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Threshold Dose (threshold + dose)
Selected AbstractsThe cause and prevention of human birth defects: What have we learned in the past 50 years?CONGENITAL ANOMALIES, Issue 1 2001Robert L. Brent ABSTRACT This review article dealig with the subject of "The Cause and Prevention of Human Birth Defects" was prepared in celebration of the 40th anniversary of the Japanese Teratology Society. It begins with recollections of some of the important contributions of Japanese scientists in the fields of teratology and embryology and a summary of the many scientific and medical accomplishments of the past 50 years in the fields of teratology, genetics, developmental biology, epidemiology and genetics. The review includes a summary of the drugs, chemicals and physical agents that have been documented to result in congenital malformations and reproductive effects when pregnant women are exposed during pregnancy. The principles of teratology were also summarized and emphasize that 1) no teratogenic agent can be described qualitatively as a teratogen, since a teratogenic exposure must include not only the agent, but also the dose and the time in pregnancy when the exposure occurs. 2) Even agents that have been demonstrated to result in malformatins cannot produce every type of malformation. 3) Known teratogens can be presumptively identified by the spectrum of malformations they produce. 4) It is easier to exclude an agent as a cause of birth defects than to definitively conclude that it was responsible for birth defects. 5) When evaluating the risk of exposures, the dose is a crucial component in determining the risk. 6) Teratogenic agents follow a toxicological dose response curve. This means that each teratogen has a threshold dose, below which, there is no risk of teratogenensis, no matter when in pregnancy the exposure occurred. 7) The evaluation of a child with congenital malformations connot be adequately performed unless it is approached with the same scholarship and detail, as is any other complicated medical problem. 8) Each physician must recognize the consequences of providing erroneous reproductive risks to pregnant women exposed to drugs and chemicals during pregnancy or alleging that a child's malformations are due to an environmental agent without performing a complete and scholarly evaluation. [source] Synergistic Combinations of Anticonvulsant Agents: What Is the Evidence from Animal Experiments?EPILEPSIA, Issue 3 2007Daniėl M. Jonker Summary:,Purpose: Combination therapy is often used in the treatment of seizures refractory to monotherapy. At the same time, the pharmacodynamic mechanisms that determine the combined efficacy of antiepileptic drugs (AEDs) are unknown, and this prevents a rational use of these drug combinations. We critically evaluate the existing evidence for pharmacodynamic synergism between AEDs from preclinical studies in animal models of epilepsy to identify useful combinations of mechanisms and to determine whether study outcome depends on the various research methods that are in use. Methods: Published articles were included if the studies were placebo-controlled, in vivo, or ex vivo animal studies investigating marketed or experimental AEDs. The animal models that were used in these studies, the primary molecular targets of the tested drugs, and the methods of interpretation were recorded. The potential association of these factors with the study outcome (synergism: yes or no) was assessed through logistic regression analysis. Results: In total, 107 studies were identified, in which 536 interaction experiments were conducted. In 54% of these experiments, the possibility of a pharmacokinetic interaction was not investigated. The majority of studies were conducted in the maximal electroshock model, and other established models were the pentylenetetrazole model, amygdala kindling, and the DBA/2 model. By far the most widely used method for interpretation of the results was evaluation of the effect of a threshold dose of one agent on the median effective dose (ED50) of another agent. Experiments relying on this method found synergism significantly more often compared with experiments relying on other methods (p < 0.001). Furthermore, experiments including antagonists of the AMPA receptor were more likely to find synergism in comparison with all other experiments (p < 0.001). Conclusions: Intensive preclinical research into the effects of AED combinations has not led to an understanding of the pharmacodynamic properties of AED