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Biomedical subjects

Christoph Stein

Publications and source records attributed to Christoph Stein.

At least 19 recordsLinked to original sources
PubMed2007

Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and beta-endorphin during painful inflammation in vivo.

Proopiomelanocortin (POMC)-derived beta-endorphin1-31 (END) released from immune cells inhibits inflammatory pain. We examined the expression of END and POMC mRNA encoding the signal sequence required for entry of the nascent polypeptide into the regulated secretory pathway in lymphocytes of rats with inflamed hindpaws. Within 12 h of inflammation, END increased in popliteal lymph nodes and at 96 h the intraplantar neutralization of END exacerbated pain. Lymphocytes expressed POMC, END, and full-length POMC mRNA. Semi-nested PCR revealed 8-fold increased exon 2-3 spanning POMC mRNA. Thus, painful inflammation enhances signal sequence-encoding lymphocytic POMC mRNA needed for regulated secretion of functionally active END.

Animals↗
PubMed2006

Influence of pain treatment by epidural fentanyl and bupivacaine on homing of opioid-containing leukocytes to surgical wounds.

Endogenous opioids released from leukocytes extravasating into injured tissue can interact with peripheral opioid receptors to inhibit nociception. Animal studies have shown that the homing of opioid-producing leukocytes to the injured site is modulated by spinal blockade of noxious input. This study investigated whether epidural analgesia (EDA) influences the migration of beta-endorphin (END) and/or met-enkephalin (ENK)-containing leukocytes into the subcutaneous wound tissue of patients undergoing abdominal surgery. In part I patients received general anesthesia combined either with intra- and postoperative EDA (with bupivacaine and fentanyl) or with postoperative patient controlled intravenous analgesia (PCIA; with the opioid piritramide). In part II patients received general anesthesia combined with either epidural fentanyl or bupivacaine which was continued postoperatively. Samples of cutanous and subcutanous tissue were taken from the wound site at the beginning, at the end and at various times after surgery, and were examined by immunohistochemistry for the presence of END and ENK. We found that (i) epidural bupivacaine, fentanyl and PCIA provided similar and clinically acceptable postoperative pain relief; (ii) compared to PCIA, epidural bupivacaine or fentanyl did not change the gross inflammatory reaction within the surgical wound; (iii) opioid-containing leukocytes were almost absent in normal subcutaneous tissue but migrated to the inflamed wound tissue in ascending numbers within a few hours, reaching a peak at about 24 h after surgery; (iv) compared to PCIA, EDA resulted in significantly decreased homing of END-containing leukocytes to the injured site at 24 h after surgery; and (v) the magnitude of this decrease was similar regardless of the epidural medication. These findings suggest that nociceptive but not sympathetic neurons are primarily involved in the attraction of opioid-containing leukocytes during early stages of inflammation.

Adjuvants, Anesthesia↗
PubMed2006

Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells.

Leukocytes counteract inflammatory pain by releasing opioid peptides, which bind to opioid receptors on peripheral sensory neurons. In the early phase of inflammation, polymorphonuclear cells (PMN) are the major source of opioids. Their recruitment is governed by ligands at the chemokine receptor CXCR2. Here, we examined whether chemokines can also induce opioid peptide secretion from PMN and thus inhibit inflammatory pain. In rats with hindpaw inflammation, intraplantar injection of CXCL2/3, but not of the CXCR4 ligand CXCL12, elicited naloxone-reversible (i.e., opioid receptor mediated) mechanical and thermal analgesia, which was abolished by systemic PMN depletion. Both CXCR1/2- and CXCR4-ligands induced PMN chemotaxis, but only CXCR1/2 ligands triggered opioid release from human and rat PMN in vitro. This release was unaltered by extracellular Ca2+ chelation, was mimicked by thapsigargin and was blocked by inhibitors of the inositol 1,4,5-triphosphate receptor (IP3) and by intracellular Ca2+ chelation, indicating that it required Ca2+ from intracellular but not extracellular sources. Furthermore, release was partially reduced by phosphoinositol-3-kinase (PI3K) inhibitors. Adoptive transfer of allogenic PMN into PMN-depleted rats reconstituted CXCL2/3-induced analgesia, which was inhibited by prior ex vivo chelation of intracellular Ca2+. These findings demonstrate that, beyond cell recruitment, CXCR2 ligands induce Ca2+-regulated opioid release from PMN and thereby inhibit inflammatory pain in vivo.

Analgesics↗
PubMed2006

Mu-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain.

