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Attacking pain at its source: new perspectives on opioids

Nature Medicine volume 9, pages 1003–1008 (2003)Cite this article

Abstract

The treatment of severe pain with opioids has thus far been limited by their unwanted central side effects. Recent research promises new approaches, including opioid analgesics acting outside the central nervous system, targeting of opioid peptide–containing immune cells to peripheral damaged tissue, and gene transfer to enhance opioid production at sites of injury.

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Figure 1: Opioid receptor transport and signaling in primary afferent neurons.

Zeichnung © Christine Voigts-Grafik/UKBF Berlin

Figure 2: Migration of opioid-producing cells and opioid secretion within inflamed tissue.

Zeichnung © Christine Voigts-Grafik/UKBF Berlin

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References

  1. Kieffer, B.L. & Gaveriaux-Ruff, C. Exploring the opioid system by gene knockout. Prog. Neurobiol. 66, 285–306 (2002).

    CAS  PubMed  Google Scholar 

  2. Brower, V. New paths to pain relief. Nat. Biotechnol. 18, 387–391 (2000).

    CAS  PubMed  Google Scholar 

  3. Machelska, H. & Stein, C. Immune mechanisms in pain control. Anesth. Analg. 95, 1002–1008 (2002).

    CAS  PubMed  Google Scholar 

  4. Pan, Z.Z. Mu-opposing actions of the kappa-opioid receptor. Trends Pharmacol. Sci. 19, 94–98 (1998).

    CAS  PubMed  Google Scholar 

  5. Stein, C., Machelska, H. & Schäfer, M. Peripheral analgesic and antiinflammatory effects of opioids. Z. Rheumatol. 60, 416–424 (2001).

    CAS  PubMed  Google Scholar 

  6. Fields, H.L., Emson, P.C., Leigh, B.K., Gilbert, R.F.T. & Iversen, L.L. Multiple opiate receptor sites on primary afferent fibres. Nature 284, 351–353 (1980).

    CAS  PubMed  Google Scholar 

  7. Young, I., W.S., Wamsley, J.K., Zarbin, M.A. & Kuhar, M.J. Opioid receptors undergo axonal flow. Science 210, 76–77 (1980).

    CAS  PubMed  Google Scholar 

  8. Hassan, A.H.S., Ableitner, A., Stein, C. & Herz, A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 55, 185–195 (1993).

    CAS  PubMed  Google Scholar 

  9. Mousa, S.A., Zhang, Q., Sitte, N., Ji, R. & Stein, C. Beta-endorphin-containing memory-cells and mu-opioid receptors undergo transport to peripheral inflamed tissue. J. Neuroimmunol. 115, 71–78 (2001).

    CAS  PubMed  Google Scholar 

  10. Truong, W., Cheng, C., Xu, Q.G., Li, X.Q. & Zochodne, D.W. Mu opioid receptors and analgesia at the site of a peripheral nerve injury. Ann. Neurol. 53, 366–375 (2003).

    CAS  PubMed  Google Scholar 

  11. Stein, C. et al. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc. Natl. Acad. Sci. USA 87, 5935–5939 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Coggeshall, R.E., Zhou, S. & Carlton, S.M. Opiate receptors on peripheral sensory axons. Brain Res. 764, 126–132 (1997).

    CAS  PubMed  Google Scholar 

  13. Wenk, H.N. & Honda, C.N. Immunohistochemical localization of delta opioid receptors in peripheral tissues. J. Comp. Neurol. 408, 567–579 (1999).

    CAS  PubMed  Google Scholar 

  14. Stein, C. et al. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J. Clin. Invest. 98, 793–799 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pare, M., Elde, R., Mazurkiewicz, J.E., Smith, A.M. & Rice, F.L. The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties. J. Neurosci. 21, 7236–7246 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Poonyachoti, S., Kulkarni-Narla, A. & Brown, D.R. Chemical coding of neurons expressing delta- and kappa-opioid receptor and type I vanilloid receptor immunoreactivities in the porcine ileum. Cell Tissue Res. 307, 23–33 (2002).