combinations. Specifically, the majority of the preclinical studies are not adequately designed to distinguish between additive, synergistic, and antagonistic interactions. Quantitative pharmacokinetic,pharmacodynamic studies of selectively acting AEDs in a battery of animal models are necessary for the development of truly synergistic drug combinations. [source] Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatumEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Ingrid Strömberg Abstract It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P < 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function. [source] Comparison of intensity modulated radiation therapy (IMRT) treatment techniques for nasopharyngeal carcinomaINTERNATIONAL JOURNAL OF CANCER, Issue 2 2001Jason Chia-Hsien Cheng M.D. Abstract We studied target volume coverage and normal tissue sparing of serial tomotherapy intensity modulated radiation therapy (IMRT) and fixed-field IMRT for nasopharyngeal carcinoma (NPC), as compared with those of conventional beam arrangements. Twelve patients with NPC (T2-4N1-3M0) at Mallinckrodt Institute of Radiology underwent computed tomography simulation. Images were then transferred to a virtual simulation workstation computer for target contouring. Target gross tumor volumes (GTV) were primary nasopharyngeal tumor (GTVNP) with a prescription of 70 Gy, grossly enlarged cervical nodes (GTVLN) with a prescription of 70 Gy, and the uninvolved cervical lymphatics [designated as the clinical tumor volume (CTV)] with a prescription of 60 Gy. Critical organs, including the parotid gland, spinal cord, brain stem, mandible, and pituitary gland, were also delineated. Conventional beam arrangements were designed following the guidelines of Intergroup (SWOG, RTOG, ECOG) NPC Study 0099 in which the dose was prescribed to the central axis and the target volumes were aimed to receive the prescribed dose ± 10%. Similar dosimetric criteria were used to assess the target volume coverage capability of IMRT. Serial tomotherapy IMRT was planned using a 0.86-cm wide multivane collimator, while a dynamic multileaf collimator system with five equally spaced fixed gantry angles was designated for fixed-beam IMRT. The fractional volume of each critical organ that received a certain predefined threshold dose was obtained from dose-volume histograms of each organ in either the three-dimensional or IMRT treatment planning computer systems. Statistical analysis (paired t -test) was used to examine statistical significance. We found that serial tomotherapy achieved similar target volume coverage as conventional techniques (97.8 ± 2.3% vs. 98.9 ± 1.3%). The static-field IMRT technique (five equally spaced fields) was inferior, with 92.1 ± 8.6% fractional GTVNP receiving 70 Gy ± 10% dose (P < 0.05). However, GTVLN coverage of 70 Gy was significantly better with both IMRT techniques (96.1 ± 3.2%, 87.7 ± 10.6%, and 42.2 ± 21% for tomotherapy, fixed-field IMRT, and conventional therapy, respectively). CTV coverage of 60 Gy was also significantly better with the IMRT techniques. Parotid gland sparing was quantified by evaluating the fractional volume of parotid gland receiving more than 30 Gy; 66.6 ± 15%, 48.3 ± 4%, and 93 ± 10% of the parotid volume received more than 30 Gy using tomotherapy, fixed-field IMRT, and conventional therapy, respectively (P < 0.05). Fixed-field IMRT technique had the best parotid-sparing effect despite less desirable target coverage. The pituitary gland, mandible, spinal cord, and brain stem were also better spared by both IMRT techniques. These encouraging dosimetric results substantiate the theoretical advantage of inverse-planning IMRT in the management of NPC. We showed that target coverage of the primary tumor was maintained and nodal coverage was improved, as compared with conventional beam arrangements. The ability of IMRT to spare the parotid glands is exciting, and a prospective clinical study is currently underway at our institution to address the optimal parotid dose-volume needs to be spared to prevent xerostomia and to improve the quality of life in patients with NPC. © 2001 Wiley-Liss, Inc. [source] Isolation and identification of 1,-hydroxy-3-epi-vitamin D3, a potent suppressor of parathyroid hormone secretionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Alex J. Brown Abstract Since our original demonstration of the metabolism of 1,,25(OH)2D3 into 1,,25(OH)2 -3-epi-D3 in human keratinocytes, there have been several reports indicating that epimerization of the 3 hydroxyl group