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Biomedical subjects

J S Walker

Publications and source records attributed to J S Walker.

At least 19 recordsLinked to original sources
PubMed1999

Zinc alleviates thermal hyperalgesia due to partial nerve injury.

Zinc has recently been shown to alleviate inflammatory hyperalgesia. In the present study, we showed that intrathecal, intraplantar or systemic injection of zinc chloride significantly relieved thermal hyperalgesia in rats with sciatic nerve injury. Alleviation of thermal hyperalgesia was dose dependent in each case, although higher doses were required for i.p. injections (ED50 = 13.6 nmole) than for intrathecal (ED50 = 0.05 nmole) or intraplantar injections (ED50 = 0.3 nmole). Neither intrathecal nor intraplantar zinc chloride influenced thermal nociception in normal rats without nerve injury. The results provide the first evidence that zinc alleviates neuropathic hyperalgesia.

Animals↗
PubMed1999

Zinc alleviates thermal hyperalgesia due to partial nerve injury.

Zinc has recently been shown to alleviate inflammatory hyperalgesia. In the present study, we showed that intrathecal, intraplantar or systemic injection of zinc chloride significantly relieved thermal hyperalgesia in rats with sciatic nerve injury. Alleviation of thermal hyperalgesia was dose dependent in each case, although higher doses were required for i.p. injections (ED50 = 13.6 nmol) than for intrathecal (ED50 = 0.05 nmol) or intraplantar injections (ED = 0.3 nmol). Neither intrathecal nor intraplantar zinc chloride influenced thermal nociception in normal rats without nerve injury. The results provide the first evidence that zinc alleviates neuropathic hyperalgesia.

Animals↗
PubMed1999

Involvement of substance P in the anti-inflammatory effects of the peripherally selective kappa-opioid asimadoline and the NK1 antagonist GR205171.

We have previously shown that kappa-opioids have antiarthritic properties. In this study, using two differently acting drugs (the peripherally selective kappa-agonist, asimadoline, and the NK1-antagonist, GR205171), we have examined possible roles of the neuropeptide substance P (SP) in the pathogenesis and maintenance of experimental arthritis in rats. The anti-inflammatory actions and the time dependence of these drugs were compared, and concentrations of SP determined in joint tissue. In untreated animals, SP levels in ankle joint tissue increased late in the disease (by day 21) but substantially lagged behind development of clinical disease. Prolonged (days 1-21 or days 12-18) but not early, short-term (days 1-3) treatment with the NK1-antagonist GR205171 (1 mg/kg/day i.p.) significantly attenuated joint damage; SP levels showed multiphasic dose dependence over the 21-day treatment. The data suggest that GR205171 antagonizes the action of SP by presynaptic as well as postsynaptic mechanisms. Treatment with asimadoline (5 mg/kg/day i.p. ) produced marked (and sustained) attenuation of the disease with all three time regimes. The effect of asimadoline on SP levels was time dependent: reduction of SP content after 3 days but an increase after 12 or 21 days treatment, paradoxically with clinical improvement in each case. Drug-induced changes in SP content could follow from changed release or synthesis from either neural or immune cells. The results suggest that both drugs have potential therapeutic value at different stages of inflammatory joint disease.

Acetamides↗
PubMed1998

Dizziness.

Dizziness is a common but difficult symptom to evaluate because, due to its subjective nature, it is virtually impossible to measure objectively. In essence, dizziness means different things to different people. The most useful historical information is the patient's own description of the dizziness, its characterization, and the effects of position on the patient's symptoms. After taking a detailed history, the clinician should perform a thorough physical examination with emphasis on determining whether the dizziness is vestibular or nonvestibular in origin. Patient disposition is determined by the prognosis of the underlying cause and the presence of support mechanisms.

Adult↗
PubMed1998

Effect of the peripherally selective kappa-opioid agonist, asimadoline, on adjuvant arthritis.

1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective kappa agonist, asimadoline, in rats with adjuvant arthritis. 2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg(-1) day(-1), i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally. 3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg(-1) day(-1)), indicating that asimadoline acts through peripheral kappa-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg(-1) day(-1)), suggesting a loss of kappa-selectivity at this dose. 4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia. 5. These data confirm our previous findings that kappa-opioids possess anti-arthritic properties and that these effects are mediated via peripheral kappa-receptors. The present results are new in showing that the peripherally acting kappa-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.

Acetamides↗
PubMed1998

Inhibitory mechanisms for cross-bridge cycling: the nitric oxide-cGMP signal transduction pathway in smooth muscle relaxation.

