Evidence for an increase in the release of CGRP from sensory nerves during inflammation.
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Animals↗
Biomedical subjects
C Stein
Publications and source records attributed to C Stein.
Conditioning of opioid reinforcement: neuroanatomical and neurochemical substrates.
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Animals↗
Dynorphin, a preferential ligand for kappa-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat.
Exogenous kappa-opioid agonists have been shown to produce peripheral antinociceptive effects in inflamed tissue. This study sought to determine whether endogenous kappa-receptor ligands are present at the site of inflammation. In Freund's adjuvant-induced hindpaw inflammation in the rat, we show, by immunohistochemistry, that dynorphin is detectable within inflammatory cells and in the cutaneous nerves in a similar distribution as calcitonin gene-related peptide, a specific marker for sensory neurons. These findings extend our previous observations in that not only beta-endorphin and Met-enkephalin (mu- and delta-receptor ligands), but also a preferential kappa-ligand is present within inflamed subcutaneous tissue.
Animals↗
Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo.
The responses of sensory neuropeptides during unilateral, Freund's adjuvant-induced, paw inflammation in the rat were examined. After five days of inflammation, the substance P and calcitonin gene-related peptide content in the sciatic nerve supplying the inflamed paw were increased by 60-75% when compared with the contralateral side. At this time-point, there was also a 30-40% increase in the substance P and calcitonin gene-related peptide content of the dorsal root ganglia (L4-L6), and a 40% increase in the calcitonin gene-related peptide content of the L4-L6 segments of the dorsal spinal cord on the inflammation side. In the dorsal root ganglia, calcitonin gene-related peptide content was also increased as early as 12 h and 48 h after induction of paw inflammation. On day 5 of inflammation, the axonal transport of both sensory neuropeptides towards the inflamed paw, as determined after sciatic nerve ligation, was also markedly increased as compared with the control side. Despite this increased transport, the amount of substance P and calcitonin gene-related peptide present in the inflamed paw itself was either reduced or remained unchanged from day 1 through to day 5 of inflammation pointing towards reduced storage and increased release of the peptides in the inflamed tissue. Nerve growth factor content was markedly increased in the sciatic nerve of the inflamed paw with a peak of +136% at time-point 24 h after induction of inflammation. When rats were systemically treated with anti-nerve growth factor serum, the increase in neuropeptide content in the sciatic nerve of the inflamed paw (day 5) was prevented. On the other hand, local injections of nerve growth factor for 5 days into a noninflamed paw were able to induce an increase in substance P and calcitonin gene-related peptide content in the supplying sciatic nerve. These findings point towards a regulatory function for nerve growth factor in vivo in the stimulation of sensory neuropeptide synthesis during prolonged inflammatory processes.
Animals↗
Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception.
Our previous studies indicate that endogenous opioids (primarily beta-endorphin) released during stressful stimuli can interact with peripheral opioid receptors to inhibit nociception in inflamed tissue of rats. This study sought to localize opioid precursor mRNAs and opioid peptides deriving therefrom in inflamed tissue, identify opioid containing cells and demonstrate their functional significance in the inhibition of nociception. In rats with Freund's adjuvant-induced unilateral hindpaw inflammation we show that: (i) pro-opiomelanocortin and proenkephalin-mRNAs (but not prodynorphin mRNA) are abundant in cells of inflamed, but absent in non-inflamed tissue; (ii) numerous cells infiltrating the inflamed subcutaneous tissue are stained intensely with beta-endorphin and [Met]enkephalin (but only few scattered cells with dynorphin) antibodies; (iii) beta-endorphin is present in T- and B-lymphocytes, monocytes and macrophages; and (iv) whole-body irradiation suppresses stress-induced antinociception in the inflamed paw. Taken together, these data suggest that endogenous opioid peptides are synthesized and processed within various types of immune cells at the site of inflammation. Immunosuppression abolishes the intrinsic antinociception in inflammatory tissue confirming the functional significance of these cells.
Analysis of Variance↗
Effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy.