of vitamin D compounds is a common metabolic process. Recent studies reported the metabolism of 25OHD3 and 24(R),25(OH)2D3 into their respective C-3 epimers, indicating that the presence of 1, hydroxyl group is not necessary for the 3-epimerization of vitamin D compounds. To determine whether the presence of a 25 hydroxyl group is required for 3-epimerization of vitamin D compounds, we investigated the metabolism of 1,OHD3, a non-25 hydroxylated vitamin D compound, in rat osteosarcoma cells (ROS 17/2.8). We noted metabolism of 1,OHD3 into a less polar metabolite which was unequivocally identified as 1,OH-3-epi-D3 using the techniques of HPLC, GC/MS, and 1H-NMR analysis. We also identified 1,OH-3-epi-D3 as a circulating metabolite in rats treated with pharmacological concentrations of 1,OHD3. Thus, these results indicated that the presence of a 25 hydroxyl group is not required for 3-epimerization of vitamin D compounds. Furthermore, the results from the same studies also provided evidence to indicate that 1,OH-3-epi-D3, like 1,OHD3, is hydroxylated at C-25. We then evaluated the biological activities of 1,OH-3-epi-D3. Treatment of normal rats every other day for 7 days with 2.5 nmol/kg of 1,OH-3-epi-D3 did not raise serum calcium, while the same dose of 1,OHD3 increased serum calcium by 3.39,±,0.52 mg/dl. Interestingly, in the same rats which received 1,OH-3-epi-D3 we also noted a reduction in circulating PTH levels by 65,±,7%. This ability of 1,OH-3-epi-D3 to suppress PTH levels in normal rats without altering serum calcium was further tested in rats with reduced renal function. The results indicated that the ED50 of 1,OH-3-epi-D3 for suppression of PTH was only slightly higher than that of 1,,25(OH)2D3, but that the threshold dose of the development of hypercalcemia (total serum Ca >,10.5 mg/dl) was nearly 80 times higher. These findings indicate that 1,OH-3-epi-D3 is a highly selective vitamin D analog with tremendous potential for treatment of secondary hyperparathyroidism in chronic renal failure patients. © 2005 Wiley-Liss, Inc. [source] Drug substances presented as sulfonic acid salts: overview of utility, safety and regulationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2009David P. Elder Abstract Objectives Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients. The potential implications of the recent establishment of a substantial human threshold dose for ethyl methanesulfonate for the safety assessment of alkyl sulfonates in general are also discussed. Key findings The formation of alkyl sulfonates requires highly acidic conditions, possibly combined with long reaction times and/or elevated temperatures, to generate significant amounts, and these conditions are most unlikely to be present in the synthesis of active pharmaceutical ingredient sulfonate salts. It is possible to design salt formation conditions, using a short-chain alcohol as solvent, to manufacture sulfonate salts that are essentially free of alkyl sulfonate impurities. Processes using non-acidic conditions such as ethanol recrystallization or wet granulation should not raise any concerns of alkyl sulfonate formation. Summary An understanding of the mechanism of formation of alkyl sulfonates is critical in order to avoid restricting or over-controlling sulfonic acid salts, which have many technical advantages as pharmaceutical counterions. Recent regulatory acceptance of a human threshold limit dose of 2 mg/kg per day for ethyl methanesulfonate, indicating that its toxicological risks have previously been considerably overestimated, could signal the beginning of the end over safety concerns on alkyl sulfonate residues, thus removing a major constraint from the exploitation of sulfonic acid counterions. [source] Allergy to peanut oil , clinically relevant?JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 4 2007J Ring Abstract The increasing prevalence of food allergies (especially allergy to peanuts) has led to a discussion of how safe topical preparations containing peanut oil are with respect to allergy. The major allergens from peanuts are proteins that have been characterized at a molecular level and cloned. Clinical signs of peanut allergy symptoms can be observed on the skin (urticaria), or in the gastrointestinal and/or respiratory tract culminating in cardiovascular symptoms and anaphylactic reactions. In most cases, symptoms are elicited by oral uptake; rarely, a contact urticaria has been described. In vegetable oils, the contents of protein differ depending on the production process: crude oils