Current therapy for inflammatory pain includes the peripheral application of opioid receptor agonists. Activation of opioid receptors modulates voltage-gated ion channels, but it is unclear whether opioids can also influence ligand-gated ion channels [e.g., the transient receptor potential vanilloid type 1 (TRPV1)]. TRPV1 channels are involved in the development of thermal hypersensitivity associated with tissue inflammation. In this study, we investigated mu-opioid receptor and TRPV1 expression in primary afferent neurons in the dorsal root ganglion (DRG) in complete Freund's adjuvant (CFA)-induced paw inflammation. In addition, the present study examined whether the activity of TRPV1 in DRG neurons can be inhibited by mu-opioid receptor (mu-receptor) ligands and whether this inhibition is increased after CFA inflammation. Immunohistochemistry demonstrated colocalization of TRPV1 and mu-receptors in DRG neurons. CFA-induced inflammation increased significantly the number of TRPV1- and mu-receptor-positive DRG neurons, as well as TRPV1 binding sites. In whole-cell patch clamp studies, opioids significantly decreased capsaicin-induced TRPV1 currents in a naloxone- and pertussis toxinsensitive manner. The inhibitory effect of morphine on TRPV1 was abolished by forskolin and 8-bromo-cAMP. During inflammation, an increase in TRPV1 is apparently rivaled by an increase of mu-receptors. However, in single dissociated DRG neurons, the inhibitory effects of morphine are not different between animals with and without CFA inflammation. In in vivo experiments, we found that locally applied morphine reduced capsaicin-induced thermal allodynia. In summary, our results indicate that mu-receptor activation can inhibit the activity of TRPV1 via G(i/o) proteins and the cAMP pathway. These observations demonstrate an important new mechanism underlying the analgesic efficacy of peripherally acting mu-receptor ligands in inflammatory pain.

Animals↗
PubMed2006

Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain.

Endomorphins (EMs) are endogenous selective mu-opioid receptor agonists. Their role in inflammatory pain has not been fully elucidated. Here we examine peripheral antinociception elicited by exogenously applied EM-1 and EM-2 and the contribution of EM-containing leukocytes to stress- and corticotropin-releasing factor (CRF)-induced antinociception. To this end, we applied behavioral (paw pressure) testing, radioligand binding, immunohistochemistry, and flow cytometry in rats with unilateral hindpaw inflammation induced with Freund's adjuvant. EMs injected directly into both hindpaws produced antinociception exclusively in inflamed paws. This was blocked by locally applied mu-receptor-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) but not kappa-receptor-selective (nor-binaltorphimine) antagonists. Delta-receptor antagonists (naltrindole and N,N-diallyl-Tyr-Aib-Aib-Phe-Leu) did not influence EM-1-induced but dose-dependently decreased EM-2-induced antinociception. Antibodies against beta-endorphin, methionine-enkephalin, or leucine-enkephalin did not significantly change EM-2-induced antinociception. Both EMs displaced binding of [3H]-[D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin to mu-receptors in dorsal root ganglia (DRG). Using [3H]-naltrindole or [(125)I]-[D-Pen2,5]-enkephalin, no detectable delta-binding was found in DRG of inflamed hindlimbs. Numerous beta-endorphin-containing and fewer EM-1- and EM-2-containing leukocytes were detected in subcutaneous tissue of inflamed paws. Leukocyte-depleting serum decreased the number of immigrating opioid-containing immune cells and attenuated swim stress- and CRF-induced antinociception in inflamed paws. Both forms of antinociception were strongly attenuated by anti-beta-endorphin and to a lesser degree by anti-EM-1 and anti-EM-2 antibodies injected into inflamed paws. Together, exogenously applied and immune cell-derived EMs alleviate prolonged inflammatory pain through selective activation of peripheral opioid receptors. Exogenous EM-2 in addition to mu-receptors also activates peripheral delta-receptors, which does not involve actions via other opioid peptides.

Analgesics↗
PubMed2006

Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain.