    CAS  PubMed  Google Scholar 

  17. Minami, M., Maekawa, K., Yabuuchi, K. & Satoh, M. Double in situ hybridization study on coexistence of mu-, delta- and kappa-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia. Brain Res. Mol. Brain Res. 30, 203–210 (1995).

    CAS  PubMed  Google Scholar 

  18. Borgland, S.L., Connor, M. & Christie, M.J. Nociceptin inhibits calcium channel currents in a subpopulation of small nociceptive trigeminal ganglion neurons in mouse. J. Physiol. 536, 35–47 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou, L., Zhang, Q., Stein, C. & Schäfer, M. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J. Pharmacol. Exp. Ther. 286, 1000–1006 (1998).

    CAS  PubMed  Google Scholar 

  20. Pertovaara, A. & Wei, H. Peripheral effects of morphine in neuropathic rats: role of sympathetic postganglionic nerve fibers. Eur. J. Pharmacol 429, 139–145 (2001).

    CAS  PubMed  Google Scholar 

  21. Zöllner, C. et al. Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol. Pharmacol. (in the press).

  22. Lewanowitsch, T. & Irvine, R.J. Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal. Eur. J. Pharmacol. 445, 61–67 (2002).

    CAS  PubMed  Google Scholar 

  23. Shannon, H.E. & Lutz, E.A. Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats. Neuropharmacol. 42, 253–261 (2002).

    CAS  Google Scholar 

  24. King, M., Su, W., Chang, A., Zuckerman, A. & Pasternak, G.W. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat. Neurosci. 4, 268–274 (2001).

    CAS  PubMed  Google Scholar 

  25. Jiang, M. et al. Multiple neurological abnormalities in mice deficient in the G protein Go . Proc. Natl. Acad. Sci. USA 95, 3269–3274 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Taddese, A., Nah, S.-Y. & McCleskey, E.W. Selective opioid inhibition of small nociceptive neurons. Science 270, 1366–1369 (1995).

    CAS  PubMed  Google Scholar 

  27. Akins, P.T. & McCleskey, E.W. Characterization of potassium currents in adult rat sensory neurons and modulation by opioids and cyclic AMP. Neuroscience 56, 759–769 (1993).

    CAS  PubMed  Google Scholar 

  28. Ingram, S.L. & Williams, J.T. Opioid inhibition of Ih via adenylyl cyclase. Neuron 13, 179–186 (1994).

    CAS  PubMed  Google Scholar 

  29. Gold, M.S. & Levine, J.D. DAMGO inhibits prostaglandin E2-induced potentiation of a TTX-resistant Na+ current in rat sensory neurons in vitro. Neurosci. Lett. 212, 83–86 (1996).

    CAS  PubMed  Google Scholar 

  30. Laird, J.M., Souslova, V., Wood, J.N. & Cervero, F. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J. Neurosci. 22, 8352–8356 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Porreca, F. et al. A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc. Natl. Acad. Sci. USA 96, 7640–7644 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Stein, C. Peripheral mechanisms of opioid analgesia. Anesth. Analg. 76, 182–191 (1993).

    CAS  PubMed  Google Scholar 

  33. Walker, J., Catheline, G., Guilbaud, G. & Kayser, V. Lack of cross-tolerance between the antinociceptive effects of systemic morphine and asimadoline, a peripherally-selective kappa-opioid agonist, in CCI-neuropathic rats. Pain 83, 509–516 (1999).

    CAS  PubMed  Google Scholar 

  34. Kalso, E., Smith, L., McQuay, H.J. & Moore, R.A. No pain, no gain: clinical excellence and scientific rigour—lessons learned from IA morphine. Pain 98, 269–275 (2002).