contain approximately 100 times more proteins than refined oils. This has clear-cut implications for allergic individuals. Quantitative data are available regarding elicitation of symptoms in allergic individuals with a threshold dose of 0.1,1 mg peanut allergen in oral provocation tests. There are anecdotal reports of adverse reactions after topical use of peanut oils. In one epidemiological trial, an association between topical use of skin care products containing peanut oil and the development of peanut allergy was observed; however, the data reflect a retrospective analysis without specifying skin care products containing peanut oil and also without analysing the quantity of topicals used. In contrast, oral tolerance was prevented and allergic sensitization was enhanced in a mouse model using high concentrations of peanut protein. So far, no reliable data are available regarding doses required to induce sensitization against peanut allergen via the epidermal route. A possible induction of sensitization against peanut proteins through contact with the skin via skin care products and the respective protein concentrations is a matter of speculation. Patients with atopic diseases, namely eczema, need appropriate skin care because of the disturbed skin barrier function. The benefit of avoiding damage to skin barrier functions of atopic individuals by the use of peanut protein-containing skin care products seems to outweigh possible risks of sensitization and/or allergy induction against substances contained in those products containing refined peanut oil. [source] Reduction in DNA Synthesis During Two-photon Microscopy of Intrinsic Reduced Nicotinamide Adenine Dinucleotide Fluorescence,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2005Michael G. Nichols ABSTRACT Two-photon laser scanning microscopy (TPLSM) of endogenous reduced nicotinamide adenine dinucleotide (NAD(P)H) provides important information regarding the cellular metabolic state. When imaging the punctate mitochondrial fluorescence originating from NAD(P)H in a rat basophilic leukemia (RBL) cell at low laser powers, no morphological changes are evident, and photobleaching is not observed when many images are taken. At higher powers, mitochondrial NAD(P)H fluorescence bleaches rapidly. To assess the limitations of this technique and to quantify the extent of photodamage, we have measured the effect of TPLSM on DNA synthesis. Although previous reports have indicated a threshold power for "safe" two-photon imaging, we find the laser power to be an insufficient indicator of photodamage. A more meaningful metric is a two-photon-absorbed dose that is proportional to the number of absorbed photon paris. A temporary reduction of DNA synthesis in RBL cells occurs whenever a threshold dose of approximately 2 × 1053 photon2 cm,4 s,1 is exceeded. This threshold is independent of laser intensity when imaging with average powers ranging from 5 to 17 mW at 740 nm. Beyond this threshold, the extent of the reduction is intensity dependent. DNA synthesis returns to control levels after a recovery period of several hours. [source] Plasma membrane permeabilization by 60- and 600-ns electric pulses is determined by the absorbed doseBIOELECTROMAGNETICS, Issue 2 2009Bennett L. Ibey Abstract We explored how the effect of plasma membrane permeabilization by nanosecond-duration electric pulses (nsEP) depends on the physical characteristics of exposure. The resting membrane resistance (Rm) and membrane potential (MP) were measured in cultured GH3 and CHO cells by conventional whole-cell patch-clamp technique. Intact cells were exposed to a single nsEP (60 or 600 ns duration, 0,22 kV/cm), followed by patch-clamp measurements after a 2,3 min delay. Consistent with earlier findings, nsEP caused long-lasting Rm decrease, accompanied by the loss of MP. The threshold for these effects was about 6 kV/cm for 60 ns pulses, and about 1 kV/cm for 600 ns pulses. Further analysis established that it was neither pulse duration nor the E-field amplitude per se, but the absorbed dose that determined the magnitude of the biological effect. In other words, exposure to nsEP at either pulse duration caused equal effects if the absorbed doses were equal. The threshold absorbed dose to produce plasma membrane effects in either GH3 or CHO cells at either pulse duration was found to be at or below 10 mJ/g. Despite being determined by the dose, the nsEP effect clearly is not thermal, as the maximum heating at the threshold dose is less than 0.01 °C. The use of the absorbed dose as a