Introduction

The interaction of immune cell-derived opioid peptides with opioid receptors on peripheral terminals of primary afferent (sensory) neurons is one of the most extensively investigated immune mechanisms inhibiting pain. Three families of opioid peptides are well characterized within the central nervous and endocrine systems. The major representatives of each family-β-endorphin, metenkephalin and dynorphincan interact with three types of opioid receptors, δ and κ, to generate analgesia. In peripheral inflamed tissue these opioid peptides are produced and released from immune cells and activate opioid receptors on sensory nerve terminals.¹ The production and other characteristics of opioid peptides in immune cells will be covered in chapters by Smith, Stefano et al, and Mousa in this volume This chapter will give an overview of current information on the anatomy and electrophysiology of opioid receptors localized on primary afferent neurons and on the analgesic effects mediated by these receptors. A closely related topic—the anti-inflammatory effects mediated by such receptors—will be discussed in the chapter by Walker in this volume.

Anatomy

In the vertebrates primary afferents are pseudounipolar neurons. Their cell body (soma) is localized in the dorsal root ganglion (or in the trigeminal ganglion for cranial nerves). Their central projections terminate in the dorsal horn of the spinal cord and their peripheral ones in the skin (or internal organs), respectively. Peripheral processes of primary afferent neurons are among the longest axons in the body (about one meter in humans) and are usually classified into myelinated (Aδ) and small diameter unmyelinated axons. The latter are also known as C-fibers and are particularly sensitive to the neurotoxin capsaicin, which is frequently used in experiments to selectively eliminate these neurons. Although both fiber types can transmit nociceptive messages from the periphery to the spinal cord, C-fibers are usually considered the dominant “pain” fibers.

Early studies have identified opioid receptors on cell bodies in the dorsal root ganglion and on central terminals of primary afferent neurons within the dorsal horn of the spinal cord.¹ More recently, we and others have detected such receptors also on peripheral processes of primary afferent neurons in animals^2–7 and in humans.⁸ Binding experiments indicate that the characteristics of opioid receptors on primary afferent neurons are very similar to those in the brain.³ In 1992 and 1993 three opioid receptors were cloned: the μ(MOR), the δ(DOR) and the κ opioid receptor (KOR).⁹ This has made it possible to demonstrate mRNA for all three receptors in the dorsal root ganglion.¹⁰ With the advent of specific antisera, MOR^4,7,11–13, DOR^12–16 and KOR^12,13 were morphologically identified in the dorsal root ganglion and on small diameter primary afferent neurons. Furthermore, we have shown that the molecular mass of the peripheral MOR is identical with that in the central nervous system by Western blot analysis of the rat sciatic nerve (which consists predominantly of primary afferent neurons).⁷ Ultrastructural analysis by electron microscopy has revealed DOR on large dense-core vesicles and on the plasmalemma of small diameter primary afferent neuron terminals within the spinal cord.¹⁶ This led the authors to speculate that the activation of opioid receptors on vesicles may be coupled to the release of neuropeptides (e.g., substance P) from primary afferent nerve terminals in the spinal cord. In the rat skin MOR and DOR were detected on peripheral terminals of unmyelinated axons, associated with the axonal membrane, microtubules and mitochondria.⁵ This is consistent with the notion that opioid receptors similar to neuropeptides and other proteins are systhesized in the dorsal root ganglion and then carried into the central and peripheral terminals via axonal transport (see below). In line with these findings are our functional studies indicating that capsaicin-sensitive (unmyelinated) primary afferent neurons are indeed primarily responsible for the peripheral antinociceptive (analgesic) effects of morphine and of m, d and k selectiveopioid agonists.^17,18

It has been suggested that opioid receptors are also located on sympathetic postganglionic neuron terminals and that they may contribute to opioid analgesia.¹⁹ However, the proposed involvement of sympathetic neurons was questioned by other groups.^20,21 Also, studies attempting the direct demonstration of opioid receptor mRNA in sympathetic ganglia have yielded negative results²² or extremely small amounts.²³ A thorough morphological investigation clearly demonstrated DOR on unmyelinated primary afferent neurons but not on postganglionic sympathetic neurons in skin, lip and cornea.⁶ In immunohistochemical and functional studies we have shown that chemical sympathectomy with 6-hydroxydopamine does not change the expression of opioid receptors in the dorsal root ganglion¹³ or the peripheral antinociceptive effects of μ-, δ- and κ-opioid agonists in a model of inflammatory pain.¹⁸ Together, these findings have corroborated the notion that peripheral opioid receptors mediating analgesia are exclusively localized on primary afferent neurons.

