RESUMO
OBJECTIVE: To investigate sex effects on pain-related behaviors in the medial meniscal transection (MMT) knee osteoarthritis (OA) model. METHODS: Experiments were performed in male and female C57BL/6J mice (12/group/sex). MMT was induced by transection of the medial collateral ligament and the medial meniscus. Sham-operated and naïve mice served as controls. Mechanical and heat sensitivity in hind paws, hind limb use, and locomotor activity were measured for 3 months. Knee histology was performed on week 12. RESULTS: In males, MMT triggered a bi-phasic mechanical hypersensitivity and decreased load on OA limb, with an acute post-operative (1-5 days) and chronic (3-12 weeks) OA phases separated by a remission in the intermediate phase (1-2 weeks). Females showed a less pronounced bi-phasic pattern, with a greater mechanical hypersensitivity, but not poorer limb use, than males in the intermediate phase (maximal difference: 1.1 g, 95% confidence intervals (CI) [0.7, 1.5]). There were no major sex differences in the chronic phase. MMT did not induce heat hypersensitivity or change in locomotor activity in the chronic phase in both sexes. MMT caused more severe cartilage damage in males than in females (maximal difference: 1.1 score points, 95% CI [1.9, 0.3]), and a comparable between sexes osteophyte formation. The knee damage did not correlate with pain. CONCLUSIONS: MMT modelled human knee OA well, capturing cartilage destruction and osteophyte formation, mechanical pain, and poorer limb use in both sexes. Sex differences in pain were modality- and time-dependent, reflecting complex sex-related features of human OA.
Assuntos
Comportamento Animal , Cartilagem Articular/patologia , Fêmur/patologia , Hiperalgesia/fisiopatologia , Locomoção/fisiologia , Meniscos Tibiais/cirurgia , Osteoartrite do Joelho/fisiopatologia , Tíbia/patologia , Suporte de Carga , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite do Joelho/patologia , Medição da Dor , Fatores SexuaisRESUMO
Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral µ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Desenho de Fármacos , Fentanila/análogos & derivados , Piperidinas/química , Piperidinas/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/química , Monofosfato de Adenosina/antagonistas & inibidores , Analgesia , Analgésicos Opioides/efeitos adversos , Animais , Simulação por Computador , Constipação Intestinal/induzido quimicamente , Fentanila/efeitos adversos , Transferência Ressonante de Energia de Fluorescência , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Modelos Moleculares , Manejo da Dor , Piperidinas/efeitos adversos , Ligação Proteica , Conformação Proteica , Ratos , Receptores Opioides mu/genética , Insuficiência Respiratória/induzido quimicamente , TransfecçãoRESUMO
BACKGROUND: A cerebral oximeter measures oxygen saturation of brain tissue noninvasively by near infrared spectroscopy. The accuracy of a commercially available oximeter was tested in healthy volunteers by precisely controlling end-tidal oxygen (P[ET]O2) and carbon dioxide (P[ET]CO2) tensions to alter global cerebral oxygen saturation. METHODS: In 30 healthy volunteers, dynamic end-tidal forcing was used to produce step changes in P[ET]O2 resulting in arterial saturation ranging from approximately 70% to 100% under conditions of controlled normocapnia (each person's resting P[ET]CO2) or hypercapnia (resting plus 7-10 mmHg). Blood arterial (SaO2) and jugular bulb venous (S[jv]O2) saturations during each P(ET)O2 interval were determined by co-oximetry. The cerebral oximeter reading (rSO2) and an estimated jugular venous saturation (S[jv]O2), derived from a combination of SaO2 and rSO2, were compared with the measured S(jv)O2. RESULTS: The S(jv)O2 was significantly higher with hypercapnia than with normocapnia for the same SaO2. The rSO2 and S(jv)O2 were both highly correlated with S(jv)O2 for individual volunteers (mean r2 = 0.91 for each relation); however, the slopes and intercepts varied widely among volunteers. In three of them, the cerebral oximeter substantially underestimated the measured S(jv)O2. CONCLUSIONS: During isocapnic hypoxia in healthy persons, cerebral oxygenation as estimated by near infrared spectroscopy precisely tracks changes in measured S(jv)O2 within individuals, but the relation exhibits a wide range of slopes and intercepts. Therefore the clinical utility of the device is limited to situations in which tracking trends in cerebral oxygenation would be acceptable.