universal exposure metric may help to compare and quantify nsEP sensitivity of different cell types and of cells in different physiological conditions. The absorbed dose may also prove to be a more useful metric than the incident E-field in determining safety limits for high peak, low average power EMF emissions. Bioelectromagnetics 30:92,99, 2009. © 2008 Wiley-Liss, Inc. [source] The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertilityBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 10 2006AH Balen Objective, To assess the influence of body weight on the outcome of ovulation induction in women with World Health Organization (WHO) group II anovulatory infertility. Design, The combined results of two studies in which either a highly purified urinary follicle-stimulating hormone or highly purified urinary menotrophin were compared with recombinant follicle-stimulating hormone. Setting, Thirty-six fertility clinics. Population, A total of 335 women with WHO group II anovulatory infertility failing to ovulate or conceive on clomifene citrate. Methods, Ovarian stimulation using a low-dose step-up protocol. Main outcome measures, The effects of body weight on ovarian response, ovulation rate and pregnancy rate after one treatment cycle. Results, With increasing body mass index (BMI), a higher threshold dose of gonadotrophins was required and there were more days of stimulation; yet, despite a greater concentration of antral follicles, there were fewer intermediate and large follicles. There was no difference in the rates of ovulation and clinical pregnancy in relation to body weight. Conclusions, Body weight affects gonadotrophin requirements but not overall outcome of ovulation induction in women with anovulatory polycystic ovary syndrome and a BMI of less than 35 kg/m2. [source] Evolution of light scattering after in vivo close to threshold dose of ultraviolet radiation 300 nmACTA OPHTHALMOLOGICA, Issue 2007S HUANG Purpose: To determine the evolution of light scattering in the albino rat lens after in vivo close to threshold UVR-300 nm. Methods: Alltogether 4 groups of 20 6 weeks old albino Sprague-Dawley rats were exposed unilaterally in vivo to 8 kJ/m2 UVR-300 nm. The animals were sacrificed at 1, 7, 48 and 336 hrs after exposure after exposure to UVR, depending on group belonging and the lenses were removed for macroscopic imaging of dark-field anatomy, and quantitative measurement of intensity of forward light scattering. Results: The intensity of light scattering increased exponentially declining with a rate constant (1/k) of 71 hrs and an asymptote maximum light scattering of 0.16 tEDC. This is consistent with findings for a dose of 30 kJ/m2 although the current time constant was higher. There was an indication of a transient increase of light scattering on the contralateral side peaking at 7 hrs after expsoure. There was an indication for some repair at 336 hrs. Conclusions: Light scattering evolves quicker, the higher the dose, but increases exponentially declining towards an assymptote. The current study suggest that observations of damage from close to threshold in vivo UVR exposure should be made at 1 week after exposure in order to detect the maximum damage. [source] Allergen dose dependency of the early- and late-phase cutaneous response in the cynomolgus monkeyCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2009A. Tomkinson Summary Background Cutaneous administration of allergen provides a means to confirm an allergic status, investigate the pathogenesis of allergic diseases, and/or provide a mechanism to evaluate the benefit of new potential therapeutics. Objective Studies were performed to characterize the allergen-induced cutaneous early- and late-phase response (EPR and LPR) in the cynomolgus monkey. Methods Following intradermal injections of Ascaris suum allergen, the cutaneous weal and flare EPR was measured 15 min post-injection, and skin biopsies were collected at 8,24 h to determine the optimal time of LPR occurrence. Biopsies were analysed for epidermal and dermal inflammatory changes. Results The EPR was dose related with a reproducible, measurable response at 1 : 10 000 and maximal at a 1 : 100 allergen dilution. In contrast, the threshold dose required for a reproducible LPR was much greater requiring a dilution of 6 : 100, suggesting independent mechanisms for the EPR and LPR. The LPR 20 h post-allergen injection induced an inflammatory response in the upper and deep dermis. The response was characterized by a moderate perivascular to diffuse inflammation