Polymorphonuclear cells (PMN) are recruited in early inflammation and are believed to contribute to inflammatory pain. However, studies demonstrating a hyperalgesic role of PMN did not examine selective PMN recruitment or did not document effective PMN recruitment. We hypothesized that hyperalgesia does not develop after chemokine-induced PMN selective recruitment and is independent of PMN infiltration in complete Freund's adjuvant (CFA)-induced, local inflammation. PMN were recruited by intraplantar injection of CXC chemokine ligand 1 (CXCL1; keratinocyte-derived chemokine), CXCL2/3 (macrophage inflammatory protein-2), or CFA, with or without preceding systemic PMN depletion. Chemokine inoculation resulted in dose (0-30 microg)- and time (0-12 h)-dependent, selective recruitment of PMN as quantified by flow cytometry. CXCL2/3, but not CXCL1, was less effective at high doses, probably as a result of significant down-regulation of CXC chemokine receptor 2 expression on blood PMN. Neither chemokine caused mechanical or thermal hyperalgesia as determined by the Randall-Selitto and Hargreaves test, respectively, despite comparable expression of activation markers (i.e., CD11b, CD18, and L-selectin) on infiltrating PMN. In contrast, CFA injection induced hyperalgesia, independent of PMN recruitment. c-Fos mRNA and immunoreactivity in the spinal cord were increased significantly after inoculation of CFA-independent of PMN-migration but not of CXCL2/3. Measurement of potential hyperalgesic mediators showed that hyperalgesia correlated with local prostaglandin E2 (PGE2) but not with interleukin-1beta production. In summary, hyperalgesia, local PGE2 production, and spinal c-Fos expression occur after CFA-induced inflammation but not after CXCL1- or CXCL2/3-induced, selective PMN recruitment. Thus, PMN seem to be less important in inflammatory hyperalgesia than previously thought.

Animals↗
PubMed2005

Controlling pain by influencing neurogenic pathways.

Neurogenic inflammation and ensuing pain can be modulated by inhibiting the function of primary afferent neurons. The best studied mechanism to accomplish such inhibition is the opioid system. Under inflammatory conditions, the anterograde axonal transport of opioid receptors from dorsal root ganglia toward the peripheral sensory nerve endings is augmented. The increased number of opioid receptors (among other mechanisms) leads to improved analgesic effects of exogenously administered ligands (eg, morphine) and of endogenous leukocyte-derived opioid peptides (eg, beta-endorphin). A current concept proposes that during inflammatory processes endogenous opioid peptides can be secreted from immunocytes, occupy peripheral opioid receptors on sensory nerve endings, and produce analgesia by inhibiting the excitability of these nerves or the release of proinflammatory neuropeptides. This article focuses on the role of peripheral opioid receptors in pain control and on novel pharmaceutical concepts for the treatment of patients who suffer from rheumatoid arthritis and other inflammatory pain.

Analgesics, Opioid↗
PubMed2005

Perioperative management of the chronic pain patient.

The chronic pain patient has certain distinctive features important for her/his perioperative management. Altered opioid sensitivity and behavior are the major points to be considered. The pre-anesthetic visit should therefore include questions regarding chronic pain and regular use of analgesics and coanalgesics, among others. Although a number of characteristics-including increased opioid demand, underreporting of pain, and non-compliance--are known, only a few specific recommendations are available, viz. adequate increase of opioid dose for analgesia, continuation of pre-operative opioids and coanalgesics to prevent withdrawal, and intensive education to strengthen the patient's coping potential. No differences between specific techniques for post-operative analgesia (e.g. systemic, patient-controlled or regional analgesia) have been shown so far.

Analgesia↗
PubMed2004

Selectins and integrins but not platelet-endothelial cell adhesion molecule-1 regulate opioid inhibition of inflammatory pain.

1. Control of inflammatory pain can result from activation of opioid receptors on peripheral sensory nerves by opioid peptides secreted from leukocytes in response to stress (e.g. experimental swim stress or surgery). The extravasation of immunocytes to injured tissues involves rolling, adhesion and transmigration through the vessel wall, orchestrated by various adhesion molecules. 2. Here we evaluate the relative contribution of selectins, integrins alpha(4) and beta(2), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) to the opioid-mediated inhibition of inflammatory pain. 3. We use flow cytometry, double immunofluorescence and nociceptive (paw pressure) testing in rats with unilateral hind paw inflammation induced by complete Freund's adjuvant. 4. In inflamed tissue, 43-58% of hematopoietic cells (CD45(+)) expressed opioid peptides. L-selectin and beta(2) were coexpressed by 7 and 98% of opioid-containing leukocytes, respectively. Alpha(4) integrin was expressed in low levels by the majority of leukocytes. Opioid-containing cells, vascular P- and E-selectin and PECAM-1 were simultaneously upregulated. 5. Swim stress produced potent opioid-mediated antinociception in inflamed tissue, unaffected by blockade of PECAM-1. However, blockade of L- and P-selectins by fucoidin, or of alpha(4) and beta(2) by monoclonal antibodies completely abolished peripheral stress-induced antinociception. This coincided with a 40% decrease in the migration of opioid-containing leukocytes to inflamed tissue. 6. These findings establish selectins and integrins alpha(4) and beta(2), but not PECAM-1, as important molecules involved in stress-induced opioid-mediated antinociception in inflammation. They point to a cautious use of anti-inflammatory treatments applying anti-selectin, anti-alpha(4) and anti-beta(2) strategies because they may impair intrinsic pain inhibition.

