Showing papers by "Christoph Stein published in 1997"

Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats.

Abstract: Localized inflammation of a rat's hindpaw elicits an accumulation of beta-endorphin-(END) containing immune cells. We investigated the production, release, and antinociceptive effects of lymphocyte-derived END in relation to cell trafficking. In normal animals, END and proopiomelanocortin mRNA were less abundant in circulating lymphocytes than in those residing in lymph nodes (LN), suggesting that a finite cell population produces END and homes to LN. Inflammation increased proopiomelanocortin mRNA in cells from noninflamed and inflamed LN. However, END content was increased only in inflamed paw tissue and noninflamed LN-immune cells. Accordingly, corticotropin-releasing factor and IL-1beta released significantly more END from noninflamed than from inflamed LN-immune cells. This secretion was receptor specific, calcium dependent, and mimicked by potassium, consistent with vesicular release. Finally, both agents, injected into the inflamed paw, induced analgesia which was blocked by the co-administration of antiserum against END. Together, these findings suggest that END-producing lymphocytes home to inflamed tissue where they secrete END to reduce pain. Afterwards they migrate to the regional LN, depleted of the peptide. Consistent with this notion, immunofluorescence studies of cell suspensions revealed that END is contained predominantly within memory-type T cells. Thus, the immune system is important for the control of inflammatory pain. This has implications for the understanding of pain in immunosuppressed conditions like cancer or AIDS.

Peripheral morphine analgesia.

Abstract: Traditionally, opioid analgesia has been attributed to the activation of opioid receptors exclusively within the central nervous system. In fact, standard text books still teach medical students that opioids are the prototypes of centrally acting analgesic drugs (Reisine and Pasternak, 1996). Over the past 15 years, however, a large number of studies have discovered and characterized potent peripheral opioid actions. Such effects occur primarily in inflamed but also in normal tissue (Antonijevic et al., 1995), and were demonstrated both in animal experiments and under clinical conditions in patients. Judged by standard pharmacological criteria (e.g., reversibility by antagonists, dose-dependency and stereospecificity), most investigations support the occurrence of opioid receptor-specific effects at peripheral sites. All three opioid receptor types (mu, delta, kappa) can be functionally active in peripheral tissues (Barber and Gottschlich, 1992; Stein, 1993). The mechanisms underlying these peripheral effects have been elucidated to some extent during the past few years. Opioid receptors have been demonstrated on peripheral terminals of thinly myelinated and unmyelinated sensory nerves in animals (Hassan et al., 1993; Stein, 1995) and in humans (Stein et al., 1996), and opioid receptor messenger ribonucleic acid (mRNA) has been detected in dorsal root ganglia (Scha ̈fer et al., 1995). These findings are in line with functional studies indicating that C-fiber neurons mediate the peripheral antinociceptive effects of morphine. Following the occupation of these neuronal opioid receptors by an agonist, the excitability of the nociceptive input terminal or the propagation of action potentials is attenuated and the peripheral release of excitatory neuropeptides (e.g., substance P) is inhibited. These events may account not only for the antinociceptive but also for the antiinflammatory actions of opioids in peripheral tissues (Yaksh, 1988; Barber and Gottschlich, 1992; Stein, 1995). An interesting phenomenon is the enhanced efficacy of peripherally applied opioids in inflammation. One possible explanation is that opioid agonists have easier access to neuronal opioid receptors because the perineurium (a normally rather impermeable barrier sheath encasing peripheral nerve fibers) is disrupted (Antonijevic et al., 1995). In addition, previously inactive neuronal opioid receptors may undergo changes in the inflammatory milieu and be rendered active. At later stages of an inflammatory process, the peripherally directed axonal transport of opioid receptors in nerve fibers is enhanced, which leads to an increase in their number (upregulation) on peripheral nerve terminals (Hassan et al., 1993; Scha ̈fer et al., 1995). Together, these factors may account for the dramatically increased efficacy of locally administered exogenous opioids in inflamed tissue. Endogenous ligands of peripheral opioid receptors, opioid peptides (endorphin, enkephalin, dynorphin), and their respective mRNAs have also been discovered in inflamed tissue. These peptides are produced by immune cells including Tand B-lymphocytes, monocytes and macrophages (Stein, 1995). Upon release, these opioid peptides interact with their receptors on nociceptive neurons to produce endogenous analgesia. This release can be elicited by corticotropin releasing factor and interleukin-1 b (Schäfer et al., 1994, 1996). Such endogenous peripheral opioid effects have also been described in humans. Opioid peptides were detected in human inflamed synovia (Stein et al., 1996) and, following the intraarticular administration of the opioid antagonist naloxone, patients with opioidcontaining synovitis had more severe pain after knee surgery (Stein et al., 1993). This shows that the endogenous opioids normally exert potent tonic pain control. Interestingly, these opioid peptides do not interfere with exogenous agonists, i.e., intraarticular morphine has equally potent analgesic effects in patients with and without opioidPain 71 (1997) 119–121