We have investigated the effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy. At the end of surgery, an interpleural catheter was inserted in 17 patients and, in a double-blind and randomized manner, either a bolus of morphine 2.5 mg interpleurally (i.p.) and normal saline i.v. (group I) or, as a control for systemic absorption, morphine 2.5 mg i.v. and i.p. saline (group II) was injected. After the initial bolus, a continuous infusion of morphine 0.5 mg h-1 i.p. and saline i.v. (group I) or morphine 0.5 mg i.v. and saline i.p. (group II) was maintained for 24 h. Postoperative pain was assessed by a visual analogue scale, a numerical rating scale and the McGill Pain Questionnaire. Pulmonary function was assessed by spirometry. Supplementary analgesics, side effects, degree of sedation, vital signs and chest tube drainage were recorded. All variables were assessed on the day before surgery and 1, 2, 3, 4, 5, 6 and 24 h and 7 days after surgery. Supplementary morphine was given upon request. There was no significant difference in any pain measure or postoperative pulmonary function variable between the groups. We conclude that, after thoracotomy, interpleural morphine does not provide superior analgesia or improve pulmonary function compared with systemic morphine.
Forced Expiratory Volume↗
Intraarticular morphine, bupivacaine, and morphine/bupivacaine for pain control after knee videoarthroscopy.
Evidence has accumulated that opioids can produce potent antinociceptive effects by interacting with opioid receptors in peripheral tissues. This study sought to compare the effects of morphine with those of bupivacaine administered intraarticularly upon pain following arthroscopic knee surgery. In a double-blind, randomized manner, 33 patients received either morphine (1 mg in 20 ml NaCl; n = 11), bupivacaine (20 ml, 0.25%; n = 11), or a combination of the two (n = 11) intraarticularly at the completion of surgery. After 1, 2, 3, and 4 h and at the end of the 1st and 2nd postoperative days, pain was assessed by a visual analogue scale, and supplemental analgesic requirements were recorded. Pain scores were significantly greater in the morphine group than in the other two groups at 1 h. There were no significant differences at 2 and 3 h. From 4 h until the end of the study period, pain scores were significantly greater in the bupivacaine group than in the other two groups. Analgesic requirements were significantly greater in the morphine group than in the other groups at 1 h but were significantly greater in the bupivacaine group than in the other groups throughout the remainder of the study period. We conclude that intraarticular morphine produces an analgesic effect of delayed onset but of remarkably long duration. The combination of these two drugs results in satisfactory analgesia throughout the entire observation period.
Adult↗
Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer.
PURPOSE: Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. PATIENTS AND METHODS: Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2. RESULTS: In 17 patients with measurable soft tissue disease, three had complete disappearance of soft tissue disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with soft tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. CONCLUSION: We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.
Aged↗
Analgesic effect of intraarticular morphine after arthroscopic knee surgery.
BACKGROUND: Opioids can produce potent antinociceptive effects by interacting with local opioid receptors in inflamed peripheral tissue. In this study we examined the analgesic effects of the intraarticular, as compared with intravenous, administration of morphine after arthroscopic knee surgery. METHODS: In a double-blind, randomized trial, we studied 52 patients who had received one of four injections at the end of surgery. The patients in group 1 (n = 18) received 1 mg of morphine intraarticularly and saline intravenously; those in group 2 (n = 15), saline intraarticularly and 1 mg of morphine intravenously; those in group 3 (n = 10), 0.5 mg of morphine intraarticularly and saline intravenously; and those in group 4 (n = 9), 1 mg of morphine and 0.1 mg of naloxone intraarticularly and saline intravenously. The volume of the intraarticular injections was 40 ml, and that of the intravenous injections was 1 ml. After 1, 2, 3, 4, 6, and 24 hours, postoperative pain was assessed with a visual-analogue scale, a numerical-rating scale, and the McGill pain questionnaire. The need for supplemental analgesic agents, the patients' vital signs, and the occurrence of side effects were monitored. RESULTS: All pain scores were lower in group 1 than in group 2 at all times. The differences were significant (P less than 0.05) at three, four, and six hours (mean [+/- SD] visual-analogue score at six hours, 9 +/- 13 mm vs. 37 +/- 31 mm). The mean (+/- SD) consumption of supplemental analgesic medication per 24 hours was significantly lower in group 1 (36 +/- 51 mg of diclofenac and 1.2 +/- 3.4 mg of meperidine) than in group 2 (75 +/- 42 mg of diclofenac and 14 +/- 18 mg of meperidine, P less than 0.05). The visual-analogue scores in group 3 were slightly but not significantly higher than those in group 1 at all times except 6 and 24 hours after injection. The visual-analogue scores were significantly higher in group 4 than in group 1 one to four hours after injection (P less than 0.05), indicating that the analgesic effect of intraarticular morphine was reversible by naloxone. CONCLUSIONS: Low doses of intraarticular morphine can significantly reduce pain after knee surgery through an action specific to local opioid receptors that reaches its maximal effect three to six hours after injection.