Animals↗
PubMed2004

Endogenous peripheral antinociception in early inflammation is not limited by the number of opioid-containing leukocytes but by opioid receptor expression.

Endogenous inhibition of inflammatory pain is mediated by leukocytes that secrete opioid peptides upon exposure to stress (cold water swim stress, CWS) or after local injection of corticotropin releasing factor (CRF). Since in early inflammation few opioid-containing leukocytes are detected and since peripheral opioid-mediated antinociception is low we examined whether antinociception could be augmented by increased recruitment of opioid-containing polymorphonuclear cells (PMN). Rats were intraplantarly (i.pl.) injected with Freund's complete adjuvant (FCA) and with the PMN-recruiting chemokine macrophage inflammatory protein-2 (MIP-2, 1-10 microg; control: saline) for 2 h. Intraplantar leukocytes were quantified by flow cytometry. Paw pressure threshold (PPT) was determined before and after exposure to CWS, i.pl. injection of CRF and opioid peptides. Opioid receptors (OR) were measured by binding studies in dorsal root ganglia (DRG) and by immunohistochemistry in the paw. Our studies showed that (i) MIP-2 injection dose-dependently augmented recruitment of PMN and opioid-containing leukocytes (5-fold increase in cells/paw, P < 0.05), (ii) PPT was not different between groups at baseline and after CWS or CRF (maximum MPE: 20+/-2.3-29+/-7.2%, P < 0.05), (iii) injection of opioid peptides dose-dependently increased the PPT (P < 0.05, maximum MPE: and 18+/-2.6-21+/-3.6%), (iv) MOR (micro OR, MOP) binding sites in the ipsilateral DRG were unchanged (24+/-2-22+/-1.2 fmol/mg protein, P < 0.05, ANOVA) and (v) the number of MOR and DOR (delta OR, DOP) stained nerve fibers in peripheral tissue were unaltered (both P > 0.05, t-test). In summary, antinociception during early inflammation is apparently not limited by the number of opioid-containing leukocytes but by OR availability.

Animals↗
PubMed2004

Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells.

Opioid-containing leukocytes can counteract inflammatory hyperalgesia. Under stress or after local injection of corticotropin releasing factor (CRF), opioid peptides are released from leukocytes, bind to opioid receptors on peripheral sensory neurons and mediate antinociception. Since polymorphonuclear cells (PMN) are the predominant opioid-containing leukocyte subpopulation in early inflammation, we hypothesized that PMN and their recruitment by chemokines are important for peripheral opioid-mediated antinociception at this stage. Rats were intraplantarly injected with complete Freund's adjuvant (CFA). Using flow cytometry, immunohistochemistry, and ELISA, leukocyte subpopulations, chemokine receptor (CXCR2) expression on opioid-containing leukocytes and the CXCR2 ligands keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant-2 (CINC-2) were quantified. Paw pressure threshold (PPT) was determined before and after intraplantar and subcutaneous injection of CRF with or without naloxone. PMN depletion was achieved by intravenous injection of an antiserum. Chemokines were blocked by intraplantar injection of anti-MIP-2 and/or anti-KC antiserum. We found that at 2 h post CFA (i) intraplantar but not subcutaneous injection of CRF produced dose-dependent and naloxone-reversible antinociception (P<0.05, ANOVA). (ii) Opioid-containing leukocytes in the paw and CRF-induced antinociception were reduced after PMN depletion (P<0.05, t-test). (iii) Opioid-containing leukocytes mostly expressed CXCR2. MIP-2 and KC, but not CINC-2 were detectable in inflamed but not in noninflamed tissue (P<0.05, ANOVA). (iv) Combined but not single blockade of MIP-2 and KC reduced the number of opioid-containing leukocytes and peripheral opioid-mediated antinociception (P<0.05, t-test; P>0.05, ANOVA). In summary, in early inflammation peripheral opioid-mediated antinociception is critically dependent on PMN and their recruitment by CXCR2 chemokines.