Opioid treatment of chronic nonmalignant pain.

Abstract: T he use nating lished of opiates to manage chronic pain origifrom cancer or its treatment is well estabclinical practice founded on a number of controlled clinical studies (1,2). Recently, the treatment of various nonmalignant chronic pain syndromes with opioids has been proposed based on an accumulation of case reports and uncontrolled open studies (3-10). In some of those reports, the authors are remarkably enthusiastic, but in others the conclusions are rather cautious (3,11,12). The only consensus is that opioid tolerance, physical dependence or addiction seldom cause difficulties (6). With regard to the efficacy of opioid treatment, however, many authors merely conclude either that only a small subpopulation of patients with chronic noncancer pain obtain partial pain reduction (ll), or that opioids neither substantially improve nor undermine the patient’s function (5). With regard to side effects, some uncontrolled reports neither demonstrate nor exclude a risk of neuropsychologic impairment and other untoward effects (5). A preliminary controlled study shows significantly disabled cognitive and psychomotor functioning, as well as typical opioid side effects such as constipation and nausea (13). Thus, the conclusions from these preliminary and uncontrolled reports are ambivalent at best. The aim of this article is to review the available controlled studies that have examined the efficacy and/ or adverse side effects of opioids in chronic nonmalignant pain.

Method of enhancing the analgesic efficacy of locally and topically administered opioids and other local anesthetics

Abstract: The present invention is a method for enhancing the analgesic efficacy of a locally applied opioid analgesic or local anesthetic agent in a mammal having an impermeable perineurium barrier sheet about the peripheral sensory nerves at the site of action of the analgesic or anesthetic agent. The method involves applying to that site an effective amount of the analgesic or anesthetic agent dissolved in a hyperosmolar solution having an osmolality of above 300 mOsm/l.

Antinociceptive effects of dynorphin peptides in a model of inflammatory pain.

Abstract: Dynorphin A (DYN) peptides, administered into the central nervous system, have produced inconsistent analgesic actions in tests using thermal stimuli. This study examined antinociceptive effects of intravenous and intraplantar DYN-(2-17) against noxious pressure in rats with Freund's adjuvant-induced unilateral hindpaw inflammation. The effects of DYN-(2-17) were compared to those of the opioid agonists morphine. (D-Ala2,N-Methyl-Phe4,Gly-ol5)-enkephalin (DAMGO) and DYN-(1-17). Intravenous DYN-(2-17) (0.188-10 mg/kg) produced dose-dependent elevations of paw pressure thresholds in inflamed and in non-inflamed paws. These effects were similar in magnitude to those of subcutaneous morphine (2 mg/kg), at doses of 0.375-1.5 mg/kg they were significantly greater on the inflamed (right) than on the non-inflamed (left) paw, and they were not reversible by intravenous naloxone (1-10 mg/kg). Intraplantar Dyn-(2-17)(0.001-0.3 mg) was ineffective, whereas both intraplantar DYN-(1-17)(0.15-0.3 mg) and DAMGO (0.008-0.016 mg) produced dose-dependent and naloxone-reversible elevations of paw pressure thresholds. The intraplantar injection of both Dyn peptides produced a transient increase in the volume of non-inflamed paws. These findings suggest that intravenous DYN-(2-17) produces possibly centrally mediated, non-opioid antinociceptive effects against noxious pressure. At certain doses these effects are more potent in inflamed than in non-inflamed paws. In contrast to the opioid peptides DYN-(1-17) and DAMGO, DYN-(2-17) does not appear to have no peripheral antinociceptive actions.