Assuntos
Encéfalo/metabolismo , Oximetria , Adulto , Dióxido de Carbono/sangue , Circulação Cerebrovascular , Feminino , Humanos , Hipóxia/sangue , Masculino , PosturaRESUMO
To evaluate whether the intact hypoxic drive from the carotid bodies during sustained hypoxia is required for the generation of hypoxic depression of ventilation (VE), 16 volunteers were exposed to two consecutive periods of isocapnic hypoxia (first period 20 min; second period 5 min; end-tidal PO2 45 Torr) separated by 6 min of normoxia. In study A, saline was given. In study B, 3 micrograms.kg-1.min-1 i.v. dopamine (DA), a carotid body inhibitor, was given during the first hypoxic exposure followed by saline during normoxia and the second hypoxic exposure. In study C, 20 min of normoxia with DA preceded 6 min of normoxia and 5 min of hypoxia without DA. The first peak hypoxic VE (PHV) in study A was approximately 100% above normoxic VE. After 20 min of hypoxia, VE declined to 60% above normoxic VE. The second PHV in study A was only 60% of the first PHV. We relate this delayed recovery from hypoxia to "ongoing" effects of hypoxic depression. During DA infusion, the changes in VE due to sustained hypoxia were insignificant (study B). The second PHV in study B was not different from the PHV after air breathing in studies A and C. This indicates that the recovery from sustained hypoxia with a suppressed carotid body drive was complete within 6 min. Our results show that despite central hypoxia the absence of ventilatory changes during 20 min of isocapnic hypoxia due to intravenous DA prevented the generation of central hypoxic depression and the depression of a subsequent hypoxic response.
Assuntos
Corpo Carotídeo/fisiopatologia , Hipóxia/fisiopatologia , Mecânica Respiratória/fisiologia , Adulto , Análise de Variância , Dióxido de Carbono/sangue , Corpo Carotídeo/efeitos dos fármacos , Dopamina/administração & dosagem , Dopamina/farmacologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Oxigênio/sangue , Testes de Função Respiratória , Mecânica Respiratória/efeitos dos fármacosRESUMO
BACKGROUND: These experiments were designed to study the effect of 0.1 minimum alveolar concentration isoflurane on the hypoxic ventilatory response as measured by two common methods of hypoxic testing: when normocapnic hypoxia was induced abruptly and when it was induced gradually. We hypothesized that any disparity in results would be due to an isoflurane effect that was manifested differently in the two tests. METHODS: After 20 min for uptake and equilibration of 0.1 minimum alveolar concentration end-tidal isoflurane or carrier gas in hyperoxia, isocapnic hypoxia was induced either abruptly over 60-80 s ("step" test) or gradually over 10 min ("ramp" test), followed by 20 min of isocapnic hypoxia at 45 mmHg end-tidal oxygen. Control of the hypoxic and isocapnic stimuli was accomplished accurately by a computer-controlled dynamic end-tidal forcing system. Eight subjects performed each test in the presence and absence of isoflurane. RESULTS: For both step tests and ramp tests, 0.1 minimum alveolar concentration isoflurane had no effect on minute ventilation during the defined periods of hypoxia. With isoflurane, delta VE45, the acute change in ventilation from hyperoxia to hypoxia, was 97 +/- 20% (mean +/- SEM) of the control response for step tests and 100 +/- 25% of the control response for ramp tests. The step tests produced significantly larger acute hypoxic responses than did the ramp tests, but by the end of 20 min of hypoxia, ventilation was similar for both tests. CONCLUSIONS: Neither method of hypoxic testing demonstrated the level of isoflurane effect reported by others. A comparison of the two methods of hypoxic testing suggests that ramp tests, as commonly performed, do not allow adequate time for full expression of the acute hypoxic ventilatory response. Step tests also better separated the opposing hypoxic effects of carotid body stimulation and central ventilatory depression.