Analysis of Variance↗
PubMed2004

Mobilization of opioid-containing polymorphonuclear cells by hematopoietic growth factors and influence on inflammatory pain.

BACKGROUND: Leukocytes can control inflammatory pain by secretion of opioid peptides, stimulated by cold-water swimming or local injection of corticotropin-releasing factor, and subsequent activation of opioid receptors on peripheral sensory neurons. This study investigated whether mobilization of polymorphonuclear cells (PMN) by granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) enhances immigration of opioid-containing PMN and peripheral opioid analgesia in rats with Freund complete adjuvant-induced hind paw inflammation. METHODS: In circulating PMN of rats treated with G-CSF+SCF and sham-treated rats, opioid peptide content was measured by radioimmunoassay. Expression of adhesion molecules (CD62L, CD49d, CD18), in vitro migration in the Boyden chamber, and infiltrating leukocytes were analyzed by flow cytometry. Chemokine messenger RNA transcription was quantified by LightCycler polymerase chain reaction. Paw pressure threshold was measured at baseline, after cold-water swimming, and after injection of corticotropin-releasing factor. RESULTS: G-CSF+SCF treatment increased circulating PMN (11-fold, P < 0.05). Mobilized PMN had decreased content of beta-endorphin but not of Met-enkephalin per cell, down-regulation of CD62L, up-regulation of CD49d (but no change in CD18), and reduced migration toward higher chemokine concentrations (all P < 0.05). In the paw, one of four chemokine messenger RNAs was significantly expressed during the first 2 h of inflammation (P < 0.05), immigration of PMN and opioid-containing cells was slightly increased (1.5-fold, P < 0.05), and baseline paw pressure threshold, as well as paw pressure threshold increases induced by corticotropin-releasing factor and cold-water swimming, were unchanged (P > 0.05). CONCLUSIONS: G-CSF+SCF mobilized circulating opioid-containing PMN but had a minor influence on cell migration and peripheral analgesia, probably because of the low expression of chemokines in the inflamed paw and one of the decreased beta-endorphin content in PMN.

Animals↗
PubMed2004

Altered cell-mediated immunity and increased postoperative infection rate in long-term alcoholic patients.

BACKGROUND: Preoperative alteration of T cell-mediated immunity as well as an altered immune response to surgical stress were found in long-term alcoholic patients. The aim of this study was to evaluate perioperative T cell-mediated immune parameters as well as cytokine release from whole blood cells after lipopolysaccharide stimulation and its association with postoperative infections. METHODS: Fifty-four patients undergoing elective surgery of the aerodigestive tract were included in this prospective observational study. Long-term alcoholic patients (n = 31) were defined as having a daily ethanol consumption of at least 60 g and fulfilling the Diagnostic and Statistical Manual of Mental Disorders for either alcohol abuse or alcohol dependence. The nonalcoholic patients (n = 23) were defined as drinking less than 60 g ethanol/day. Blood samples to analyze the immune status were obtained on morning before surgery and on the morning of days 1, 3, and 5 after surgery. RESULTS: Basic patient characteristics did not differ between groups. Before surgery, the T helper 1:T helper 2 ratio (Th1: Th2) was significantly lower (P < 0.01), whereas plasma interleukin 1beta and lipopolysaccharide-stimulated interleukin 1ra from whole blood cells were increased in long-term alcoholic patients. After surgery, a significant suppression of the cytotoxic lymphocyte ratio (Tc1:Tc2), the interferon gamma:interleukin 10 ratio from lipopolysaccharide-stimulated whole blood cells, and a significant increase of plasma interleukin 10 was observed. Long-term alcoholics had more frequent postoperative infections compared with nonalcoholic patients (54%vs. 26%; P = 0.03). CONCLUSIONS: T helper cell-mediated immunity was significantly suppressed before surgery and possibly led to inadequate cytotoxic lymphocyte and whole blood cell response in long-term alcoholic patients after surgery. This altered cell-mediated immunity might have accounted for the increased infection rate in long-term alcoholic patients after surgery.

Alcoholism↗
PubMed2004

Tissue monocytes/macrophages in inflammation: hyperalgesia versus opioid-mediated peripheral antinociception.