    CAS  PubMed  Google Scholar 

  35. Kraus, J. et al. Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site. J. Biol. Chem. 276, 43901–43908 (2001).

    CAS  PubMed  Google Scholar 

  36. Borner, C., Höllt, V. & Kraus, J. Involvement of activator protein-1 in transcriptional regulation of the human mu-opioid receptor gene. Mol. Pharmacol. 61, 800–805 (2002).

    CAS  PubMed  Google Scholar 

  37. Ji, R.-R. et al. Expression of μ-, δ-, and κ-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J. Neurosci. 15, 8156–8166 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Jeanjean, A.P., Moussaoui, S.M., Maloteaux, J.-M. & Laduron, P.M. Interleukin-1β induces long-term increase of axonally transported opiate receptors and substance P. Neuroscience 68, 151–157 (1995).

    CAS  PubMed  Google Scholar 

  39. Selley, D.E., Breivogel, C.S. & Childers, S.R. Modification of G protein-coupled functions by low pH pretreatment of membranes from NG108-15 cells: increase in opioid agonist efficacy by decreased inactivation of G proteins. Mol. Pharmacol. 44, 731–741 (1993).

    CAS  PubMed  Google Scholar 

  40. Antonijevic, I., Mousa, S.A., Schäfer, M. & Stein, C. Perineurial defect and peripheral opioid analgesia in inflammation. J. Neurosci. 15, 165–172 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Picard, P.R., Tramer, M.R., McQuay, H.J. & Moore, R.A. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 72, 309–318 (1997).

    CAS  PubMed  Google Scholar 

  42. Murphy, D.B., McCartney, C.J. & Chan, V.W. Novel analgesic adjuncts for brachial plexus block: a systematic review. Anesth. Analg. 90, 1122–1128 (2000).

    CAS  PubMed  Google Scholar 

  43. Schulte-Steinberg, H. et al. Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy. Anesthesiology 82, 634–640 (1995).

    CAS  PubMed  Google Scholar 

  44. Likar, R. et al. Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J. Pain Symptom Manage. 21, 330–337 (2001).

    CAS  PubMed  Google Scholar 

  45. Aley, K.O., Green, P.G. & Levine, J.D. Opioid and adenosine peripheral antinociception are subject to tolerance and withdrawal. J. Neurosci. 15, 8031–8038 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kolesnikov, Y. & Pasternak, G.W. Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl-D-aspartate antagonist. J. Pharmacol. Exp. Ther. 290, 247–252 (1999).

    CAS  PubMed  Google Scholar 

  47. Honore, P., Catheline, G., Le Guen, S. & Besson, J.M. Chronic treatment with systemic morphine induced tolerance to the systemic and peripheral antinociceptive effects of morphine on both carrageenin induced mechanical hyperalgesia and spinal c-Fos expression in awake rats. Pain 71, 99–108 (1997).

    CAS  PubMed  Google Scholar 

  48. Nozaki-Taguchi, N. & Yaksh, T.L. Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist-loperamide. Anesthesiology 90, 225–234 (1999).

    CAS  PubMed  Google Scholar 

  49. Ferreira, S.H., Lorenzetti, B.B. & Rae, G.A. Is methylnalorphinium the prototype of an ideal peripheral analgesic. Eur. J. Pharmacol. 99, 23–29 (1984).

    CAS  PubMed  Google Scholar 

  50. Ueda, H. & Inoue, M. Peripheral morphine analgesia resistant to tolerance in chronic morphine-treated mice. Neurosci. Lett. 266, 105–108 (1999).

    CAS  PubMed  Google Scholar 

  51. Kieffer, B.L. & Evans, C.J. Opioid tolerance - in search of the holy grail. Cell 108, 587–590 (2002).

    CAS  PubMed  Google Scholar 

  52. Smith, E.M. Opioid peptides in immune cells. Adv. Exp. Med. Biol. 521, 51–68 (2003).

    CAS  PubMed  Google Scholar 

  53. Cabot, P.J. et al. Immune cell-derived β-endorphin: production, release and control of inflammatory pain in rats. J. Clin. Invest. 100, 142–148 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Cabot, P.J., Carter, L., Schäfer, M. & Stein, C. Methionine-enkephalin- and Dynorphin A-release from immune cells and control of inflammatory pain. Pain 93, 207–212 (2001).

