Stress induces analgesia by mechanisms within and outside the brain. Here we show that the sympathetic nervous system is an essential trigger of intrinsic opioid analgesia within peripheral injured tissue. Noradrenaline, injected directly into inflamed hind paws of male Wistar rats, produced dose-dependent antinociception, reversible by alpha(1)-, alpha(2)- and beta(2)-antagonists. alpha(1)-, alpha(2)- and beta(2)-adrenergic receptors were demonstrated on beta-endorphin-containing immune cells and noradrenaline induced adrenergic receptor-specific release of beta-endorphin from immune cell suspensions. This antinociceptive effect of noradrenaline was reversed by micro - and delta-opioid antagonists as well as by anti-beta-endorphin. Stress-induced peripheral analgesia was abolished by chemical sympathectomy and by adrenergic antagonists. These findings indicate that sympathetic neuron-derived noradrenaline stimulates adrenergic receptors on inflammatory cells to release beta-endorphin, which induces analgesia via activation of peripheral opioid receptors.

Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral μ-opioid receptors (μ-receptors) in the presence of painful CFA-induced paw inflammation. In sensory neurons of these animals, internalization of μ-receptors was significantly increased and G protein coupling of μ-receptors as well as inhibition of cAMP accumulation were preserved. Opioid receptor trafficking and signaling were reduced, and tolerance was restored when endogenous opioid peptides in inflamed tissue were removed by antibodies or by depleting opioid-producing granulocytes, monocytes, and lymphocytes with cyclophosphamide (CTX). Our data indicate that the continuous availability of endogenous opioids in inflamed tissue increases recycling and preserves signaling of μ-receptors in sensory neurons, thereby counteracting the development of peripheral opioid tolerance. These findings infer that the use of peripherally acting opioids for the prolonged treatment of inflammatory pain associated with diseases such as chronic arthritis, inflammatory neuropathy, or cancer, is not necessarily accompanied by opioid tolerance. IntroductionOpioids are the most widely used drugs in acute and chronic pain. Long-term application of opioids can result in pharmacological tolerance in animals, i.e., a decreased effect with prolonged administration of a constant dose (1, 2). However, surprisingly little data document opioid tolerance in humans (3, 4). Some clinical publications claim that opioid tolerance does not develop frequently in patients with chronic pain resulting from cancer (5, 6) or nonmalignant tissue injury (7,8), both of which are usually accompanied by inflammation. In inflammatory pain a substantial component of opioid analgesia is mediated via opioid receptors on peripheral sensory neurons (9, 10). Consequently, we chose to examine the development of tolerance at peripheral μ-opioid receptors (μ-receptors) in animals with and without chronic inflammatory pain.Regulation of intracellular receptor trafficking is of fundamental importance for the function of opioid receptors. Receptor internalization and recycling to the membrane following agonist exposure is a well-documented response for a wide variety of G protein coupled receptors (11) and has been proposed to underlie the rapid recovery of opioid responsiveness after acute agonist application (12). The enhancement of opioid receptor recycling provides receptor recuperation and counteracts the development of opioid tolerance (13). However, there are differences between ligands and between in vitro and in vivo conditions. For example, morphine-activated opioid receptors in heterologous cells (14) and neurons (15) are relatively resistant to this regulatory process. Potential mechanisms include ...

FE 200665 is a peripherally selective kappa-agonist with potent analgesic and antiinflammatory properties that may lead to improved analgesic-antiinflammatory therapy compared with centrally acting opioids or standard nonsteroidal antiinflammatory drugs.

1 Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-eect and time-dependence relationships of a new peripherally selective k agonist, asimadoline, in rats with adjuvant arthritis. 2 The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely eective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg 71 day 71 , i.p.) throughout the disease or during its early phase; treatment was less successful if con®ned to the latter stages. Ten fold higher doses were eective orally. 3 Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the k-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic eects of asimadoline (5 mg kg 71 day 71 ), indicating that asimadoline acts through peripheral k-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic eects of the highest dose of asimadoline (40 mg kg 71 day 71 ), suggesting a loss of k-selectivity at this dose. 4 Asimadoline also exhibited analgesic eects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that in¯ammation is necessary for asimadoline-induced analgesia. 5 These data con®rm our previous ®ndings that k-opioids possess anti-arthritic properties and that these eects are mediated via peripheral k-receptors. The present results are new in showing that the peripherally acting k-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side eects, herald new treatments for rheumatoid arthritis.

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