Peripheral opioid analgesia: Basic and clinical aspects*

Abstract: T RADITIONALLY, analgesics have been divided into two groups: centrallyand peripherally-acting compounds. Typical representatives of centrally-acting compounds are opioids (eg, morphine), which are known to act on opioid receptors in the brain and spinal cord. Typical examples of peripherally-acting compounds are nonsteroidal anti-inflammatory drugs (NSAIDs; eg, aspirin), which are thought to act by inhibition of cyclooxygenase in peripheral tissues. This strict distinction has been challenged by recent advances in pharmacological research. Not only have opioids been found to elicit local analgesic effects in peripheral tissue, but conversely, NSAIDs have been shown to act within the central nervous system. Anecdotal reports of local opioid effects appeared a century ago. 1 Nonetheless, until very recently, the majority of these reports have been discounted, largely because of a lack of scientific scrutiny. Renewed interest in these former ideas has been spurred by the untoward side effects of all these agents. Well-known examples are respiratory depression, dependence, sedation, itch, nausea, and dysphoria in the case of opioids and coagulation defects, gastrointestinal bleeding, and liver and kidney toxicity in the case of NSAIDs. Opioids are generally accepted as the more potent class of analgesics and are accordingly used in more severely painful conditions (eg, trauma, myocardial infarction, and intraoperative, postoperative, and malignancy-related pain). The ideal drug of the future would, of course, combine the advantages of both classes while avoiding their disadvantages. For example,

Schmerz in der postoperativen Phase Medizinische und ökonomische Aspekte

Abstract: Akuter Schmerz kann schadliche Wirkungen auf beinahe jedes Organsystem im Korper ausuben. Storungen des respiratorischen, kardiovaskularen und neuroendokrinen Systems sind unmittelbar erkennbar. Nicht sofort erkennbar sind Veranderungen in der Genexpression von Neuropeptiden, Zytokinen, Wachstumsfaktoren, u.a. Diese konnen zu Storungen fuhren, die spater einsetzen und langer andauern. Interaktionen zwischen dem Immun- und Nervensystem tragen gleichermasen zur Entstehung wie auch zur Kontrolle des Entzundungsschmerzes bei. Ein Gewebstrauma triggert eine Kaskade an lokalen Vorgangen, die in einer erhohten Sensibilitat und Schmerzhaftigkeit resultieren. Etwa zur gleichen Zeit werden Mechanismen aktiviert, die dieser Entwicklung entgegenwirken. Sie fuhren durch zentrale wie auch lokale Wirkungen von endogenen Opioidpeptiden zu einer zunehmenden Inhibition des Entzundungsschmerzes. Der Ubergang von akutem in chronischen Schmerz hangt moglicherweise einerseits von Storungen dieser intrinsischen Kontrollmechanismen, andererseits von dem rechtzeitigen Einsetzen wirkungsvoller Therapiemasnahmen ab.

Novel peripheral mechanisms of opioid analgesia

Abstract: dickenson briefly mentions that peripheral opioid receptors somehow become active following inflammation and that the appearance of endogenous opioid peptides at the injury site may be related to immune cell proliferation. Recent findings elucidate the underlying mechanisms in more detail and provide an incentive for the development of a novel generation of analgesics devoid of typical central opioid side effects.