    CAS  PubMed  Google Scholar 

  55. Stein, C., Hassan, A.H.S., Lehrberger, K., Giefing, J. & Yassouridis, A. Local analgesic effect of endogenous opioid peptides. Lancet 342, 321–324 (1993).

    CAS  PubMed  Google Scholar 

  56. Rittner, H.L. et al. Opioid peptide-expressing leukocytes: identification, recruitment, and simultaneously increasing inhibition of inflammatory pain. Anesthesiology 95, 500–508 (2001).

    CAS  PubMed  Google Scholar 

  57. Mousa, S.A., Machelska, H., Schäfer, M. & Stein, C. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J. Neuroimmunol. 126, 5–15 (2002).

    CAS  PubMed  Google Scholar 

  58. von Andrian, U.H. & Mackay, C.R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

    CAS  PubMed  Google Scholar 

  59. Mousa, S.A., Machelska, H., Schäfer, M. & Stein, C. Co-expression of beta-endorphin with adhesion molecules in a model of inflammatory pain. J. Neuroimmunol. 108, 160–170 (2000).

    CAS  PubMed  Google Scholar 

  60. Machelska, H. et al. Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1. J. Neurosci. 22, 5588–5596 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Machelska, H., Cabot, P.J., Mousa, S.A., Zhang, Q. & Stein, C. Pain control in inflammation governed by selectins. Nat. Med. 4, 1425–1428 (1998).

    CAS  PubMed  Google Scholar 

  62. Schäfer, M., Carter, L. & Stein, C. Interleukin-1β and corticotropin-releasing-factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proc. Natl. Acad. Sci. USA 91, 4219–4223 (1994).

    PubMed  PubMed Central  Google Scholar 

  63. Schäfer, M., Mousa, S.A., Zhang, Q., Carter, L. & Stein, C. Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia. Proc. Natl. Acad. Sci. USA 93, 6096–6100 (1996).

    PubMed  PubMed Central  Google Scholar 

  64. Schmitt, T.K. et al. Modulation of peripheral endogenous opioid analgesia by central afferent blockade. Anesthesiology 98, 195–202 (2003).

    CAS  PubMed  Google Scholar 

  65. Parsons, C.G., Czlonkowski, A., Stein, C. & Herz, A. Peripheral opioid receptors mediating antinociception in inflammation. Activation by endogenous opioids and role of the pituitary-adrenal axis. Pain 41, 81–93 (1990).

    CAS  PubMed  Google Scholar 

  66. Khodorova, A. et al. Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat. Med. 9, 1055–1061 (2003).

    CAS  PubMed  Google Scholar 

  67. Braz, J. et al. Therapeutic efficacy in experimental polyarthritis of viral-driven enkephalin overproduction in sensory neurons. J. Neurosci. 21, 7881–7888 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Barber, A. et al. A pharmacological profile of the novel, peripherally-selective κ-opioid receptor agonist, EMD 61753. Br. J. Pharmacol. 113, 1317–1327 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Jonker, J.W. et al. Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug. Br. J. Pharmacol. 127, 43–50 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. DeHaven-Hudkins, D.L. et al. Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J. Pharmacol. Exp. Ther. 289, 494–502 (1999).

    CAS  PubMed  Google Scholar 

  71. Sandner-Kiesling, A. et al. Effect of kappa opioid agonists on visceral nociception induced by uterine cervical distension in rats. Pain 96, 13–22 (2002).

    CAS  PubMed  Google Scholar 

  72. Eisenach, J.C., Carpenter, R. & Curry, R. Analgesia from a peripherally active κ-opioid receptor agonist in patients with chronic pancreatitis. Pain 101, 89–95 (2003).