Electrophysiology

What are the mechanisms leading to analgesia following the activation of such neuronal opioid receptors? μ^24–34, δ^35,36 and κ^26,37,38 opioid agonists inhibit calcium currents in cultured dorsal root ganglion (or trigeminal ganglion) neurons. In most of these studies opioids were found to preferentially inhibit the high-voltage activated calcium channels. These effects are mediated by G-proteins (G_i and/or G_o).^{29,31,32,37,38} It is known that potassium currents are increased by μ- and δ-opioids in neurons of the central nervous system (e.g., locus coeruleus).^39,40 However, in dorsal root ganglion neurons opioid effects on resting or voltage-dependent potassium channels could not be detected so far.⁴¹ Thus, the modulation of calcium currents seems to be the primary mechanism for the inhibitory effects of opioids on primary afferent neurons. In addition, the inhibition of a tetrodotoxin-resistant sodium current by a μ-opioid agonist was described.⁴²

Provided that these electrophysiological events are similar throughout the neuron, they may underlie the following observations: Opioids attenuate the excitability of the peripheral nociceptive terminal and the propagation of action potentials.^43–45 Similar to their effects at the soma^46,47 and at central terminals⁴⁸, opioids inhibit the (calcium-dependent) release of excitatory proinflammatory compounds (e.g., substance P) from peripheral sensory nerve endings.^49–51 In addition, morphine was found to inhibit vasodilatation evoked by the antidromic electrical stimulation of C-fibers.⁵² All of these mechanisms can result in pain inhibition. Moreover, they may also account for the anti-inflammatory actions of opioids (see chapter by Walker in this volume).

Alterations During Inflammation

A large number of studies have shown that peripheral analgesic effects of exogenous opioids are enhanced under inflammatory conditions.^53,54 One possible underlying mechanism is an up-regulation, i.e., an increased number of receptors. Opioid receptors are synthesized in the dorsal root ganglion^10,22,53,55 and their expression can be modulated by inflammation in the vicinity of peripheral primary afferent neuron terminals.^12,13 We observed a moderate up-regulation of MOR and down-regulation of DOR and KOR in dorsal root ganglion¹³ while levels of μ-receptor mRNA were not significantly changed.⁵³ However, several days after the induction of peripheral inflammation, the axonal transport of opioid receptors in fibers of the sciatic nerve is greatly enhanced.^3,7,56 We have shown that the density of opioid receptors on cutaneous nerve fibers in the inflamed tissue increases and that this increase is abolished by ligating the sciatic nerve.³ These findings indicate that inflammation enhances the peripherally directed axonal transport of opioid receptors which leads to an up-regulation on peripheral nerve terminals.

On the other hand, preexistent, but possibly inactive neuronal opioid receptors may undergo changes owing to the specific milieu (e.g., low pH) of inflamed tissue, and thus be rendered active. Indeed, low pH increases opioid agonist efficacy in vitro by altering the interaction of opioid receptors with G-proteins in neuronal membranes.^57–59 Furthermore, the ability of opioids to decrease the excitability of primary afferent neurons (via inhibition of adenylyl cyclase and subsequent inhibition of cation currents) is much more pronounced when neuronal cyclic adenosine monophosphate (cAMP) levels are increased, a common scenario in inflammation.⁶⁰ Together, these findings suggest that a low pH in inflamed tissue may lead to an enhanced functional efficacy of opioid receptors on primary afferent neurons.

Another important question is how opioid peptides (e.g., those derived from immune cells in the vicinity, see chapters by Machelska, Mousa and Schäfer, this volume) reach their receptors on sensory neurons. Under normal circumstances, tight intercellular contacts at the innermost layer of the perineurium (a sheath encasing peripheral nerve fibers) act as a diffusion barrier for high molecular weight or hydrophilic substances such as peptides.⁶¹ However, inflammatory conditions entail a disruption of the perineurial barrier.⁶¹ We demonstrated that this disruption clearly enhances the passage of opioid peptides to sensory neurons.⁶² In addition, we found that the number of primary afferent neuron terminals is increased in inflamed tissue (“sprouting”).⁶³ Together, these observations suggest that the access of opioid peptides to opioid receptors on primary afferent neurons is greatly facilitated---if not unrestricted---in inflamed tissue.