Relaxation follows sequestration of Ca2+ mobilized by an excitatory stimulus in striated muscle. Removal of excitatory stimuli also relaxes smooth muscle in vitro after reductions in the myoplasmic [Ca2+] and dephosphorylation of the myosin regulatory light chains. However, there are several experimental procedures that produce relaxation in the presence of excitatory stimuli and elevated Ca(2+)-dependent cross-bridge phosphorylation. Of potential widespread physiological importance are treatments that increase myoplasmic [cGMP] owing to the ubiquity of nitric oxide (NO) as a signalling molecule for endothelial-mediated vasodilation and inhibitory nerves in most types of smooth muscle. Several mechanisms are implicated in the NO-cGMP mediated relaxation. Most studies support reductions in myoplasmic Ca2+. However, there is evidence that increases in cGMP also lower the Ca(2+)-sensitivity of cross-bridge phosphorylation. This would contribute to a decline in force through actions on the myosin light chain kinase/phosphatase system. In addition, changes in the dependence of force on phosphorylation are observed in tissues partially relaxed by treatments that elevate cGMP. This demonstrates that either the attachment and cycling of phosphorylated cross-bridges is impaired or blocked, or that the formation of dephosphorylated, force-generating cross-bridges ('latch-bridges') is reduced. Protein kinase G-catalysed phosphorylation of either a thin filament protein that blocks attachment of cross-bridges or a protein that inhibits myosin light chain phosphatase may explain the NO-induced relaxation with elevated cross-bridge phosphorylation.

Animals↗
PubMed1998

Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen.

UNLABELLED: We used electrically induced pain in healthy young subjects to study gender differences in nociception and the analgesic efficacy of ibuprofen. Cutaneous stimulation of the earlobe allowed measurement of pain detection thresholds and maximal pain tolerance. Drug and placebo were each administered twice using a double-blind, randomized, multiple cross-over design. Male subjects had greater stimulus thresholds (lower nociception) compared with female subjects (18 +/- 0.3 vs 15 +/- 0.3 volts, mean +/- SEM; n = 10 in each group) and a greater pain tolerance (24 +/- 0.4 vs 21 +/- 0.4 volts). Response variability was also greater in the male subjects, yet only the men exhibited a statistically significant analgesic response to ibuprofen (deltavolts; ibuprofen versus placebo: 2.80 +/- 0.33 vs -0.18 +/- 0.34; P < 0.05, n = 10). None of these results could be attributed to pharmacokinetic differences. The finding that ibuprofen was less effective in women than in men has potential clinical significance, especially as a factor in the response variability to nonsteroidal antiinflammatory drugs. IMPLICATIONS: In this study, we examined ibuprofen, a widely used nonsteroidal antiinflammatory drug, for its ability to reduce experimental pain. We found that it had such properties in healthy young male subjects but not in young female subjects. This is a paradox because many of the painful conditions for which nonsteroidal antiinflammatory drugs are used (e.g., rheumatoid arthritis) occur more often in women.

Adolescent↗
PubMed1998

Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats: inhibition by kappa-opioid agonist but not by NSAID.

OBJECTIVE: To quantify intercellular adhesion molecule-1 (ICAM-1) expression in normal and adjuvant arthritic rats and to determine the extent to which ICAM-1 expression in arthritic animals is altered by treatment with a prototype nonsteroidal antiinflammatory drug (NSAID) and a kappa-opioid agonist. METHODS: Unilateral hind paw inflammation was induced by intradermal injection of Freund's complete adjuvant (FCA) into the right hind paw of female Lewis rats. Polyarthritis was induced by intradermal injection of FCA into the base of the tail of female dark Agouti rats. The NSAID naproxen [5 mg/kg intraperitoneally (ip)] or the kappa-opioid PD117302 (15 mg/kg ip) was administered twice daily throughout the experiment (21 days). ICAM-1 expression was quantified using monoclonal antibodies against rat ICAM-1 that bind to the endothelium in proportion to the degree of adhesion molecule expression. RESULTS: ICAM-1 expression was significantly upregulated in the joints of affected limbs of animals with both unilateral hind paw inflammation and polyarthritis. In animals treated with PD 117302 and naproxen there was a significant attenuation of arthritis; however, only treatment with PD117302 was able to significantly inhibit the upregulation of ICAM-1 expression in arthritic joints. CONCLUSION: ICAM-1 expression is upregulated in experimental arthritis. It appears that the kappa-opioid PD117302, but not the NSAID naproxen, inhibits the upregulation of ICAM-1 in arthritic joints, suggesting these agents act via different mechanisms. The ability of the kappa-agonist, PD117302, to inhibit both the inflammation and upregulation of ICAM-1 in arthritic joints emphasizes the potential of kappa-agonists as antiarthritic agents.

Animals↗
PubMed1997

Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis: support for the concept of "responders" and "nonresponders".

