Opioids II pp 91-103 | Cite as

Peripheral Mechanisms of Opioid Analgesia

  • C. Stein
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 104 / 2)


Traditionally, opioids are considered to exert analgesic effects through actions within the central nervous system (CNS) (see also chaps. 31, 32, 33 and 36 of this volume). Recently, however, evidence has begun to accumulate that opioid antinociception can be brought about by activation of opioid receptors located outside the CNS. One of the earliest reports was that of Wood (1855), who showed that morphine elicited analgesic effects when applied topically to “painful areas” in the periphery. Since then there have been numerous clinical and experimental reports of similar observations. However, most of the former are merely anecdotal and many of the latter have been discounted because of their lack of demonstration of principal criteria for opioid receptor-mediated effects, in particular naloxone reversibility. Moreover, the question as to whether these effects result from a truly peripheral rather than from a central site of action (e.g., via uptake of the agent into the circulation and transport to the CNS) has been raised repeatedly. This chapter will give an overview of controlled experimental and clinical studies examining peripheral antinociceptive actions of opioids and will discuss mechanisms and potential implications for novel therapeutic approaches.


Dorsal Root Ganglion Opioid Receptor Antinociceptive Effect Inflame Tissue Opioid Analgesia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbott F (1988) Peripheral and central antinociceptive actions of ethylketocyclazocine in the formalin test. Eur J Pharmacol 152:93–100PubMedCrossRefGoogle Scholar
  2. Barthó L, Stein C, Herz A (1990) Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation. Naunyn Schmiedebergs Arch Pharmacol 342:666–670PubMedCrossRefGoogle Scholar
  3. Bentley GA, Newton SH, Starr J (1981) Evidence for an action of morphine and the enkephalins on sensory nerve endings in the mouse peritoneum. Br J Pharmacol 73:325–332PubMedGoogle Scholar
  4. Botticelli LJ, Cox BM, Goldstein A (1981) Immunoreactive dynorphin in mammalian spinal cord and dorsal root ganglia. Proc Natl Acad Sci USA 78:7783–7786PubMedCrossRefGoogle Scholar
  5. Bullingham RES, O’Sullivan G, McQuay H, Poppleton P, Rolfe M, Evans P, Moore A (1983) Perineural injection of morphine fails to relieve postoperative pain in humans. Anesth Analg 62:164–167PubMedCrossRefGoogle Scholar
  6. Bullingham RES, McQuay HJ, Moore RA (1984) Studies on the peripheral action of opioids in postoperative pain in man. Acta Anaesthesiol Belg 35 Suppl:285–290PubMedGoogle Scholar
  7. Dahl JB, Daugaard JJ, Kristoffersen E, Johannsen HV, Dahl JA (1988) Perineuronal morphine: a comparison with epidural morphine. Anaesthesia 43:463–465PubMedCrossRefGoogle Scholar
  8. Fang GF, Fields HL, Lee NM (1986) Action at the mu receptor is sufficient to explain the supraspinal analgesic effect of opiates. J Pharmacol Exp Ther 238:1039–1044PubMedGoogle Scholar
  9. Ferreira SH, Nakamura M (1979) Prostaglandin hyperalgesia II: the peripheral analgesic activity of morphine, enkephalins and opioid antagonists. Prostaglandins 18:191–200PubMedCrossRefGoogle Scholar
  10. Ferreira SH, Molina N, Vettore O (1982) Prostaglandin hyperalgesia, V: a peripheral analgesic receptor for opiates. Prostaglandins 23:53–60PubMedCrossRefGoogle Scholar
  11. Ferreira SH, Lorenzetti BB, Rae GA (1984) Is methylnalorphinium the prototype of an ideal peripheral analgesic? Eur J Pharmacol 99:23–29PubMedCrossRefGoogle Scholar
  12. Fields HL, Emson PC, Leigh BK, Gilbert RFT, Iversen LL (1980) Multiple opiate receptor sites on primary afferent fibres. Nature 284:351–353PubMedCrossRefGoogle Scholar
  13. Follenfant RL, Hardy GW, Lowe LA, Schneider C, Smith TW (1988) Antinociceptive effects of the novel opioid peptide BW443C compared with classical opiates; peripheral versus central actions. Br J Pharmacol 93:85–92PubMedGoogle Scholar
  14. Frank GB (1985) Stereospecific opioid receptors on excitable cell membranes. Can J Physiol Pharmacol 63:1023–1032PubMedCrossRefGoogle Scholar
