RESUMEN
OBJECTIVE: In the present study, we sought to develop/characterize the pain profile of a rat model of surgically induced osteoarthritis (OA). METHODS: OA was surgically induced in male Lewis rats (200-225 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial joint. In order to characterize the pain profile, animals were assessed for a change in hind paw weight distribution (HPWD), development of mechanical allodynia, and the presence of thermal and mechanical hyperalgesia. Rofecoxib and gabapentin were examined for their ability to decrease change in weight distribution and tactile allodynia. RESULTS: Transection of the medial collateral ligament and medial meniscus of male Lewis rats resulted in rapid (<3 days) changes in hind paw weight bearing and the development of tactile allodynia (secondary hyperalgesia). There was, however, no appreciable effect on thermal hyperalgesia or mechanical hyperalgesia. Treatment with a single dose of rofecoxib (10 mg/kg, PO, day 21 post surgery) or gabapentin (100mg/kg, PO, day 21 post surgery) significantly attenuated the change in HPWD, however, only gabapentin significantly decreased tactile allodynia. CONCLUSION: The rat medial meniscal tear (MMT) model mimics both nociceptive and neuropathic OA pain and is responsive to both a selective cylooxygenase-2 (COX-2) inhibitor commonly utilized for OA pain (rofecoxib) and a widely prescribed drug for neuropathic pain (gabapentin). The rat MMT model may therefore represent a predictive tool for the development of pharmacologic interventions for the treatment of the symptoms associated with OA.
Asunto(s)
Artralgia/patología , Hiperalgesia/patología , Osteoartritis de la Rodilla/patología , Aminas/uso terapéutico , Analgésicos/uso terapéutico , Animales , Artralgia/tratamiento farmacológico , Artralgia/etiología , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Modelos Animales de Enfermedad , Gabapentina , Miembro Posterior , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Lactonas/uso terapéutico , Masculino , Osteoartritis de la Rodilla/complicaciones , Ratas , Sulfonas/uso terapéutico , Soporte de Peso/fisiología , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
The phosphodiesterase-IV (PDE-IV) inhibitor, rolipram, is antiinflammatory in a number of animal models and inhibits the release of a variety of cytokines, including TNFalpha. Arthritis induced in rats by systemic reactivation with streptococcal cell walls (SCW) following intraarticular sensitization is a TNFalpha-dependent, delayed-type hypersensitivity (DTH) reaction. Rolipram administered during the reactivation phase dose-dependently inhibited hind paw edema through day 24, the day of peak swelling. PMN and T-cell recruitment to the arthritic joint were also attenuated in rolipram-treated rats. Histologic examination of ankle sections from rolipram-treated animals showed a marked attenuation of synovial inflammation. Mechanistic studies to determine the role of glucocorticoids in mediating rolipram action showed that the inhibitory effect of rolipram on swelling was not reversed by RU 486, a glucocorticoid antagonist. In contrast, RU 486 reversed the inhibitory effects of rolipram on TNFalpha secretion. To further evaluate the role of cAMP in the model, the beta-adrenergic receptor (betaAR) agonist isoproterenol was tested, and found to inhibit swelling but not the release of TNFalpha. These results are consistent with the view that the inhibitory effects of rolipram may be partially mediated by cAMP-dependent, but TNFalpha-independent, mechanisms. The betaAR antagonists propranolol and nadolol had no appreciable affect on the antiinflammatory effect of rolipram. However, rolipram reversed the lethal effects of the antagonists observed when either was administered alone. Apparently, beta-adrenergic mechanisms moderate the response to challenge, and rolipram treatment, presumably as a result of its effects on cAMP levels, reverses the toxic effect of the antagonists.
Asunto(s)
Artritis Infecciosa/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Rolipram/uso terapéutico , Infecciones Estreptocócicas/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Agonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , AMP Cíclico/metabolismo , Femenino , Miembro Posterior , Antagonistas de Hormonas/uso terapéutico , Isoproterenol/uso terapéutico , Mifepristona/uso terapéutico , Neutrófilos/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Linfocitos T/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Intra-articular injection of streptococcal cell wall Ag followed by i.v. challenge ("reactivation") results in a destructive lymphocyte-dependent monoarticular arthritis. To further define the role of immune mechanisms in the model, Abs to Th1 and Th2-related cytokines were evaluated. Treatment of rats with antibodies to IL-4 reduced swelling, while treatment with anti-IL-10 or anti-IFN-gamma either had no effect or slightly enhanced the inflammatory response. These results suggest that Th-2 immune mechanisms may be, at least in part, operative in the model. To more precisely define the role of IL-4, the effects of anti-IL-4 on monocyte chemoattractant protein-1 (MCP-1) expression were evaluated. Initial studies demonstrated that mRNA (as determined by in situ hybridization) and protein (as determined by immunofluorescence) for MCP-1 were detectable in inflamed synovial tissue in a time-dependent manner. Anti-IL-4 treatment significantly reduced the expression of mRNA for MCP-1 24 and 72 h after reactivation. In addition, anti-MCP-1 inhibited swelling and reduced influx of (111)In-labeled T cells. These data suggest that the reactivation model of streptococcal cell wall Ag-induced arthritis is Th-2 dependent, and that an inter-relationship exists between IL-4 and the expression of MCP-1.
