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Morphological Correlates of Immune-Mediated Peripheral Opioid Analgesia



Recent research has shown that effective inhibition of pain by endogenous mechanisms can be generated within peripheral tissue, outside the central nervous system. Studies using sensitive and specific techniques of immunohistochemistry have demonstrated that opioid receptors are present on small diameter neurons in the dorsal root ganglia (DRG). Under inflammatory conditions the expression of opioid receptors in the DRG is enhanced. In addition, these receptors are axonally transported in fibers of the sciatic nerve towards the peripheral sensory nerve terminals. Consequently, the number of opioid receptors on nerve fibers in the inflamed subcutaneous tissue increases and this increase is abolished by ligating the sciatic nerve (see also chapter 5). In parallel, endogenous ligands at opioid receptors (mainly β-endorphin) are synthesized in circulating immune cells which migrate to the injured tissue. The extravasation of immunocytes to sites of inflammation is mediated by adhesion molecules, glycoproteins located on the surface of leukocytes and endothelial cells of the vessels. These mechanisms are also involved in the opioid control of inflammatory pain (see chapter 7).1 This is supported by findings showing an up-regulation of adhesion molecules and their colocalization with β-endorphin in immune cells which have migrated to inflamed tissue. Environmental stressful stimuli and releasing agents (corticotropin-releasing factor, CRF; cytokines) can activate immune cells to release opioid peptides. These bind to opioid receptors localized on peripheral sensory nerve terminals. As a consequence of this interaction, inflammatory pain is inhibited. 2,3 This chapter focuses on the anatomical substrates of the interaction between the peripheral nervous system and opioid-containing immunocytes.

Expression of Opioid Receptors on Peripheral Sensory Neurons

Peripheral antinociceptive (analgesic) effects of exogenous opioids are enhanced under inflammatory conditions (see refs. 2, 4 and chapter 5). One possible underlying mechanism for the increased efficacy of opioid agonists is an up-regulation of opioid receptors. Using a specific antibody against μ opioid receptors (MOR) we were able to immunolocalize MOR on small-diameter neurons in the DRG. Furthermore, we found a significant increase in the percentage of MOR-positive neurons in the ipsilateral DRG 4 days after induction of hindpaw inflammation with complete Freund's adjuvant (CFA) (Fig. 1).5,6 This is consistent with a previous report showing a similar increase 3 days after carrageenan-produced peripheral inflammation.7 The MOR immunoreactive neurons in DRG are small and they are vulnerable to capsaicin, a specific neurotoxin that destroys nociceptive C-fibers and abolishes μ, δ and κ receptor agonist-induced peripheral analgesia.5,8

Figure 1. Immunohistochemical (A, B, D) and immunofluorescence (C) staining of m opioid receptors in rat dorsal horn of the spinal cord (A), dorsal root ganglia (B), ligated sciatic nerve ipsilateral to the inflamed hindpaw (C) and in inflamed subcutaneous paw tissue (D).

Figure 1

Immunohistochemical (A, B, D) and immunofluorescence (C) staining of m opioid receptors in rat dorsal horn of the spinal cord (A), dorsal root ganglia (B), ligated sciatic nerve ipsilateral to the inflamed hindpaw (C) and in inflamed subcutaneous paw (more...)

Previous studies have shown that opioid receptors are synthesized in the cell body of sensory neurons in DRG and undergo axonal transport to reach the nerve terminals.9 Further experiments using autoradiography have demonstrated that inflammation induces an increase in the transport of opioid receptors along the sciatic nerve 4 days after CFA.10 We extended these studies by use of a specific antibody against cloned MOR. Our present results confirmed an increased, especially anterograde transport of MOR along the sciatic nerve (Fig. 1).6 At the peripheral sensory nerve terminals we detected MOR-immunoreactivity (IR) in inflamed (Fig. 1) and noninflamed subcutaneous tissue.6 In addition, these studies clearly showed that MOR-positive nerve terminals were more abundant in inflamed subcutaneous tissue.6 These new findings provide the first direct evidence to support the notion that the number of MOR is increased in inflammatory pain.