Adult↗
Periaqueductal gray stimulation produces a spinally mediated, opioid antinociception for the inflamed hindpaw of the rat.
The objective of the present study was to characterize stimulation-produced antinociception from the periaqueductal gray matter (PAG) in rats with unilateral hindlimb inflammation induced by an intraplantar injection of Freund's complete adjuvant. Rats were chronically implanted with a bipolar stimulating electrode in the PAG. Nociception was assessed using a paw pressure test. Prior to inflammation, PAG stimulation significantly increased paw pressure threshold in both paws compared to non-stimulated controls. Following inflammation, PAG stimulation inhibited nociception in the inflamed, but not the non-inflamed paw. Systemic administration of naloxone blocked antinociception from ventral, but not dorsal PAG stimulation sites. Intrathecal, but not subcutaneous, administration of quaternary naltrexone completely blocked stimulation-produced antinociception from the PAG. The known increased levels of endogenous opioids occurring in the spinal cord ipsilateral to the site of inflammation suggest a mechanism for the selective antinociceptive effect of ventral PAG stimulation seen for the inflamed paw.
Analysis of Variance↗
Peripheral analgesic actions of opioids.
This paper will review experimental and clinical studies investigating analgesic effects of opioids outside the central nervous system. The experimental data indicate that 1) opioids can produce antinociceptive effects in the periphery mediated by local opioid receptors, 2) three different receptor types (mu, delta, kappa) can become active in peripheral tissue, 3) inflammatory hyperalgesic conditions are especially amenable to peripheral opioid actions and 4) the activation of opioid receptors located on primary afferent neurons is the most likely mechanism of action. The evidence from clinical studies is equivocal so far, partly because of methodological shortcomings. More extensive controlled studies investigating the effects of local application of opioids in the vicinity of peripheral nerve terminals or of compounds unable to cross the blood-brain barrier are warranted in view of the potential avoidance of central side effects such as respiratory depression, dependence, nausea or sedation.
Animals↗
Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides.
Antisense oligodeoxynucleotides specific for sequences in mRNAs from the B-cell lymphoma/leukemia-2 (BCL2) gene were used to inhibit the growth in culture of a human leukemia cell line, 697. Normal phosphodiester (PO) and nuclease-resistant phosphorothioate (PS) oligodeoxynucleotides were compared with regard to specificity, potency, and kinetics. Both PO and PS antisense BCL2 oligodeoxynucleotides were specific inhibitors of cellular proliferation, since sense versions of these synthetic DNAs were inactive at similar concentrations. Specificity was further confirmed by quantitative immunofluorescence studies, showing that PO and PS antisense BCL2 oligodeoxynucleotides (when used at appropriate concentrations) reduced levels of BCL2 protein without influencing expression of HLA-DR and other control antigens. The onset of inhibition by PO oligodeoxynucleotides was faster, with reductions in cell numbers occurring within 1 day of addition to cultures, in contrast to phosphorothioates, which were ineffective until 3-4 days. Phosphorothioates were more potent that phosphodiesters, however, with half-maximal inhibition of leukemic cell growth occurring at concentrations 5-10 times lower. As expected from previous studies demonstrating the importance of BCL2 for regulating lymphoid cell survival, BCL2 antisense oligodeoxynucleotides also led to 697 leukemic cell death through sequence-specific mechanisms, with reductions in cellular viability generally lagging the inhibitory effects on cellular growth by about 2 days. Taken together, these data indicate that PO and PS oligodeoxynucleotides targeted against the human BCL2 protooncogene can be sequence-specific inhibitors of leukemic cell growth and survival.