Assuntos
Hipóxia/fisiopatologia , Isoflurano/farmacologia , Alvéolos Pulmonares/metabolismo , Respiração/efeitos dos fármacos , Adulto , Dióxido de Carbono/fisiologia , Relação Dose-Resposta a Droga , Humanos , Isoflurano/farmacocinética , Masculino , Oxigênio/fisiologia , Pressão Parcial , Alvéolos Pulmonares/efeitos dos fármacos , Respiração/fisiologia , Testes de Função RespiratóriaRESUMO
The normal ventilatory response to the sudden imposition of sustained hypoxia is characterized by an acute increase followed by a modest decline in ventilation. Since subanesthetic concentrations of potent inhalational anesthetics greatly attenuate the acute response, we hypothesized that ventilation might decrease to less than normoxic levels when hypoxia is sustained. We therefore measured the ventilatory response to 20 min of sustained hypoxia (PETO2 45 mmHg) at two levels of strict isocapnia--normocapnia (PETCO2 1-2 mmHg above resting) and hypercapnia (PETCO2 49 mmHg)--in eight healthy male subjects during inhalation of 0.1 MAC isoflurane or carrier gas (control). An abrupt end-tidal step from normoxia to isocapnic hypoxia was induced using a dynamic end-tidal forcing system. Isoflurane and control experiments were performed on separate days; the order of isoflurane and control days and the order of normocapnia and hypercapnia within days were randomized. Subjects were studied while fasted, always at the same time of day, and were required to watch a documentary videotape to minimize differences in level of consciousness. With normocapnia, there was no difference in ventilation at any time between isoflurane and control (prehypoxic 9.6 +/- 1.5 vs. 9.5 +/- 2.6 1/min, peak hypoxic 24.7 +/- 10.4 vs. 26.2 +/- 10.4 1/min, final hypoxic 15.0 +/- 4.4 vs. 15.9 +/- 3.5 1/min; mean +/- SD). With hypercapnia, prehypoxic ventilation increased to the same level for isoflurane and control (24.8 +/- 6.7 vs. 24.8 +/- 9.6 1/min). Although peak hypoxic ventilation was slightly less in isoflurane than in control hypercapnic experiments, this was not significant (49.6 +/- 16.3 vs. 56.5 +/- 24.3 1/min; P = .22).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hipóxia/fisiopatologia , Isoflurano/administração & dosagem , Respiração/efeitos dos fármacos , Adulto , Humanos , Isoflurano/uso terapêutico , Masculino , Respiração/fisiologia , Testes de Função RespiratóriaRESUMO
alpha 2-Adrenergic agonists have been used as potent adjuncts to anesthesia and have anesthetic properties themselves. For this reason, we studied the effects of medetomidine, and isoflurane (1 MAC) on ventilatory drive in dogs. Six chronically tracheotomized mongrel dogs were studied during spontaneous ventilation. Arterial blood samples were analyzed for pH, PaCO2, and PaO2. Airway O2, CO2, N2, and isoflurane were continuously monitored using a mass spectrometer; respiratory rate was determined. The hypercapnic ventilatory response was assessed using the Read rebreathing technique. Control measurements were made under isoflurane anesthesia. Fifteen minutes after the medetomidine (20 ug/kg) was given and the isoflurane discontinued, all measurements were repeated. Isoflurane levels were 1.38 volume % during the isoflurane test period and had declined to 0.3 volume % by the time the medetomidine measurements were obtained. The slope of the CO2 response curve was significantly steeper after medetomidine (0.582 vs 0.269 1.min-1.mmHg), suggesting less respiratory depression when compared to the measurements under isoflurane. PaCO2 and endtidal CO2 were significantly lower in the medetomidine group. No other significant differences were found. Under these conditions, medetomidine (20 ug/kg) resulted in normal blood gas values with less depression of the hypercapnic response curve than under isoflurane anesthesia.