The fact that peripheral analgesic effects of opioids are pronounced in inflamed tissue but negligible under normal conditions,4 suggests an inflammation-induced process. In addition to the enhanced axonal receptor transport, there is evidence that the accessibility of opioid receptors on sensory nerves is facilitated in injured tissue. The detection of MOR-IR at the peripheral nerve terminals in noninflamed tissue is in accord with our previous studies using biotinylated anti-id-14 (a monoclonal anti-idiotypic antibody against μ- and δ-opioid receptors), 11 and with functional studies showing fentanyl (μ-agonist)-induced peripheral analgesia in noninflamed tissue.12 This is supported by other studies showing μ-opioid receptors on unmyelinated cutaneous sensory axons in noninjured tissue.13 In addition, opioid receptors are located not only at the tips of afferent nerve terminals but also more proximally along the axon.10 These loci are ensheathed by perineurium 14 and are potential sites of opioid action. Inflammatory conditions entail a deficiency of the perineurial barrier and/or an enhanced permeability of endoneurial capillaries.14,15 A similar leakage can be produced experimentally by the extraneural application of hyperosmolar solutions.16 Consistently, our histochemical experiments demonstrated that horseradish peroxidase, applied extraneurally in vivo, does not penetrate into the endoneurium of cutaneous nerves in noninflamed paws but does so at both early and later stages of the inflammatory reaction (Fig. 2).12 In normal tissue, the perineural administration of either hypertonic saline or mannitol strikingly enhances the passage of horseradish peroxidase into the endoneurium. These anatomical findings strongly support the contention that either inflammatory or artificial disruption of the blood-nerve barrier facilitates the access of macromolecules (e.g., opioid peptides) to sensory neurons.

Figure 2. Cross-sections of rat plantar subcutaneous paw tissue.

Figure 2

Cross-sections of rat plantar subcutaneous paw tissue.After intraplantar injection of horseradish peroxidase, reaction products are seen in epineurial connective tissue and in perineurium of plantar nerves (A-D). The endoneurium of nerves is stained only (more...)

Expression of Opioid Peptides in Immune Cells

Three families of opioid peptides, ligands at opioid receptors, are well characterized. Each family derives from a distinct gene and precursor protein, proopiomelanocortin (POMC), proenkephalin (PENK) and prodynorphin. Their respective major representative opioid peptides are β-endorphin, met-enkephalin and dynorphin. Each peptide exhibits different affinities and selectivities for the three opioid receptor types μ (β-endorphin, enkephalin), δ (enkephalin, β-endorphin) and κ (dynorphin).17 Two additional endogenous opioid peptides specific at μ receptors have been detected recently: endomorphin-1 and endomorphin-2.18

POMC-derived peptides were first reported in human lymphocytes by Blalock and Smith.20 Since then, POMC-related opioid peptides have been found in immune cells of many vertebrates and nonvertebrates (reviewed in refs. 20, 21 and in chapters 4, 11). Extending the initial notion that only truncated forms of POMC messenger ribonucleic acid (mRNA) are present in immune cells,20,22 full-length POMC mRNA, identical in sequence to that isolated from the pituitary gland, has been demonstrated in rat mononuclear leukocytes recently. This POMC transcript is spliced in the same way as the pituitary transcript and consequently contains the sequence for the signal peptide. The POMC protein is also proteolytically processed in a way consistent with the pituitary gland (see ref. 23 and chapter 4).

PENK-derived opioid peptides have also been detected in human and rodent immune cells (reviewed in ref. 24 and in chapter 4). Upon in vitro stimulation or under pathological conditions these cells express enhanced levels of PENK mRNA. In subpopulations of these cells this mRNA is highly homologous to brain PENK mRNA, abundant and apparently translated, since immunoreactive met-enkephalin is present and/or released.24 PENK mRNA and enkephalins have been found in activated CD4 (activated/memory T cell marker) T cells,25 CD4 thymocytes,26 macrophages, monocytes and mast cells.27 The appropriate enzymes necessary for posttranslational processing of both POMC and PENK have also been identified in immune cells (see ref. 28 and chapter 4).

