Spinal Opioid Tolerance Depends upon Platelet-Derived Growth Factor Receptor-ß Signaling, Not µ-Opioid Receptor Internalization.

Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of µ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this view has also been called into question. We recently discovered that the platelet-derived growth factor receptor(PDGFR)-ß signaling system is both necessary and sufficient to cause opioid tolerance. We therefore propose a completely new hypothesis: that opioid tolerance is mediated by selective cellular signals and is independent of MOR internalization. To test this hypothesis, we developed an automated software-based method to perform unbiased analyses of opioid-induced MOR internalization in the rat substantia gelatinosa. We induced tolerance with either morphine, which did not cause MOR internalization, or fentanyl, which did. We also blocked tolerance by administering morphine or fentanyl with the PDGFR-ß inhibitor imatinib. We found that imatinib blocked tolerance without altering receptor internalization induced by either morphine or fentanyl. We also showed that imatinib blocked tolerance to other clinically used opioids. Our findings indicate that opioid tolerance is not dependent upon MOR internalization and support the novel hypothesis that opioid tolerance is mediated by intracellular signaling that can be selectively targeted. This suggests the exciting possibility that undesirable opioid side effects can be selectively eliminated, dramatically improving the safety and efficacy of opioids. SIGNIFICANCE STATEMENT: Classically, it was thought that analgesic tolerance to opioids was caused by desensitization and internalization of µ-opioid receptors (MORs). More recently, it was proposed that sustained, rather than reduced, MOR signaling caused tolerance. Here, we present conclusive evidence that opioid tolerance occurs independently of MOR internalization and that it is selectively mediated by platelet-derived growth factor receptor signaling. This novel hypothesis suggests that dangerous opioid side effects can be selectively targeted and blocked, improving the safety and efficacy of opioids.

Comparison of treatment modalities in burning mouth syndrome.

BACKGROUND: Burning mouth syndrome (BMS) is characterized by a spontaneous burning pain in the oral mucosa without known organic cause or standardized treatment. The aims of this study were to assess and compare the efficacy of clonazepam and diazepam in relieving the symptoms associated with BMS and evaluate for which patients this treatment might be effective by correlating treatment efficacy with underlying psychological status. METHODS: The medical records of BMS patients attending an oral medicine private practice (1999-2004) were reviewed. The patients were then contacted and asked to complete a short questionnaire regarding their response to diazepam/clonazepam drug therapies. A second group of patients attending the above clinic (n = 30) were asked to fill out a hospital anxiety and depression assessment form in an attempt to correlate treatment success with underlying psychological status. RESULTS: A total of 71.4 per cent of patients treated with clonazepam had partial or complete resolution of their oral symptoms, while 55.1 per cent of patients treated with diazepam had improvement of their oral symptoms. There was no correlation between underlying anxiety or depression and efficacy of benzodiazepine medication. CONCLUSIONS: A greater percentage of patients taking clonazepam reported either partial or complete relief of symptoms compared to diazepam. However, the differences were not statistically significant. There was no correlation found between underlying psychopathology and treatment success with benzodiazepines.

Burning mouth syndrome: an update on recent findings.

Burning mouth syndrome (BMS) is characterized by a burning sensation of the oral mucosa in the absence of mucosal abnormality. Various local, systemic and psychological factors are associated with BMS, but its aetiology is not fully understood. Recently, significant inroads have been made, producing a better understanding of this complex condition. The aim of the current paper is to explore the condition of BMS in an educational context with the specific outcome of increasing awareness of the condition.