  15. Guillemin RT, Vargo T, Rossier J, Minick S, Ling N, Rivier C, Vale W, Bloom FE (1977) β-Endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland. Science 197:1367–1369PubMedCrossRefGoogle Scholar
  16. Hardy GW, Lowe LA, Sang PY, Simpkin DSA, Wilkinson S, Follenfant RL, Smith TW (1988) Peripherally acting enkephalin analogues. I. Polar pentapeptides. J Med Chem 31:960–966PubMedCrossRefGoogle Scholar
  17. Hassan AHS, Przewlocki R, Herz A, Stein C (1992) Dynorphin, a preferential ligand for kappa-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat. Neurosci Lett 140:85–88PubMedCrossRefGoogle Scholar
  18. Hiller JM, Simon EJ, Crain SM, Peterson ER (1978) Opiate receptors in cultures of fetal mouse dorsal root ganglia (DRG) and spinal cord: predominance in DRG neurites. Brain Res 145:396–400PubMedCrossRefGoogle Scholar
  19. Holland RL, Harkin NE, Coleshaw SPK, Jones DA, Peck AW, Telekes A (1987) Dipipanone and nifedipine in cold induced pain; analgesia not due to skin warming. Br J Clin Pharmacol 24:823–826PubMedGoogle Scholar
  20. Illes P (1989) Modulation of transmitter and hormone release by multiple neuronal opioid receptors. Rev Physiol Biochem Pharmacol 112:169–171.Google Scholar
  21. International Association for the Study of Pain (1986) Classification of chronic pain. Pain Suppl 3:S217Google Scholar
  22. Joris JL, Dubner R, Hargreaves KM (1987) Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation. Anesth Analg 66:1277–1281PubMedCrossRefGoogle Scholar
  23. Karoly P, Jensen MP (1987) Multimethod assessment of chronic pain. Pergamon, New Youk, pp 42–57Google Scholar
  24. Kayser V, Gobeaux D, Lombard MC, Guilbaud G, Besson JM (1990) Potent and long lasting antinociceptive effects after injection of low doses of a mu-opioid receptor agonist, fentanyl, into the brachial plexus sheath of the rat. Pain 42:215–225PubMedCrossRefGoogle Scholar
  25. Kosterlitz HW, Waterfield A A (1975) In vitro models in the study of structure activity relationships of narcotic analgesics. Annu Rev Pharmac Toxicol 15:2947Google Scholar
  26. Laduron P (1984) Axonal transport of opiate receptors in capsaicin sensitive neurones. Brain Res 294:157–160PubMedCrossRefGoogle Scholar
  27. LaMotte C, Pert CB, Synder SH (1976) Opiate receptor binding in primate spinal cord: distribution and changes after dorsal root section. Brain Res 112:407–412PubMedCrossRefGoogle Scholar
  28. Lembeck F, Donnerer J (1985) Opioid control of the function of primary afferent substance P fibres. Eur J Pharmacol 114:241–246PubMedCrossRefGoogle Scholar
  29. Levine JD, Taiwo YO (1989) Involvement of the mu-opiate receptor in peripheral analgesia. Neuroscience 32:571–575PubMedCrossRefGoogle Scholar
  30. Mays KS, Lipman JJ, Schnapp M (1987) Local analgesia without anesthesia using peripheral perineural morphine injections. Anesth Analg 66:417–420PubMedCrossRefGoogle Scholar
  31. Millan MJ (1986) Multiple opioid systems and pain. Pain 27:303–347PubMedCrossRefGoogle Scholar
  32. Ninkovic M, Hunt SP, Gleave JRW (1982) Localization of opiate and histamine H1-receptors in the primary sensory ganglia and spinal cord. Brain Res 241:197–206PubMedCrossRefGoogle Scholar
  33. Parsons CG, Herz A (1990) Peripheral opioid receptors mediating antinociception in inflammation. Evidence for activation by enkephalin-like opioid peptides after cold water swim stress. J Pharmacol Exp Ther 255:795–802PubMedGoogle Scholar
  34. Parsons CG, Członkowski A, Stein C, Herz A (1990) Peripheral opioid receptors mediating antinociception in inflammation. Activation by endogenous opioids and role of the pituitary-adrenal axis. Pain 41:81–93PubMedCrossRefGoogle Scholar
  35. Porreca F, Mosberg HJ, Hurst R, Hruby VJ, Burks TF (1984) Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse. J Pharmacol Exp Ther 230:341–348PubMedGoogle Scholar
  36. Posner J, Moody SG, Peck AW, Rutter D, Telekes A (1990) Analgesic, central, cardiovascular and endocrine effects of the enkephalin analogue Tyr-d-Arg-Gly- Phe(4NO2)-Pro-NH2 (443C81) in healthy volunteers. Eur J Clin Pharmacol 38:213–218PubMedCrossRefGoogle Scholar