Analgesic Effects

This section will concentrate on analgesic effects following the activation of peripheral opioid receptors on primary afferent neurons by exogenous opioid agonists. Effects of endogenous (immune-derived) opioids are discussed in the chapters by Machelska and Schäfer in this volume.

Many conventional opioid agonists produce potent opioid receptor-mediated analgesia when administered in small, systemically inactive doses in rodents, primates and humans.^54,64 These effects have been observed mostly under pathological conditions like neuropathic pain⁶⁵, colorectal distension⁶⁶,bone damage⁶⁷ and inflammation^54,64, but also in noninflamed tissue.⁶² Central side effects typically associated with systemically (e.g., intravenously) administered opioids like tolerance, sedation, dependence and respiratory depression can be avoided by this peripheral application of agents. Thus, strategies to restrict the access of opioid agonists to the central nervous system have been developed. Such approaches include the incorporation of highly polar hydrophilic substituents or the inclusion of both hydrophilic and hydrophobic portions in molecules. The aim is to achieve peripheral selectivity and high analgesic potency of these compounds.^64,68,69 Recently, novel peptidic k-ligands were identified by positional scanning of a tetrapeptide combinatorial library screened in opioid receptor binding assays. We demonstrated that these ligands are peripherally selective, as shown by the lack of sedative activity after systemic administration, and that they have potent analgesic effects.⁷⁰ Moreover, these peptides exhibited significant anti-inflammatory properties, as measured by paw volume and histological signs.⁷⁰ These preclinical studies show that both conventional and novel opioid analgesics are useful and available for peripheral administration.

Peripheral opioid actions are undoubtedly of clinical relevance. We have detected opioid receptors on peripheral nerve terminals as well as opioid peptides in human synovia.^8,71 A sizeable body of clinical literature has recently been reviewed and has demonstrated the analgesic efficacy of locally applied opioids in various clinical settings.⁷² The most extensively studied clinical situation is the intraarticular application of opioid agonists for pain control after knee surgery.^54,64,72 A recent important development is the analogous use in chronic arthritis.^73,74 Novel routes of administration include the perineural, intra-abdominal, orbital and topical wound infiltration with opioids.^64,72 The majority of these studies has clearly produced evidence for the clinical usefulness of peripheral opioid analgesics. A major goal for the future is the development of peripherally selective opioids which are suitable for oral or intravenous administration in chronic and acute (e.g., postoperative) pain. Preliminary clinical studies are currently testing the oral and intravenous application of peripheral μ- and κ-agonists.⁶⁹

Tolerance

An important question is whether tolerance (i.e., a loss of analgesic efficacy after repeated or continuous application of agonists) does or does not develop at peripheral opioid receptors. Peripheral tolerance has been observed in animal models without inflammation.⁷⁵ However, since the number, affinity and coupling efficacy of opioid receptors appear to be enhanced under inflammatory conditions (see above under “alterations during inflammation”) these studies do not permit conclusions regarding tolerance in the pathological situation. In another model peripherally (but not centrally) mediated morphine analgesia was reported to be resistant to tolerance development.^76,77 A lack of tolerance development was also shown after repeated local administration of loperamide (a μ-agonist) in a thermal inflammatory model.⁷⁸ In the same study systemically applied morphine produced only partial cross-tolerance with loperamide.⁷⁸ In clinical studies we found a lack of cross-tolerance between local morphine and endogenous opioid-induced analgesia.⁸ So far the weight of the evidence tends to argue for a relative lack of tolerance development at peripheral opioid receptors under inflammatory conditions. Clearly more basic and clinical investigations are needed to resolve this important issue and to elucidate the underlying mechanisms.

Conclusions

In summary, this chapter discussed developments in the field of peripheral opioid receptors, including localization, signalling pathways, novel peripherally restricted agonists, clinical applications and tolerance development. Major recent findings are the functionally exclusive localization of opioid receptors to primary afferent (but not sympathetic) neurons, the relative lack of tolerance under inflammatory conditions and tetrapeptides as peripherally restricted compounds. Clinical studies have now moved into the field of chronic arthritic pain, a problem of major importance and prevalence. An important long-term goal remains to develop opioid analgesics which exclusively activate peripheral opioid receptors on sensory neurons. Such compounds should be devoid of centrally mediated side effects (e.g., sedation, respiratory depression, tolerance, dependence, addiction) and they should be suitable for the oral and/or intravenous route for the widespread use in patients with acute and chronic pain.