    CAS  PubMed  Google Scholar 

  73. Binder, W. et al. Analgesic and antiinflammatory effects of two novel kappa opioid peptides. Anesthesiology 94, 1034–1044 (2001).

    CAS  PubMed  Google Scholar 

  74. Stein, C., Millan, M.J., Shippenberg, T.S., Peter, K. & Herz, A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J. Pharmacol. Exp. Ther. 248, 1269–1275 (1989).

    CAS  PubMed  Google Scholar 

  75. Machelska, H. et al. Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans. J. Pharmacol. Exp. Ther. 290, 354–361 (1999).

    CAS  PubMed  Google Scholar 

  76. Averbeck, B., Reeh, P.W. & Michaelis, M. Modulation of CGRP and PGE2 release from isolated rat skin by alpha-adrenoceptors and kappa-opioid-receptors. Neuroreport 12, 2097–2100 (2001).

    CAS  PubMed  Google Scholar 

  77. Yaksh, T.L. Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res. 458, 319–324 (1988).

    CAS  PubMed  Google Scholar 

  78. Chao, C.C., Molitor, T.W., Close, K., Hu, S. & Peterson, P.K. Morphine inhibits the release of tumor necrosis factor in human peripheral blood mononuclear cell cultures. Int. J. Immunopharmacol. 15, 447–453 (1993).

    CAS  PubMed  Google Scholar 

  79. Wilson, J.L., Walker, J.S., Antoon, J.S. & Perry, M.A. Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats: inhibition by kappa-opioid agonist but not by NSAID. J. Rheumatol. 25, 499–505 (1998).

    CAS  PubMed  Google Scholar 

  80. Sengupta, J.N., Snider, A., Su, X. & Gebhart, G.F. Effects of kappa opioids in the inflamed rat colon. Pain 79, 175–185 (1999).

    CAS  PubMed  Google Scholar 

  81. Houghton, A.K., Valdez, J.G. & Westlund, K.N. Peripheral morphine administration blocks the development of hyperalgesia and allodynia after bone damage in the rat. Anesthesiology 89, 190–201 (1998).

    CAS  PubMed  Google Scholar 

  82. Likar, R. et al. Intraarticular morphine analgesia in chronic pain patients with osteoarthritis. Anesth. Analg. 84, 1313–1317 (1997).

    CAS  PubMed  Google Scholar 

  83. Stein, A., Yassouridis, A., Szopko, C., Helmke, K. & Stein, C. Intraarticular morphine versus dexamethasone in chronic arthritis. Pain 83, 525–532 (1999).

    CAS  PubMed  Google Scholar 

  84. Khoury, G.F., Chen, A.C.N., Garland, D.E. & Stein, C. Intraarticular morphine, bupivacaine and morphine/bupivacaine for pain control after knee videoarthroscopy. Anesthesiology 77, 263–266 (1992).

    CAS  PubMed  Google Scholar 

  85. Reuben, S.S. et al. Local administration of morphine for analgesia after iliac bone graft harvest. Anesthesiology 95, 390–394 (2001).

    CAS  PubMed  Google Scholar 

  86. Peyman, G.A., Rahimy, M.H. & Fernandes, M.L. Effects of morphine on corneal sensitivity and epithelial wound healing: implications for topical ophthalmic analgesia. Br. J. Ophthalmol. 78, 138–141 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Duckett, J.W., Cangiano, T., Cubina, M., Howe, C. & Cohen, D. Intravesical morphine analgesia after bladder surgery. J. Urol. 157, 1407–1409 (1997).

    CAS  PubMed  Google Scholar 

  88. Rorarius, M. et al. Peripherally administered sufentanil inhibits pain perception after postpartum tubal ligation. Pain 79, 83–88 (1999).

    CAS  PubMed  Google Scholar 

  89. Rosseland, L.A., Stubhaug, A., Skoglund, A. & Breivik, H. Intra-articular morphine for pain relief after knee arthroscopy. Acta Anaesthesiol. Scand. 43, 252–257 (1999).