  37. Przewłocki R, Gramsch C, Pasi A, Herz A (1983) Characterization and localization of immunoreactive dynorphin, a-neoendorphin, met-enkephalin and substance P in human spinal cord. Brain Res 280:95–103PubMedCrossRefGoogle Scholar
  38. Przewłocki R, Hassan AHS, Lason W, Epplen C, Herz A, Stein C (1992) Gene expression and localization of opioid peptides in immune cells of inflamed tissue. Functional role in antinociception. Neuroscience 48:491–500PubMedCrossRefGoogle Scholar
  39. Rios L, Jacob JJC (1982) Inhibition of inflammatory pain by naloxone and its N-methyl quaternary analogue. Life Sci 31:1209–1212PubMedCrossRefGoogle Scholar
  40. Rios L, Jacob JJC (1983) Local inhibition of inflammatory pain by naloxone and its N-methyl quaternary analogue. Eur J Pharmacol 96:277–283PubMedCrossRefGoogle Scholar
  41. Russell NJM, Schaible HG, Schmidt RF (1987) Opiates inhibit the discharges of fine afferent units from inflamed knee joint of the cat. Neurosci Lett 76:107–112PubMedCrossRefGoogle Scholar
  42. Schiller PW, Nguyen TMD, Chung NN, Dionne G, Martel R (1990) Peripheral antinociceptive effect of an extremely μ-selective polar dermorphin analog (DALDA). In: Quirion R, Jhamandas K, Gianoulakis C (eds) The international narcotics research conference (INRC) 1989. Liss, New York, pp 53–56Google Scholar
  43. Shaw JS, Carroll JA, Alcock P, Main BG (1989) ICI 204448: a κ-opioid agonist with limited access to the CNS. Br J Pharmacol 96:986–992PubMedGoogle Scholar
  44. Sibinga NES, Goldstein A (1988) Opioid peptides and opioid receptors in cells of the immune ststem. Annu Rev Immunol 6:219–249PubMedCrossRefGoogle Scholar
  45. Smith TW, Buchan P, Parsons DN, Wilkinson S (1982) Peripheral antinociceptive effects of N-methyl morphine. Life Sci 31:1205–1208PubMedCrossRefGoogle Scholar
  46. Stein C, Millan MJ, Herz A (1988a) Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds. Pharmacol Biochem Behav 31:445–451PubMedCrossRefGoogle Scholar
  47. Stein C, Millan MJ, Shippenberg TS, Herz A (1988b) Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neurosci Lett 84:225–228PubMedCrossRefGoogle Scholar
  48. Stein C, Millan MJ, Yassouridis A, Herz A (1988c) Antinociceptive effects of μ- and κ-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism of action. Eur J Pharmacol 155:255–264PubMedCrossRefGoogle Scholar
  49. Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A (1989) Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 248:1269–1275PubMedGoogle Scholar
  50. Stein C, Gramsch C, Herz A (1990a) Intrinsic mechanisms of antinociception in inflammation. Local opioid receptors and β-endorphin. J Neurosci 10:1292–1298PubMedGoogle Scholar
  51. Stein C, Hassan AHS, Przewłocki, R, Gramsch C, Peter K, Herz A (1990b) Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA 87:5935–5939PubMedCrossRefGoogle Scholar
  52. Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, Peter K (1991) Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 325:1123–1126PubMedCrossRefGoogle Scholar
  53. Taiwo YO, Levine JD (1991) κ- and δ-opioids block sympathetically dependent hyperalgesia. J Neurosci 11:928–932PubMedGoogle Scholar
  54. Weihe E, Hartschuh W, Weber E (1985) Prodynorphin opioid peptides in small somatosensory primary afferents of guinea pig. Neurosci Lett 58:347–352PubMedCrossRefGoogle Scholar
  55. Werz MA, Macdonald RL (1982) Heterogeneous sensitivity of cultured dorsal root ganglion neurones to opioid peptides selective for μ- and δ-opiate receptors. Nature 299:730–733PubMedCrossRefGoogle Scholar
  56. Wood A (1855) New method of treating neuralgia by the direct application of opiates to the painful points. Edinburgh Med Surg J 82:265–281Google Scholar
  57. Yaksh TL (1988) Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res 458:319–324PubMedCrossRefGoogle Scholar
  58. Yong WS III, Wamsley JK, Zarbin MA, Kuhar MJ (1980) Opioid receptors undergo axonal flow. Science 210:76–77CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • C. Stein

There are no affiliations available

Personalised recommendations