PubMed Health⌕ Search

Biomedical subjects

Alexander Brack

Publications and source records attributed to Alexander Brack.

14 recordsLinked to original sources
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

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↗
PubMed2006

Chemokines and pain.

Chemokines are chemotactic mediators controlling cell trafficking under physiological and pathological conditions. Recently, it has been discovered that chemokines are not only important in various inflammatory conditions, but that they also play a role in pain and analgesia. Chemokine function in the periphery has been evaluated under non-inflammatory, inflammatory and neuropathic conditions. While many studies have examined the hyperalgesic action of chemokines, increasing evidence points to the antinociceptive properties of chemokines. This review focuses on the role of chemokines in the peripheral tissue.

Analgesics↗
PubMed2005

Extensive abscess formation after repeated paravertebral injections for the treatment of chronic back pain.

Paravertebral injections are commonly used for the treatment of chronic back pain despite the lack of evidence for their efficacy. Here, we report a case in which repeated paravertebral injections of local anesthetics, corticosteroids and botulinum toxin resulted in extensive abscess formation involving the entire paravertebral musculature descending to the level of the midthighs. These abscesses induced a systemic inflammatory response syndrome and required surgical drainage as well as broad-spectrum antibiotic therapy.

Abdominal Abscess↗
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

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↗
PubMed2003

Modulation of peripheral endogenous opioid analgesia by central afferent blockade.

BACKGROUND: Peripheral tissue injury causes a migration of opioid peptide-containing immune cells to the inflamed site. The subsequent release and action of these peptides on opioid receptors localized on peripheral sensory nerve terminals causes endogenous analgesia. The spinal application of opioid drugs blocks the transmission of nociceptive information from peripheral injury. This study investigates the influence of exogenous spinal opioid analgesia on peripheral endogenous opioid analgesia. METHODS: Six and forty-eight hours after initiation of continuous intrathecal morphine infusion and administration of Freund's complete adjuvant into the hind paw of rats, antinociceptive and antiinflammatory effects were measured by paw pressure threshold, paw volume, and paw temperature, respectively. Inflammation and quantity of opioid-containing cells were evaluated by immunocytochemistry and flow cytometry. Cold water swim stress-induced endogenous analgesia was examined 24 h after discontinuation of intrathecal morphine administration. RESULTS: Intrathecal morphine (10 micro g/h) resulted in a significant and stable increase of paw pressure threshold ( P< 0.05) without changing inflammation, as evaluated by paw volume, paw temperature, and flow cytometry ( P> 0.05). At 48 but not at 6 h after Freund's complete adjuvant, the number of beta-endorphin-containing cells and cold water swim-induced antinociception were significantly reduced in intrathecal morphine-treated rats compared with those treated with intrathecal vehicle ( P< 0.05). CONCLUSIONS: These findings suggest an interplay of central and peripheral mechanisms of pain control. An effective central inhibition of pain apparently signals a reduced need for recruitment of opioid-containing immune cells to injured sites.

Analgesics, Opioid↗
PubMed2003

Pro-algesic versus analgesic actions of immune cells.

PURPOSE OF REVIEW: When tissue is destroyed, pain arises. Tissue destruction is associated with an inflammatory reaction. This leads to activation of nociceptors. The following review will concentrate on pro-algesic and analgesic mediators, which arise from immune cells or resident cells in the periphery or the circulation during inflammation. RECENT FINDINGS: In early inflammation endogenous hyperalgesic mediators are produced, including cytokines, chemokines, nerve growth factor as well as bradykinin, prostaglandins and ATP. Simultaneously, analgesic mediators are secreted: opioid peptides, somatostatin, endocannabinoids and certain cytokines. Inflammation increases the expression of peripheral opioid receptors on sensory nerve terminals and enhances their signal transduction, as well as the amount of opioid peptides in infiltrating immune cells. Interference with the recruitment of opioid-containing immune cells into inflamed tissue by blockade of adhesion molecules or by intrathecal morphine injection reduces endogenous analgesia. SUMMARY: Inflammatory pain is the result of the interplay between pro-algesic and analgesic mediators. To avoid central side effects, future analgesic therapy should be targeted at either selectively blocking novel pro-algesic mediators or at enhancing endogenous peripheral analgesic effects.

Journal Article↗
PubMed2002

Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1.

Pain can be effectively controlled by endogenous mechanisms based on neuroimmune interactions. In inflamed tissue immune cell-derived opioid peptides activate opioid receptors on peripheral sensory nerves leading to potent analgesia. This is brought about by a release of opioids from inflammatory cells after stimulation by stress or corticotropin-releasing hormone (CRH). Immunocytes migrate from the circulation to inflamed tissue in multiple steps, including their rolling, adhesion, and transmigration through the vessel wall. This is orchestrated by adhesion molecules on leukocytes and vascular endothelium. Intercellular adhesion molecule-1 [ICAM-1 (or CD54)] is expressed by endothelium and mediates adhesion and extravasation of leukocytes. The goal of this study was to show that ICAM-1 regulates the homing of opioid-producing cells and the subsequent generation of analgesia within sites of painful inflammation. This was accomplished using immunofluorescence, flow cytometry, and behavioral (paw pressure) testing. We found that ICAM-1 is upregulated on the vascular endothelium, simultaneously with an enhanced immigration of opioid-containing immune cells into inflamed paw tissue. The intravenous administration of a monoclonal antibody against ICAM-1 markedly decreased the migration of opioid-containing leukocytes and of granulocytes, monocytes-macrophages, and T cells to the inflamed tissue. At the same time, circulating immunocytes increased in numbers, and macroscopic inflammation (hyperalgesia, paw volume, and paw temperature) remained primarily unchanged. Most importantly, peripheral opioid analgesia elicited either by cold water swim stress or by intraplantar administration of CRH was dramatically reduced. Together, these findings indicate that ICAM-1 expressed on vascular endothelium recruits immunocytes containing opioids to promote the local control of inflammatory pain.

Analgesia↗