Cell Division↗
Intra-articular morphine for pain after knee arthroscopy.
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Arthroscopy↗
Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation.
The effects of capsaicin pretreatment of adult rats was investigated on consequences of unilateral paw inflammation induced by inoculation with Freund's adjuvant. Decrease in mechanical nociceptive threshold in the inflamed paw, as measured by the paw pressure test, was dose-dependently inhibited by capsaicin (20-150 mg/kg s.c.). In control rats, the antinociceptive action of morphine (0.8-1.9 mg/kg s.c.) was greater in the inflamed than in the non-inflamed paw; this difference was absent in capsaicin-treated animals. Increased volume or skin temperature of the inflamed paw was not influenced by capsaicin. It is concluded that capsaicin-sensitive, presumably C-fibre neurones, but not an alteration of the inflammation itself by capsaicin, mediate hyperalgesia and increased morphine antinociception in the rat paw with adjuvant-induced inflammation.
Analgesics↗
Rats with dorsal hippocampal lesions do react to new stimuli but not to spatial changes of known stimuli.
The effect of visual distracting stimuli upon the straight alleyway performance of dorsal hippocampectomized Wistar rats was investigated. In comparison with control animals it was observed that dorsal hippocampectomized animals (1) ambulated more during the preexposure phase, (2) acquired at the same rate a running response for food (training phase), (3) reacted similarly to a new visual stimulus (black cards) presented in a sector of the alleyway, and (4) habituated to successive presentations of that stimulus in the same place. (5) However, dorsal hippocampectomized rats did not react, unlike the controls, to the presentation of the same stimulus in another place of the alleyway but (6) reacted to the visual pattern change of the stimulus (now black/white check cards) in the same place. These results indicate that under certain experimental conditions, hippocampus-lesioned animals are capable of interrupting a running response for food in order to explore a new conspicuously located stimulus, habituate to repeated presentations of that stimulus, and to react to a new pattern of visual stimulation. They suggest that hippocampectomized rats do not lose the capacity to react to a new stimulus; the disruption seems to be related to the spatial context of stimulus presentation, supporting a spatial mapping hypothesis of hippocampal function.
Animals↗
Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation.
Exogenous opioids can produce localized opioid receptor-mediated antinociception in peripheral inflamed tissue. Previous studies show that activation of endogenous opioids by a cold water swim in rats with hind paw inflammation results in a similar local antinociceptive effect but suggest that pituitary-adrenal opioid pools are not directly involved in producing this effect. Here we show increased amounts of opioid peptides in immune cells infiltrating the inflamed tissue. Furthermore, we demonstrate immunoreactive opioid receptors on peripheral terminals of sensory neurons. The local administration of antibodies against opioid peptides or receptors or systemic pretreatment with the immunosuppressant cyclosporine blocks cold water swim-induced antinociception. These findings suggest that antinociception in inflammation can be brought about by endogenous opioids from immune cells interacting with opioid receptors on peripheral sensory nerves.
Animals↗
A test of fine finger dexterity.
The lack of instruments available for the measurement of fine dexterity (i.e., speed of interdigital manipulation) implies a gap not only in the occupational therapist's ability to quantify and deal precisely with patients' problems in this area, but also in the knowledge base of occupational therapy itself. The Rosenbusch Test of Finger Dexterity (developed by Doris F. Rosenbusch, MA, OTR), a new instrument that measures the speed of interdigital manipulation of objects by each hand separately, was tested on 64 subjects with normal hand function and 10 subjects known to have disabilities affecting fine dexterity. The determination of significant differences by the subjects' sex, dominant and nondominant hands, and normal and dysfunctional hands was performed with t tests. The scores of the subjects with normal hand function versus those with disabled hand function were then compared on all variables. The findings demonstrate that this instrument is ready to be used experimentally and compares favorably with current commercial tests on both reliability and validity coefficients.
Adult↗
Local opioid receptors mediating antinociception in inflammation: endogenous ligands.
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Animals↗