Acknowledgments

Supported by grants from the Deutsche Forschungsgemeinschaft, the International Anesthesia Research Society and the National Institutes of Health. Current industrial collaborators include Ferring B.V. and EpiCept Corp.

References

1.

Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med. 1995;332(25):1685–1690. [PubMed: 7760870]

2.

Stein C, Hassan A H S, Przewlocki R. et al. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA. 1990;87:5935–5939. [PMC free article: PMC54444] [PubMed: 1974052]

3.

Hassan A H S, Ableitner A, Stein C. et al. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience. 1993;55:185–195. [PubMed: 7688879]

4.

Li JL, Kaneko T, Mizuno N. Effects of peripheral nerve ligation on expression of muopioid receptor in sensory ganglion neurons: an immunohistochemical study in dorsal root and nodose ganglion neurons of the rat. Neurosci Lett. 1996;214(23):91–94. [PubMed: 8878091]

5.

Coggeshall RE, Zhou S, Carlton SM. Opiate receptors on peripheral sensory axons. Brain Res. 1997;764(12):126–132. [PubMed: 9295201]

6.

Wenk HN, Honda CN. Immunohistochemical localization of delta opioid receptors in peripheral tissues. J Comp Neurol. 1999;408(4):567–79. [PubMed: 10340506]

7.

Mousa SA, Zhang Q, Sitte N. et al. bEndorphin containing memorycells and mopioid receptors undergo transport to peripheral inflamed tissue. J Neuroimmunol. 2001;115:71–78. [PubMed: 11282156]

8.

Stein C, Pflüger M, Yassouridis A. et al. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest. 1996;98:793–799. [PMC free article: PMC507490] [PubMed: 8698872]

9.

Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: Receptors for opioid peptides. Cell Mol Neurobiol. 1995;15(6):615–635. [PubMed: 8719033]

10.

Mansour A, Fox CA, Burke S. et al. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J Comp Neurol. 1994;350(3):412–38. [PubMed: 7884049]

11.

Arvidsson U, Riedl M, Chakrabarti S. et al. Distribution and targeting of a muopioid receptor (MOR1) in brain and spinal cord. J Neurosci. 1995;15(5):3328–3341. [PMC free article: PMC6578209] [PubMed: 7751913]

12.

Ji RR, Zhang Q, Law PY. et al. Expression of m, d, and kopioid receptorlike immunoreactivities in rat dorsal root ganglia after carrageenaninduced inflammation. J Neurosci. 1995;15(12):8156–8166. [PMC free article: PMC6577939] [PubMed: 8613750]

13.

Zhang Q, Schäfer M, Elde R. et al. Effects of neurotoxins and hindpaw inflammation on opioid receptor immunoreactivities in dorsal root ganglia. Neuroscience. 1998;85(1):281–291. [PubMed: 9607719]

14.

Dado RJ, Law PY, Loh HH. et al. Immunofluorescent identification of a deltaopioid receptor on primary afferent nerve terminals. NeuroReport. 1993;5:341–344. [PubMed: 8298100]

15.

Zhang X, Bao L, Xu ZQ. et al. Localization of neuropeptide Y Y1 receptors in the rat nervous system with special reference to somatic receptors on small dorsal root ganglion neurons. Proc Natl Acad Sci USA. 1994;91(24):11738–42. [PMC free article: PMC45307] [PubMed: 7972133]

16.

Zhang X, Bao L, Arvidsson U. et al. Localization and regulation of the deltaopioid receptor in dorsal root ganglia and spinal cord of the rat and monkey: evidence for association with the membrane of large densecore vesicles. Neuroscience. 1998;82(4):1225–42. [PubMed: 9466442]

17.

Bartho L, Stein C, Herz A. Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation. Naunyn Schmiedebergs Arch Pharmacol. 1990;342:666–670. [PubMed: 2096298]

18.

Zhou L, Zhang Q, Stein C. et al. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. J Pharmacol Exp Ther. 1998;286(2):1000–1006. [PubMed: 9694961]

19.

