatory model in the Wistar rat, a number of pioneering studies4 5 have described the ability of (i) the immune system to deliver endogenous opioids,6 and (ii) inflammation to stimulate delivery of opioid receptors to the site of insult, and hence produce a degree of antinociception.7
When rats are killed up to 24 h after an injection of Freund's complete adjuvant into a hind paw (which produces a local inflammatory response), these animals show an increased expression of mu-opioid receptors in the ipsilateral lumbar dorsal root ganglia,8 with an absence of increase in similar receptors in the central nervous system. This up-regulation of mu-opioid receptors can be observed by both immunochemical staining of histological specimens, and radioligand-binding experiments, carried out on dorsal root ganglia cell suspensions. At 4 days, receptor up-regulation can also be seen within laminae I and II of the lumbar dorsal horn.9 However, early infiltration of mu-opioid agonists into the inflamed paw, within 2 h of initial insult, produces little analgesia as judged by the paw pressure test (a standard behavioural test used in animal models of pain).10 This suggests a limited expression of mu-opioid receptors on primary afferent neurones in the periphery at this time.
Additional studies carried out at 96 h after administration of Freund's complete adjuvant, again utilizing similar imaging techniques, provide evidence for an increased expression of mu-opioid receptors on peripheral nerve terminals, in inflamed compared with non-inflamed tissue.11 Administration of mu-opioid agonists into the inflamed paws of these animals also elicited significant degrees of long-lived analgesia in behavioural tests, when compared with matched controls receiving saline injection, or mu-opioid agonists injected into non-inflamed paws.12
This work coupled with studies investigating the trafficking of receptors from the dorsal root ganglia to the periphery by a number of investigators,13 14 strongly suggests that mu-opioid receptors are synthesized in the dorsal root ganglia in response to inflammation, before transport along intra-axonal microtubules to peripheral sensory neurones. Here they are incorporated into the membranes of neurones and take up a functional role, capable of binding to endogenous and exogenous opioid receptor ligands where they may elicit analgesia when stimulated (Fig. 1).
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Sections of rat paw taken from animals subjected to an inflammatory insult show not only increased infiltration of white cells into the inflamed tissue, but also enhanced intracellular staining for endogenous mu-agonists (ß-endorphin, endomorphin-1, and endomorphin-2) within immune cells.6 9 Differential staining of these cells also confirmed that the initial cellular infiltration is by granulocytes followed by monocytes and macrophages and finally, T-lymphocytes. This follows the order of response expected for a typical non-specific inflammatory reaction. These findings were replicated with flow cytometric analysis of cell suspensions taken from the inflamed paws, and additionally in the case of ß-endorphin by radioimmunoassay of cell suspensions. Analysis of the paw tissue also showed that the concentration of endogenous opioids within the inflamed tissue rose in parallel with increases in white cell recruitment.6 Further experiments focusing on the blockade of a range of adhesion molecules (L-selectin, integrins 4 and ß2, and intercellular adhesion molecule-1 [ICAM-1]) involved in the passage of immune cells through the endothelium to inflamed tissue, resulted in not only a limitation of immune cell numbers at the site of inflammation, as would be expected, but also a reduction in endogenous opioids at that site.7 15
Additionally, proopioimelanocortin (the peptide precursor for ß-endorphin) and the convertases necessary for further processing have been found in immune cells, indicating expression of the gene coding for ß-endorphin.16 Collectively, these studies suggest immunocytes are capable of synthesizing and presenting endogenous opioids to sites of inflammation where opioid receptors are up-regulated, perhaps in anticipation of increased endogenous ligand presentation (Fig. 1).
Behavioural studies in animals with locally induced inflammation indicate that sympathetic stimulation causes the release of opioids from immunocytes into the surrounding tissue. This stimulation can be induced in the laboratory either by local infiltration directly into inflamed tissue of and/or ß-adrenergic compounds, or by subjecting an animal to a physiological challenge known to activate the sympathetic nervous system (commonly, a cold water swim test). In both cases, increased local concentrations of endogenous opioids result, yielding comparatively greater degrees of analgesia in inflamed compared with non-inflamed tissue. These effects can be reversed by the local infiltration of sympatholytics.17
Collectively, these well-designed studies provide a clear and coherent argument for the release of immune cell-derived opioids upon sympathetic stimulation, which on peripheral opioid receptors, have in turn been recently up-regulated in the face of local inflammation. By necessity, however, this series of experiments has been carried out in a laboratory, using small animal models of inflammation and pain. In a recent paper in this journal,18 and with this in mind, an attempt to transfer some of these findings to the clinical setting has been made. In this study, patients were randomized to receive one of four different doses of intra-articular (i.a.) morphine or placebo (0, 1, 2, or 4 mg) at the end of knee arthroscopy. Visual analogue scores (VAS), time to first rescue analgesia, and 24 h PCA opiate consumption were then recorded, and correlated with the degree of synovial inflammation and ß-endorphin content of the synovium. The investigators found no significant difference in VAS scores 1 h after operation regardless of the dose of morphine administered. They did, however, find a linear increase in time to first analgesic request with increasing i.a. morphine dose, and a reduction in total 24 h opiate requirement with increasing i.a. morphine, both of which were significant (P<0.05). Interestingly, though synovial inflammation correlated with ß-endorphin, neither had a bearing on any of the recorded indices. Elevated ß-endorphin levels produced neither a rightward shift of the doseresponse curve for i.a. morphine, an expected finding if high levels of endogenous opioids are capable of producing central tolerance,19 20 as has been suggested, nor was a leftward shift of the doseresponse curve seen, as has been recorded in stress-induced ß-endorphin release from immune cells in animal models.17 Rats injected locally with sympathomimetics or subjected to a cold water swim test, show increased response to a standard stimulus and increased concentrations of ß-endorphin in inflamed tissue. Similarly, a leftward shift of the doseresponse curve may be predicted if immunocytes were releasing a relative excess of opioids into the surrounding tissue. This paper18 therefore seems to reinforce the view that i.a. morphine is effective in providing analgesia in inflamed tissue. However, increased concentrations of endogenous opioid appear only to balance the increased nociceptive traffic associated with inflammation, rather than contributing to any additional analgesia beyond the body's own homeostatic equilibrium.
Basic scientific research of the peripheral nervous and immune systems over the past two decades has provided a clearer insight into the workings of both systems, and while at this moment in time there is little evidence to support a clinically advantageous effect of endogenous opioids in the control of inflammatory pain, a number of studies have lent credence to the opinion that peripherally administered exogenous opioids can produce analgesia, in medically relevant scenarios,2124 by their action on peripherally expressed opioid receptors. Perhaps more exciting, however, is the potential for manipulation of the immune system to provide a means of endogenous opioid delivery. Observations in our own laboratories and others have indicated a link between immune cell delivery of nociceptin25 26 (a novel endogenous opioid/receptor system first described in the mid 1990s), vascular reactivity,2729 and immunocyte sequestration30 in animal models of inflammation. These observations of opioid and immunocyte physiology and pharmacology make it increasingly clear that a peripheral, as well as central, neuralimmune axis may have clinical relevance to anaesthetic practice today.
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