Thus, a growing body of evidence indicates that both POMC- and PENK-derived opioid peptides are produced by immune cells. Immune-derived opioid peptides are involved in the modulation of inflammatory pain.2 Apparently, persistent inflammation is a pathophysiological in vivo stimulus for the immune system and represents a condition that is closer to the clinical setting than some of the early in vitro studies. Recent studies by Mechanick et al29 detected POMC mRNA in macrophages and monocytes by in situ hybridization. In addition, in double immunohistochemistry β-endorphin was localized in macrophages and monocytes of lung and spleen but not in lymphocytes. In CFA-induced arthritis levels of adrenocorticotrophin and β-endorphin are increased in the spleen and thymus in rats.30 Also, in CFA-induced hind paw inflammation in rats, immune cells which have migrated to the inflamed tissue contain elevated levels of POMC, PENK and prodynorphin mRNA and of the corresponding opioid peptides β-endorphin, met-enkephalin and dynorphin (Fig. 3).31 The detection of mRNAs encoding opioid peptide precursors in immune cells during inflammation suggests that these peptides are synthesized locally. Histomorphological and double-staining procedures have identified the β-endorphin containing cells as T- and B-lymphocytes as well as monocytes and macrophages.31,32 Our recent studies using double immunofluorescence introduced more anatomical evidence that β-endorphin is present in activated/memory T cells. Indeed, we found that memory but not naive T cells are the predominant population in the inflamed subcutaneous tissue that contain β-endorphin.6 This is consistent with the widely held view that activated/memory T cells migrate to peripheral inflamed tissue, while naive cells typically do not enter peripheral but migrate to lymphoid tissue.33 Many studies have shown that immunocytes can produce and release β-endorphin and that this peptide is identical to its pituitary gland counterpart in terms of bioactivity, antigenicity, and molecular weight.3,23 Our double staining experiments showed that β-endorphin and the activated/memory T cell marker CD4 were largely colocalized.6 Also, some β-endorphin positive cells stained for the macrophage/monocyte marker ED1.6 Recently, we showed that recruitment of more opioid peptide-containing immune cells led to more profound analgesia.34 Accordingly, immunohistochemical procedures found a substantial increase of immune cells containing β-endorphin with the duration of inflammation (2 hours--4 days).34

Figure 3. Immunohistochemical localization of opioid peptides and corticotropin-releasing factor (CRF) in inflamed subcutaneous paw tissue in the rat.

Figure 3

Immunohistochemical localization of opioid peptides and corticotropin-releasing factor (CRF) in inflamed subcutaneous paw tissue in the rat. A, β-endorphin; B, met-enkephalin; C, dynorphin; D, CRF.

Expression of Corticotropin-Releasing Factor and Interleukin-1 (IL-1) Receptors on Immune Cells

CRF and IL-1 are the major agents releasing opioids from immune cells (reviewed in chapters 3, 7). CRF is produced predominantly in the paraventricular nucleus of the hypothalamus and delivered into portal capillaries converging in the anterior lobe of the pituitary.35 CRF is also widely expressed in extracranial tissues such as the immune system36 but at levels much lower than in hypothalamus. In parallel to the increased CRF-IR in immune cells (lymphocytes and monocytes/macrophages; Fig. 4),37 specific binding sites for radiolabeled CRF have been shown on resident macrophages of the mouse spleen,38 on human monocytes, macrophages and T lymphocytes.39 Using autoradiographic techniques we were able to detect receptors for CRF and IL-1 on monocytes/ macrophages and T lymphocytes in inflamed subcutaneous tissue (Fig. 4).40

Figure 4. Photoemulsion autoradiography of 125I-corticotropin releasing factor (CRF)- (A, B) and 125I-interleukin (IL)-1β- (D, E) binding sites in noninflamed (A, D) and inflamed (B, E) subcutaneous paw tissue in the rat.

Figure 4

Photoemulsion autoradiography of 125I-corticotropin releasing factor (CRF)- (A, B) and 125I-interleukin (IL)-1β- (D, E) binding sites in noninflamed (A, D) and inflamed (B, E) subcutaneous paw tissue in the rat.125I-interleukin (IL)-1β- (more...)

These anatomical findings are consistent with the finding that CRF or IL-1 can induce the secretion of opioid peptides from immune cells.41,42 Short-term incubation with CRF or IL-1 can release β-endorphin from immune cell suspensions prepared from lymph nodes in vitro (see ref. 3 and chapters 3, 7).

Expression of Adhesion Molecules

The mechanisms underlying the migration of opioid-containing immunocytes to inflamed tissue are beginning to be unraveled. The recruitment of immune cells to sites of inflammation is a multistep process involving the sequential activation of various adhesion molecules located on immune cells and vascular endothelium. Initially, members of the selectin family present on leukocytes (L-selectin) and endothelial cells (P- and E-selectin) tether flowing leucocytes to endothelium which subsequently roll along the blood vessel wall. In the second step, chemoattractants activating integrins and Ig superfamily members mediate firm adhesion to the endothelium. In the final step, chemotaxis and transmigration across the endothelial lining into the surrounding tissue take place, mediated by e.g., platelet-endothelial adhesion molecule-1 (PECAM-1) (see ref. 43 and chapter 7).