Taiwo YO, Levine JD. Kappa and deltaopioids block sympathetically dependent hyperalgesia. J Neurosci. 1991;11:928–932. [PMC free article: PMC6575370] [PubMed: 2010815]

20.

Koltzenburg M, Kress M, Reeh PW. The nociceptor sensitization by bradykinin does not depend on sympathetic neurons. Neuroscience. 1992;46:465–473. [PubMed: 1542419]

21.

Schuligoi R, Donnerer J, Amann R. Bradykinininduced sensitization of afferent neurons in the rat paw. Neuroscience. 1994;59(1):211–5. [PubMed: 8190269]

22.

Schäfer M K H, Bette M, Romeo H. et al. Localization of kappaopioid receptor mRNA in neuronal subpopulations of rat sensory ganglia and spinal cord. Neurosci Lett. 1994;167:137–140. [PubMed: 8177512]

23.

Buzas B, Cox BM. Quantitative analysis of mu and delta opioid receptor gene expression in rat brain and peripheral ganglia using competitive polymerase chain reaction. Neuroscience. 1997;76(2):479–489. [PubMed: 9015332]

24.

Samoriski GM, Gross RA. Functional compartmentalization of opioid desensitization in primary sensory neurons. J Pharmacol Exp Ther. 2000;294(2):500–9. [PubMed: 10900225]

25.

Xie W, Samoriski GM, McLaughlin JP. et al. Genetic alteration of phospholipase C beta3 expression modulates behavioral and cellular responses to mu opioids. Proc Natl Acad Sci USA. 1999;96(18):10385–90. [PMC free article: PMC17897] [PubMed: 10468617]

26.

Abdulla FA, Smith PA. Axotomy reduces the effect of analgesic opioids yet increases the effect of nociceptin on dorsal root ganglion neurons. J Neurosci. 1998;18(23):9685–94. [PMC free article: PMC6793289] [PubMed: 9822729]

27.

Khasar SG, Gold MS, Dastmalchi S. et al. Selective attenuation of muopioid receptormediated effects in rat sensory neurons by intrathecal administration of antisense oligodeoxynucleotides. Neurosci Lett. 1996;218(1):17–20. [PubMed: 8939470]

28.

Rusin KI, Moises HC. mOpioid receptor activation reduces multiple components of highthreshold calcium current in rat sensory neurons. J Neurosci. 1995;15(6):4315–4327. [PMC free article: PMC6577714] [PubMed: 7540671]

29.

Wilding TJ, Womack MD, McCleskey EW. Fast, local signal transduction between the μ opioid receptor and Ca²⁺ channels. J Neurosci. 1995;15(5):4124–4132. [PMC free article: PMC6578243] [PubMed: 7538571]

30.

Taddese A, Nah SY, McCleskey EW. Selective opioid inhibition of small nociceptive neurons. Science. 1995;270:1366–1369. [PubMed: 7481826]

31.

Nomura K, Reuveny E, Narahashi T. Opioid inhibition and desensitization of calcium channel currents in rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 1994;270(2):466–474. [PubMed: 8071838]

32.

Moises HC, Rusin KI, Macdonald RL. mOpioid receptormediated reduction of neuronal calcium current occurs via a G_otype GTPbinding protein. J Neurosci. 1994;14(6):3842–3851. [PMC free article: PMC6576957] [PubMed: 8207492]

33.

Schroeder JE, McCleskey EW. Inhibition of Ca2+ currents by a muopioid in a defined subset of rat sensory neurons. J Neurosci. 1993;13:867–873. [PMC free article: PMC6576659] [PubMed: 7678862]

34.

Schroeder JE, Fischbach PS, Zheng D. et al. Activation of muopioid receptors inhibits transient high and lowthreshold Ca2+ currents, but spares a sustained current. Neuron. 1991;6:13–20. [PubMed: 1846076]

35.

Acosta CG, Lopez HS. delta opioid receptor modulation of several voltagedependent Ca(2+) currents in rat sensory neurons. J Neurosci. 1999;19(19):8337–48. [PMC free article: PMC6783030] [PubMed: 10493735]

36.

Werz MA, Macdonald RL. Heterogeneous sensitivity of cultured dorsal root ganglion neurones to opioid peptides selective for mu and deltaopiate receptors. Nature. 1982;299:730–733. [PubMed: 6289131]

37.