    CAS  PubMed  Google Scholar 

  90. Bickel, A. et al. Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man. Pain 76, 317–325 (1998).

    CAS  PubMed  Google Scholar 

  91. Polydefkis, M. et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 58, 115–119 (2002).

    CAS  PubMed  Google Scholar 

  92. Lu, C.Y. et al. Gene-gun particle with pro-opiomelanocortin cDNA produces analgesia against formalin-induced pain in rats. Gene Ther. 9, 1008–1014 (2002).

    CAS  PubMed  Google Scholar 

  93. Taguchi, A. et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N. Engl. J. Med. 345, 935–940 (2001).

    CAS  PubMed  Google Scholar 

  94. Simonin, F. & Kieffer, B.L. Two faces for an opioid peptide - and more receptors for pain research. Nat. Neurosci. 5, 185–186 (2002).

    CAS  PubMed  Google Scholar 

  95. Stein, C., Millan, M.J., Shippenberg, T.S. & Herz, A. Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neurosci. Lett. 84, 225–228 (1988).

    CAS  PubMed  Google Scholar 

  96. Stein, C. et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N. Engl. J. Med. 325, 1123–1126 (1991).

    CAS  PubMed  Google Scholar 

  97. Joris, J.L., Dubner, R. & Hargreaves, K.M. Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation? Anesth. Analg. 66, 1277–1281 (1987).

    CAS  PubMed  Google Scholar 

  98. Koppert, W. et al. Peripheral antihyperalgesic effect of morphine to heat, but not mechanical, stimulation in healthy volunteers after ultraviolet-B irradiation. Anesth. Analg. 88, 117–122 (1999).

    CAS  PubMed  Google Scholar 

  99. Likar, R., Kapral, S., Steinkellner, H., Stein, C. & Schäfer, M. Dose-dependency of intra-articular morphine analgesia. Br. J. Anaesth. 83, 241–244 (1999).

    CAS  PubMed  Google Scholar 

  100. Dionne, R.A. et al. Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation. Clin. Pharmacol. Ther. 70, 66–73 (2001).

    CAS  PubMed  Google Scholar 

  101. Moiniche, S., Dahl, J.B. & Kehlet, H. Peripheral antinociceptive effects of morphine after burn injury. Acta Anaesthesiol. Scand. 37, 710–712 (1993).

    CAS  PubMed  Google Scholar 

  102. Binder, W., Carmody, J. & Walker, J. Effect of gender on anti-inflammatory and analgesic actions of two kappa-opioids. J. Pharmacol. Exp. Ther. 292, 303–309 (2000).

    CAS  PubMed  Google Scholar 

  103. Krajnik, M., Zylicz, Z., Finlay, I., Luczak, J. & van Sorge, A.A. Potential uses of topical opioids in palliative care—report of 6 cases. Pain 80, 121–125 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. Voigts for the preparation of the illustrations, and B. Oldörp and C. Wiegand-Löhnert for their critical comments on the manuscript. The authors are supported by the Deutsche Forschungsgemeinschaft (KFO 100, GRK 276, STE 477), the International Anesthesia Research Society (Frontiers in Anesthesia Research Program), the Bundesministerium für Bildung und Forschung (01GZ0311) and the Freie Universität Berlin (Research Program Inflammatory Diseases).

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  1. Klinik für Anaesthesiologie und Operative Intensivmedizin, Freie Universität Berlin, Klinikum Benjamin Franklin, Hindenburgdamm 30, Berlin, 12200, Germany

    Christoph Stein, Michael Schäfer & Halina Machelska

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Correspondence to Christoph Stein.

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Stein, C., Schäfer, M. & Machelska, H. Attacking pain at its source: new perspectives on opioids. Nat Med 9, 1003–1008 (2003). https://doi.org/10.1038/nm908

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