Using specific monoclonal antibodies against adhesion molecules we examined the expression of E-, P- and L-selectin and PECAM-1, and their co-expression with β-endorphin in inflamed and noninflamed subcutaneous tissue and lymph nodes.44 We showed that L-selectin was expressed on immune cells (lymphocytes and macrophages) in lymph nodes and on cells migrating to the inflamed subcutaneous paw tissue. P-selectin and PECAM-1 were constitutively expressed on endothelium of blood vessels in noninflamed lymph nodes and subcutaneous paw tissue and they were up-regulated in inflammation. Double immunofluorescence demonstrated that β-endorphin-positive cells stained for L-selectin in lymph nodes and inflamed subcutaneous paw tissue (Fig. 5). The β-endorphin-positive cells expressing L-selectin appeared to be more abundant in inflamed compared to noninflamed tissue. Double staining experiments revealed that P-selectin and PECAM-1 were present on endothelial cells but not on β-endorphin-positive cells in lymph nodes and subcutaneous paw tissue (Fig. 6). These findings suggest the requirement of PECAM-1, L- and P-selectin for the migration of immunocytes containing β-endorphin to peripheral inflamed tissue and indicate the involvement of adhesive mechanisms in pain control.44 Indeed, recently we showed that selectin blockade strongly reduced endogenous peripheral opioid analgesia (see ref. 1 and chapter 7).

Figure 5. Colocalization of β-endorphin and L-selectin in subcutaneous paw tissue in the rat.

Figure 5

Colocalization of β-endorphin and L-selectin in subcutaneous paw tissue in the rat. β-endorphin (red; A, B, C); L-selectin (green; A, B); L-selectin/β-endorphin (yellow; C). Bar = 20 mm. Reprinted with permission from Mousa et (more...)

Figure 6. Double-staining of β-endorphin (red) with P-selectin (green) (A, B) and with PECAM-1 (green) (D, E) in noninflamed (A, D) and inflamed (B, E) subcutaneous paw tissue in the rat.

Figure 6

Double-staining of β-endorphin (red) with P-selectin (green) (A, B) and with PECAM-1 (green) (D, E) in noninflamed (A, D) and inflamed (B, E) subcutaneous paw tissue in the rat. C and F are controls: Preabsorption of β-endorphin antiserum (more...)

Clinical Studies

Clinical trials have demonstrated the analgesic efficacy of endogenous opioids and of small, systemically inactive doses of exogenous opioid receptor agonists administered into the vicinity of peripheral nerve teminals (see refs. 45–48 and chapters 5, 7). Tissue samples from inflamed human synovia exhibited specific binding of [3H]naloxone, indicating the presence of opioid binding sites/receptors.45 Moreover, opioid receptors were identified on peripheral terminals of sensory neurons in inflamed synovial tissue from patients undergoing arthroscopic knee surgery using receptor autoradiography.47 The presence of β-endorphin was immunohistologically demonstrated in synovial tissue biopsied from patients with rheumatoid arthritis and osteoarthritis.49 The amount of β-endorphin in culture supernatants of synovial tissue explants was also determined by radioimmunoassay.49 Morphological studies revealed the presence of β-endorphin and met-enkephalin in lymphocytes, macrophages and mast cells in inflamed human synovia (Fig. 7).47

Figure 7. Immunohistochemical localization of β-endorphin in human synovium.

Figure 7

Immunohistochemical localization of β-endorphin in human synovium. A, noninflamed synovium; B, inflamed synovium. Bar = 20 μm.


The immune system is a source of opioid peptides and plays an important role in the control of inflammatory pain. Inflammation not only increases the opioid receptor expression in DRG neurons but also enhances transport and accumulation of opioid receptors on the peripheral terminals of sensory neurons. Immune cells containing opioid peptides migrate to the inflamed tissue. This is orchestrated by adhesion molecules up-regulated on vessel endothelia and co-expressed by opioid-containing immunocytes. The peptides are secreted by stressful stimuli, CRF and cytokines and the corresponding receptors are present on opioid-expressing leukocytes. The opioids bind to their receptors localized on peripheral sensory nerves leading to pain inhibion. In the more distant future, these findings might stimulate the development of novel analgesics based on enhancing the transport and release of immune-derived opioid peptides into injured tissue.


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