Wiley JW, Moises HC, Gross RA. et al. Dynorphin Amediated reduction in multiple calcium currents involves a G(o) alphasubtype G protein in rat primary afferent neurons. J Neurophysiol. 1997;77(3):1338–48. [PubMed: 9084601]

38.

Su X, Wachtel RE, Gebhart GF. Inhibition of calcium currents in rat colon sensory neurons by K but not mu or deltaopioids. J Neurophysiol. 1998;80(6):3112–9. [PubMed: 9862909]

39.

North RA, Williams JT, Surprenant A. et al. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc Natl Acad Sci USA. 1987;84(15):5487–91. [PMC free article: PMC298884] [PubMed: 2440052]

40.

Miyake M, Christie MJ, North RA. Single potassium channels opened by opioids in rat locus ceruleus neurons. Proc Natl Acad Sci USA. 1989;86(9):3419–22. [PMC free article: PMC287144] [PubMed: 2566172]

41.

Akins PT, McCleskey EW. Characterization of potassium currents in adult rat sensory neurons and modulation by opioids and cyclic AMP. Neuroscience. 1993;56:759–769. [PubMed: 8255432]

42.

Gold MS, Levine JD. DAMGO inhibits prostaglandin E₂induced potentiation of a TTXresistant Na current in rat sensory neurons in vitro. Neurosci Lett. 1996;212:83–86. [PubMed: 8832644]

43.

Russell N J W, Schaible HG, Schmidt RF. Opiates inhibit the discharges of fine afferent units from inflamed knee joint of the cat. Neurosci Lett. 1987;76:107–112. [PubMed: 2884605]

44.

Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience. 1994;58:793–798. [PubMed: 8190256]

45.

Su X, Julia V, Gebhart GF. Effects of intracolonic opioid receptor agonists on polymodal pelvic nerve afferent fibers in the rat. J Neurophysiol. 2000;83(2):963–70. [PubMed: 10669508]

46.

Jessell TM, Iversen LL. Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature. 1977;268:549–551. [PubMed: 18681]

47.

Mudge AW, Leeman SE, Fischbach GD. Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proc Natl Acad Sci USA. 1979;76:526–530. [PMC free article: PMC382975] [PubMed: 218204]

48.

Yaksh TL, Jessell TM, Gamse R. et al. Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature. 1980;286:155–156. [PubMed: 6157098]

49.

Yaksh TL. Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res. 1988;458:319–324. [PubMed: 2463049]

50.

Yonehara N, Imai Y, Chen JQ. et al. Influence of opioids on substance P release evoked by antidromic stimulation of primary afferent fibers in the hind instep of rats. Regul Pept. 1992;38:13–22. [PubMed: 1374191]

51.

Yonehara N, Takiuchi S. Involvement of calciumactivated potassium channels in the inhibitory prejunctional effect of morphine on peripheral sensory nerves. Regul Pept. 1997;68(3):147–53. [PubMed: 9100281]

52.

Shakhanbeh J, Lynn B. Morphine inhibits antidromic vasodilatation without affecting the excitability of Cpolymodal nociceptors in the skin of the rat. Brain Res. 1993;607:314–318. [PubMed: 8481806]

53.

Schäfer M, Imai Y, Uhl GR. et al. Inflammation enhances peripheral mopioid receptormediated analgesia, but not mopioid receptor transcription in dorsal root ganglia. Eur J Pharmacol. 1995;279:165–169. [PubMed: 7556397]

54.

Stein C, Schäfer M, Cabot PJ. et al. Peripheral opioid analgesia. Pain Reviews. 1997;4:171–185.

55.

Maekawa K, Minami M, Yabuuchi K. et al. In situ hybridization study of mu and kappaopioid receptor mRNAs in the rat spinal cord and dorsal root ganglia. Neurosci Lett. 1994;168:97–100. [PubMed: 8028801]

56.

Jeanjean AP, Moussaoui SM, Maloteaux JM. et al. Interleukin1b induces longterm increase of axonally transported opiate receptors and substance P. Neuroscience. 1995;68(1):151–157. [PubMed: 7477920]

57.

Childers SR. Opiateinhibited adenylate cyclase in rat brain membranes depleted of G_sstimulated adenylate cyclase. J Neurochem. 1988;50:543–553. [PubMed: 2826699]

58.

