ABSTRACT
BACKGROUND: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor. OBJECTIVE: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. METHODS: Comparisons of spontaneous mutant C57BL/6-Mc1r(e/e) mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. RESULTS: C57BL/6-Mc1r(e/e) mutant mice and human redheads--both with non-functional MC1Rs--display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the mu-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. CONCLUSIONS: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.
Subject(s)
Analgesia , Genetic Variation , Pain/genetics , Receptor, Melanocortin, Type 1/genetics , Receptors, Opioid, mu/drug effects , Adolescent , Adult , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/therapeutic use , Animals , Dose-Response Relationship, Drug , Female , Genotype , Hair Color/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Morphine/pharmacokinetics , Morphine/therapeutic use , Morphine Derivatives/pharmacokinetics , Morphine Derivatives/therapeutic use , Pain/drug therapy , Pain Measurement/drug effects , Pain Threshold/drug effects , Reference ValuesABSTRACT
BACKGROUND: Steroid-resistant or recurrent acute rejection is a risk factor for the development of chronic graft failure in lung transplant recipients. The best treatment for these patients is not known. Methotrexate has been used successfully in heart transplant recipients with persistent or recurrent acute rejection. This study was performed to evaluate the efficacy of methotrexate in lung transplant recipients with steroid-resistant acute rejection. METHODS: From January 1991 to December 1995, 12 patients with steroid-resistant acute rejection were treated with methotrexate given weekly for 6 weeks and dose-adjusted according to laboratory data and clinical side effects. After completion of therapy, all patients underwent transbronchial biopsy to evaluate the efficacy of methotrexate treatment. RESULTS: Twelve patients underwent treatment with methotrexate for steroid-resistant acute rejection. Acute rejection resolved in all patients completing at least 4 weeks of therapy; 10 of 12 patients (83%) had no further episodes of acute rejection during a mean follow-up period of 12.5 months (range 1 to 42 months). Acute rejection recurred in two patients 6 and 16 months after methotrexate therapy. Both resolved with high-dose corticosteroid therapy. One patient had asymptomatic cytomegalovirus shedding 8 weeks after completion of methotrexate therapy. One patient had aseptic meningitis after her fourth dose of methotrexate. Neither infectious complication was associated with neutropenia. One patient had bone marrow suppression and neutropenic fevers after augmentation of her methotrexate dose. Two patients received shortened methotrexate courses because of gastrointestinal side effects. CONCLUSIONS: Methotrexate is efficacious in the treatment of lung transplant recipients with steroid-resistant acute rejection. Patients must be monitored for side effects during therapy and dosing must be individualized based on laboratory and clinical parameters.