Asunto(s)
Artritis/inmunología , Quimiocina CCL2/fisiología , Interferón gamma/fisiología , Interleucina-10/fisiología , Interleucina-4/fisiología , Peptidoglicano/administración & dosificación , Streptococcus/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Artritis/etiología , Artritis/patología , Movimiento Celular/inmunología , Quimiocina CCL2/análisis , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Femenino , Inmunohistoquímica , Hibridación in Situ , Inyecciones Intraarticulares , Inyecciones Intravenosas , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-4/inmunología , Ratas , Ratas Endogámicas Lew , Bazo/citología , Bazo/inmunología , Linfocitos T/patologíaRESUMEN
We investigated the effects of subtype-selective muscarinic receptor antagonists upon aerosol antigen-induced bronchoconstriction in anesthetized guinea pigs. Neither pirenzepine (muscarinic M1 receptor-selective), 4-methylpiperidine methiodide (4-DAMP, muscarinic M3 receptor-selective), [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCl (DAC-5945, muscarinic M3 receptor-selective), ipratropium or atropine inhibited bronchoconstriction, but methoctramine (muscarinic M2 receptor-selective) produced a dose-dependent increase in bronchoconstriction (up to 46%). Methoctramine also produced increases in bronchoconstriction induced by aerosols of histamine (up to 45%) and platelet activating factor (up to 118%), demonstrating nonspecific airway hyperresponsiveness. This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to altered arachidonic acid metabolism or beta-adrenergic antagonism. However, propranolol prevented methoctramine-induced airway hyperresponsiveness, suggesting that this effect resulted from the reported ganglionic blocking activity of methoctramine. In conclusion, muscarinic receptors do not appear to play an important role in antigen-induced bronchoconstriction in anesthetized guinea pigs. Furthermore, caution should be exercised in using methoctramine to characterize the roles of muscarinic receptors in airway inflammatory responses in vivo.
Asunto(s)
Hiperreactividad Bronquial/inducido químicamente , Broncoconstricción/efectos de los fármacos , Diaminas/farmacología , Antagonistas Muscarínicos , Parasimpatolíticos/farmacología , Aerosoles , Albuterol/administración & dosificación , Albuterol/farmacología , Animales , Ácido Araquidónico/metabolismo , Atropina/farmacología , Diaminas/toxicidad , Sinergismo Farmacológico , Trietyoduro de Galamina/farmacología , Cobayas , Histamina/toxicidad , Masculino , Ovalbúmina/toxicidad , Parasimpatolíticos/toxicidad , Piperazinas/farmacología , Piperidinas/farmacología , Factor de Activación Plaquetaria/toxicidad , Propranolol/farmacología , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/metabolismoRESUMEN
The need for a smooth muscle-selective muscarinic antagonist that could provide oral bronchodilator activity with minimal side effects has led to the discovery of 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (NPC-14695). Orally administered NPC-14695 was as potent as albuterol in the prevention of aerosolized carbachol-induced collapse in conscious guinea pigs. After s.c. administration in conscious guinea pigs challenged with aerosolized carbachol, NPC-14695 was more potent in the inhibition of collapse than in the inhibition of salivation or the production of mydriasis. Moreover, NPC-14695 exhibited a greater selectivity for the inhibition of collapse over salivary or pupillary effects than either ipratropium or oxybutynin. NPC-14695 was more M3/M2 selective than diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) in vivo, which was determined from the reversal of bronchoconstriction and bradycardia after i.v. administration in anesthetized guinea pigs infused with methacholine, but was less potent than ipratropium or 4-DAMP. At increasing equieffective bronchodilator doses of aerosolized ipratropium and intraduodenally administered NPC-14695 in anesthetized guinea pigs infused with methacholine, ipratropium reversed the bradycardia and then produced tachycardia whereas NPC-14695 did not alter the heart rate. At doses that produced 50% of the maximum bronchodilation, neither aerosolized ipratropium or intraduodenally administered NPC-14695 affected the pupillary diameter or salivation. At doses that produced a maximum bronchodilation, the two drugs produced an equivalent inhibition of salivation and NPC-14695 produced mydriasis. NPC-14695 did not inhibit the bronchoconstriction induced by three other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Broncodilatadores/farmacología , Ciclobutanos/farmacología , Pulmón/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Parasimpatolíticos/farmacología , Piperazinas/farmacología , Animales , Femenino , Cobayas , Antagonistas MuscarínicosRESUMEN
We investigated the M3/M2 antagonist selectivity of [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCI (DAC 5945) in vivo. ED50 values for reversal of methacholine-induced bronchoconstriction and bradycardia by muscarinic antagonists were determined in anesthetized and ventilated guinea pigs. Atropine, ipratopium, pirenzepine and diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) were non-selective, whereas methoctramine was cardioselective. In contrast, DAC 5945 was a more potent muscarinic antagonist in the airways than in the heart, demonstrating M3/M2 selectivity in vivo.