consisting of mononuclear cells, neutrophils and eosinophils. Dexamethasone, while having no effect on the EPR, reduced dermal inflammation (upper dermis, P=0.004; deep dermis, P=0.03). Similarly, dermal eosinophilia was also reduced (upper dermis, P<0.001; deep dermis, P=0.02). Conclusion Collectively, the results indicate the dose dependency of the EPR and LPR. Furthermore, our observations indicate the value of the LPR response in the cynomolgus monkey to evaluate new therapeutics for the treatment of allergic diseases such as atopic dermatitis. [source] Threshold levels of purified natural Bos d 2 for inducing bronchial airway response in asthmatic patientsCLINICAL & EXPERIMENTAL ALLERGY, Issue 10 2002T. Zeiler Summary Background Provocation tests are invaluable in establishing threshold levels and a causal relationship between atopic asthma and a certain allergen source, especially in relation to work-associated exposure. Purified major allergens open possibilities for a more accurate assessment of sensitization. Objective To determine the threshold dose of purified major bovine dander allergen Bos d 2 in bronchial provocation in comparison with the standard allergen and a set of other parameters of allergy. Method Nine consecutive patients referred to hospital for confirming the bovine origin of their occupational asthma were subjected to bronchial provocation tests with purified natural Bos d 2 and a standard bovine dander allergen. Additional tests included bronchial histamine challenge, measurements of total IgE, specific IgE antibody determinations and skin prick tests (SPT) with both allergens. Results In the provocation tests with Bos d 2, a 15% decrease in the forced expiratory volume in 1 s (FEV1) and/or peak expiratory flow (PEF) values in eight out of nine patients confirmed the predominant role of Bos d 2 in the sensitization. The threshold dose of Bos d 2 varied from 0.1 µg to > 100 µg (median ± median absolute deviation = 4.5 ± 3.9 µg). A positive SPT was induced by a median dose of 13.9 ± 9.8 µg of Bos d 2. Bronchial response to histamine and IgE antibodies against Bos d 2 showed the highest correlations to the provocations results. Conclusions The efficacy of Bos d 2 in bronchial provocation in patients with occupational cattle-associated asthma was confirmed and the range of the threshold level was determined. There were individual variations, but the response in provocation remains the reference method for identification of the cause of occupational atopic asthma. SPT and the measurement of specific IgE antibodies, preferably with purified or recombinant major allergens, increase the accuracy of the diagnosis. [source] ELECTROPHYSIOLOGICAL EVIDENCE FOR THE INTERACTION OF SUBSTANCE P AND GLUTAMATE ON A, AND C AFFERENT FIBRE ACTIVITY IN RAT HAIRY SKINCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2006Qi Zhang SUMMARY 1The purpose of the present study was to investigate whether there was a cooperative interaction between substance P (SP) and glutamate (GLU) administered subcutaneously on A, and C primary afferent fibre activity in dorsal hairy skin of the rat in vivo. The single unit activities of A, and C afferent fibres were recorded by isolation of fibre filaments from the dorsal cutaneous nerve branches and the effects of subcutaneous injections of low doses of SP, GLU and SP + GLU on activity were determined. 2Sub-threshold doses of SP (1 µmol/L, 10 µL) administered subcutaneously into the dorsal hairy skin had no effect on the afferent discharges of either A, or C units. 3The afferent discharges of 35% (11/31) of A, fibres and 33% (6/18) of C fibres were increased by local injection of the submaximal doses of GLU (10 µmol/L, 10 µL) into the receptive fields. 4The GLU-induced excitatory response was significantly enhanced by coinjection of subthreshold doses of SP. The mean discharge rates of A, fibres and C fibres were increased from 5.84 ± 1.54 and 5.02 ± 2.65 impulses/min to 19.91 ± 4.35 and 17.58 ± 5.59 impulses/min, respectively, whereas the excitatory proportions of A, and C fibres were increased from 35 and 33% to 84 and 83%, respectively. The duration of the excitation for A, fibres and C fibres was also significantly increased after coinjection of SP + GLU compared with that observed when either substance was given alone. 5The present study provides electrophysiological evidence for an interaction between receptors for SP and GLU on the fine fibres activities in rat hairy skin, which may be involved in the mechanisms of hyperalgesia. [source] | |||||||||||||