BACKGROUND: Opioid-containing leukocytes migrate to peripheral sites of inflammation. On exposure to stress, opioid peptides are released, bind to opioid receptors on peripheral sensory neurons, and induce endogenous antinociception. In later stages of Freund's complete adjuvant-induced local inflammation, monocytes/macrophages are a major opioid-containing leukocyte subpopulation, but these cells also produce proalgesic cytokines. In this study, the role of tissue monocytes/macrophages in hyperalgesia and in peripheral opioid-mediated antinociception was investigated. METHODS: After intraplantar injection of Freund's adjuvant, leukocyte subpopulations and opioid-containing leukocytes were analyzed by flow cytometry in the inflamed paw in the presence or absence of monocyte/macrophage depletion by intraplantar injection of clodronate-containing liposomes (phosphate-buffered saline and empty liposomes served as controls). Paw volume was measured with a plethysmometer. Hyperalgesia was determined by measuring heat-induced paw withdrawal latency and paw pressure threshold. Paw pressure threshold was also measured after swim stress and injection of fentanyl. RESULTS: At 48 and 96 h of inflammation, it was found that (1). monocytes/macrophages were the largest leukocyte subpopulation (> 55% of all leukocytes) and the predominant producers of opioid peptides (71-77% of all opioid-containing leukocytes in the paw), (2). clodronate-containing liposomes depleted monocytes/macrophages by 30-35% (P < 0.05), (3). hyperalgesia was unaltered by liposome injection (P > 0.05), and (4) opioid-containing leukocytes and swim stress but not fentanyl-induced antinociception were significantly decreased by clodronate-containing liposomes (P < 0.05, P > 0.05, all by t test; opioid-containing cells and swim stress-induced increase of paw pressure threshold were reduced by 35-42% and 20%, respectively). CONCLUSION: Partial depletion of tissue monocytes/macrophages impairs peripheral endogenous opioid-mediated antinociception without affecting hyperalgesia.

Analgesics, Non-Narcotic↗
PubMed2004

Neurogenic painful inflammation.

PURPOSE OF REVIEW: Neurogenic inflammation results from the release of neuropeptides from peripheral nerve terminals. This secretion can be induced by two mechanisms: activation of afferent sensory nerves (e.g. by disease processes or experimentally by electrical stimulation) or activation of receptors expressed on peripheral nerve terminals. While the role of these mechanisms in the regulation of inflammation is well described, its significance for the generation of pain is much less clear and will be examined in this review. RECENT FINDINGS: Activation of two receptors on peripheral sensory neurons (i.e. transient receptor potential vanilloid-1 channel and proteinase activated receptor-2) has been shown to induce neurogenic inflammation. Interference with this activation can ameliorate pain, but it remains uncertain whether this effect is indeed mediated by blockage of neurogenic inflammation. Two human diseases (complex regional pain syndrome and migraine) are believed to result from aberrant neuronal activation. In complex regional pain syndrome, studies in human patients and in a recently established animal model do not support a role for neurogenic inflammation in pain. In migraine, antagonists to the receptor for calcitonin gene related peptide ameliorated headache and could be the first conclusive evidence for the role of neurogenic inflammation in the generation of pain. Lastly, spinal mechanisms also appear to regulate immune cell recruitment to a peripheral site and seem to interfere with antinociception. SUMMARY: While considerable experimental and clinical evidence supports the existence of neurogenic inflammation, it is less clear whether this process plays an important role in the generation of pain.

Journal Article↗
PubMed2004

Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue.

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.

Adrenergic alpha-Antagonists↗
PubMed2003

Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain.

The opioid peptide beta-endorphin (END) as well as mRNA for its precursor proopiomelanocortin (POMC) are found not only in the pituitary gland, but also within various types of immune cells infiltrating inflamed sc tissue. During stressful stimuli END is released and interacts with peripheral opioid receptors to inhibit pain. However, the subcellular pathways of POMC processing and END release have not yet been delineated in inflammatory cells. The aim of the present study was to examine the presence of POMC, carboxypeptidase E, the prohormone convertases 1 (PC1), and 2 (PC2), PC2-binding protein 7B2, and the release of END from inflammatory cells in rats. Using immunohistochemistry we detected END and POMC alone or colocalized with PC1, PC2, carboxypeptidase E, and 7B2 in macrophages/monocytes, granulocytes, and lymphocytes of the blood and within inflamed sc paw tissue. Immunoelectron microscopy revealed that END is localized within secretory granules packed in membranous structures in macrophages, monocytes, granulocytes, and lymphocytes. Finally, END is released by noradrenaline from immune cells in vitro. Taken together, our results indicate that immune cells express the entire machinery required for POMC processing into functionally active peptides such as END and are able to release these peptides from secretory granules.

Animals↗