OBJECTIVE: A range of functional, biochemical, and psychological indicators was used to test the concept of "responders"/"nonresponders" and to seek predictors of response to 2 nonsteroidal antiinflammatory drugs in 9 patients with rheumatoid arthritis (RA) and 11 with osteoarthritis (OA). METHODS: In a balanced, randomized, double-blind, latin-square study design that involved four 4-week treatment periods, patients received ketoprofen or piroxicam (each for 2 of the 4 periods). Clinical and laboratory responses (pain, tenderness, swelling, patient and physician global assessments, acute-phase protein levels, and disability) were assessed in the last 2 weeks of each period. Responders were those who showed >30% improvement in at least 5 of 7 measures of disease activity. Mood was also assessed. RESULTS: At baseline, variables were higher in RA than in OA patients. The drugs produced clear improvements in patients' visual analog scale scores, physicians' overall assessments, and patients' responses to the McGill Pain Questionnaire, as well as plasma prostaglandin concentrations. In patients with either RA or OA, responders could be distinguished from nonresponders; about one-third of patients were unambiguous responders. In RA, there were responder/nonresponder differences in lymphocyte counts, erythrocyte sedimentation rate (ESR), and levels of tumor necrosis factor alpha, but no differences were seen in OA patients. However, caution in interpretation of the data is necessary because of the small number of patients. Responders had improved mood scores compared with nonresponders in both disease groups. Baseline ESR and white blood cell counts were correlated with responder status in RA patients. CONCLUSION: This study provides support for the responder/nonresponder concept. It also indicates that in RA, pretreatment ESR and lymphocyte counts are possibly useful indicators of therapeutic response.

Adult↗
PubMed1997

Myosin isoforms and functional diversity in vertebrate smooth muscle.

The expression of fast and slow myosin isoforms in individual cells is associated with differences in shortening velocities and power output in fully differentiated vertebrate striated muscle. This paradigm in which shortening velocity is determined by the myosin isoform (and load) is inappropriate for smooth muscle. Smooth muscle tissues express multiple myosin heavy and light chain isoforms, and it is not currently possible to separate and identify chemically distinct native myosin hexamers (i.e., isoforms). It is not known if different isoforms are localized in subpopulations of cells or in specific cellular domains nor whether they combine preferentially to form a small number of native myosin hexamer isoforms. Potentially, thick filaments are aggregates of many different combinations of heavy and light chain isoforms that may or may not exhibit different kinetics. Shortening velocities in smooth muscle are regulated by Ca(2+)-dependent crossbridge phosphorylation of the myosin regulatory light chains. Much of the observed diversity in power output in smooth muscle may be attributed to regulatory mechanisms modulating crossbridge cycling rates rather than contractile protein isoform expression.

Animals↗
PubMed1996

Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats.

OBJECTIVE AND DESIGN: On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine. MATERIAL: Male Lewis rats were used. TREATMENT: Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. METHODS: The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb. RESULTS: Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose. CONCLUSION: Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.

Analgesics, Opioid↗
PubMed1996

Vascular abdominal emergencies.

Vascular emergencies are an uncommon but significant cause of abdominal pain, back pain, hemorrhagic shock, and death in adults. This article reviews abdominal vascular anatomy, risk factors, signs and symptoms, abdominal vascular thrombosis, mesenteric ischemia and infarction, and abdominal vascular emboli and aneurysms.

Abdomen↗
PubMed1996

The site of anti-arthritic action of the kappa-opioid, U-50, 488H, in adjuvant arthritis: importance of local administration.

1. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (kappa)-opioid, U-50,488H (trans-(+/-)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]- benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, kappa-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a kappa-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the anti-arthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (+/-)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (+/-)-U-50,488H on radiology and histology varied according to treatment time. Administration of (+/-)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (+/-)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (+/-)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 +/- 1.6 vs 19.5 +/- 0.8 mg kg-1). 3. Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (+/-) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+/-)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4. Both the peripherally selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), were able to reverse fully the peripheral anti-arthritic effects of U-50,488H, indicating that it exerts its effects through peripheral kappa-opioid receptors. 5. Taken together, these results not only confirm our previous findings that demonstrate anti-arthritic effects of U-50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral kappa-receptors in the arthritic joint. Peripherally acting kappa-opioid agonists should lead to new therapies for arthritis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Inferior glenohumeral dislocation (luxatio erecta humeri).

A 67-year-old woman was seen in the emergency department because of severe pain and inability to move her left shoulder after falling on an abducted left arm. The fall was the result of a near-syncopal episode. On examination, the left arm was hyperabducted and elevated approximately 80 degrees from the horizontal plane. Furthermore, the patient was unable to move her left arm. Radiographs of the shoulder revealed an inferior dislocation of the glenohumeral joint. Closed reduction in the emergency department was successful. This rare but classic case of inferior glenohumeral dislocation (luxatio erecta humeri) serves to emphasize that a heightened awareness for this injury is necessary if it is to be recognized and treated appropriately. It is important to obtain orthopedic consultation or follow-up (or both) for this injury, because of the high incidence of accompanying tears of the rotator cuff. Neurovascular compromise is also commonly associated with this dislocation. The neurologic injuries are more common than the vascular injuries but tend to resolve after reduction.

Accidental Falls↗
PubMed1995

Pain due to nerve damage: are inflammatory mediators involved?

Damage to peripheral nerves often results in pain and hyperalgesia. We suggest that nerve damage causes an inflammatory response in which cells associated with the nerve release inflammatory mediators such as eicosanoids; these mediators may contribute to the hyperalgesia which results from nerve injury. The cell types most likely to be responsible include macrophages and postganglionic sympathetic neurones. A better understanding of the mechanisms involved should lead to improved therapies for neuropathic pain.

Animals↗