Rasenick MM, Childers SR. Modification of G_sstimulated adenylate cyclase in brain membranes by low pH pretreatment: correlation with altered guanine nucleotide exchange. J Neurochem. 1989;53:219–225. [PubMed: 2498464]

59.

Selley DE, Breivogel CS, Childers SR. Modification of G proteincoupled functions by low pH pretreatment of membranes from NG10815 cells: increase in opioid agonist efficacy by decreased inactivation of G proteins. Mol Pharmacol. 1993;44:731–741. [PubMed: 8232223]

60.

Ingram SL, Williams JT. Opioid inhibition of Ih via adenylyl cyclase. Neuron. 1994;13:179–186. [PubMed: 7519024]

61.

Olsson Y. Microenvironment of the peripheral nervous system under normal and pathological conditions. Crit Rev Neurobiol. 1990;5(3):265–311. [PubMed: 2168810]

62.

Antonijevic I, Mousa SA, Schäfer M. et al. Perineurial defect and peripheral opioid analgesia in inflammation. J Neurosci. 1995;15(1):165–172. [PMC free article: PMC6578300] [PubMed: 7823127]

63.

Hassan A H S, Przewlocki R, Herz A. et al. Dynorphin, a preferential ligand for kappaopioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat. Neurosci Lett. 1992;140:85–88. [PubMed: 1357608]

64.

Stein C, Machelska H, Binder W. et al. Peripheral opioid analgesia. Curr Opin Pharmacol. 2001;1(1):62–65. [PubMed: 11712537]

65.

Kayser V, Lee SH, Guilbaud G. Evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in rats with peripheral mononeuropathy. Neuroscience. 1995;64(2):537–45. [PubMed: 7700537]

66.

Gebhart GF, Su X, Joshi S. et al. Peripheral opioid modulation of visceral pain. Ann NY Acad Sci. 2000;909:41–50. [PubMed: 10911923]

67.

Houghton AK, Valdez JG, Westlund KN. Peripheral morphine administration blocks the development of hyperalgesia and allodynia after bone damage in the rat. Anesthesiology. 1998;89(1):190–201. [PubMed: 9667309]

68.

Machelska H, Binder W, Stein C. Opioid receptors in the periphery In: Kalso E, McQuay H, WiesenfeldHallin Z, eds. Opioid Sensitivity of Chronic Noncancer Pain Seattle: IASP Press,199945–58.

69.

Brower V. New paths to pain relief. Nat Biotechnol. 2000;18(4):387–91. [PubMed: 10748517]

70.

Binder W, Machelska H, Mousa S. et al. Analgesic and anti-inflammatory effects of two novel kappa opioid peptides. Anesthesiology. 2001;94:1034–1044. [PubMed: 11465595]

71.

Stein C, Hassan A H S, Lehrberger K. et al. Local analgesic effect of endogenous opioid peptides. Lancet. 1993;342:321–324. [PubMed: 8101583]

72.

Schäfer M. Peripheral opioid analgesia: from experimental to clinical studies. Curr Opin Anaesth. 1999;12:603–607. [PubMed: 17016256]

73.

Likar R, Schäfer M, Paulak F. et al. Intraarticular morphine analgesia in chronic pain patients with osteoarthritis. Anesth Analg. 1997;84(6):1313–1317. [PubMed: 9174312]

74.

Stein A, Yassouridis A, Szopko C. et al. Intraarticular morphine versus dexamethasone in chronic arthritis. Pain. 1999;83(3):525–532. [PubMed: 10568861]

75.

Kolesnikov Y, Pasternak GW. Topical opioids in mice: analgesia and reversal of tolerance by a topical NmethylDaspartate antagonist. J Pharmacol Exp Ther. 1999;290(1):247–52. [PubMed: 10381783]

76.

Tokuyama S, Inoue M, Fuchigami T. et al. Lack of tolerance in peripheral opioid analgesia in mice. Life Sci. 1998;62(1718):1677–81. [PubMed: 9585156]

77.

Ueda H, Inoue M. Peripheral morphine analgesia resistant to tolerance in chronic morphinetreated mice. Neurosci Lett. 1999;266(2):105–8. [PubMed: 10353338]

78.

NozakiTaguchi N, Yaksh TL. Characterization of the antihyperalgesic action of a novel peripheral muopioid receptor agonistloperamide. Anesthesiology. 1999;90(1):225–34. [PubMed: 9915332]