Faculty Bibliography

The primary molecular target for clinically used opioids is the mu-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with beta2-adrenergic receptors (beta2-ARs) through an interaction with the fifth and sixth helices of beta2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective beta2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and beta2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with beta2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by beta2-AR antagonists, providing a new avenue for opioid therapy.

The pharmacological effect of opioids originates, at the cellular level, by their interaction with the mu-opioid receptor (mOR) resulting in the regulation of voltage-gated Ca2+ channels and inwardly rectifying K+ channels that ultimately modulate the synaptic transmission. Recently, an alternative six trans-membrane helix isoform of mOR, (6TM-mOR) has been identified, but its function and signaling are still largely unknown. Here, we present the structural and functional mechanisms of 6TM-mOR signaling activity upon binding to morphine. Our data suggest that despite the similarity of binding modes of the alternative 6TM-mOR and the dominant seven trans-membrane helix variant (7TM-mOR), the interaction with morphine generates different dynamic responses in the two receptors, thus, promoting the activation of different mOR-specific signaling pathways. We characterize a series of 6TM-mOR-specific cellular responses, and observed that they are significantly different from those for 7TM-mOR. Morphine stimulation of 6TM-mOR does not promote a cellular cAMP response, while it increases the intracellular Ca2+ concentration and reduces the cellular K+ conductance. Our findings indicate that 6TM-mOR has a unique contribution to the cellular opioid responses. Therefore, it should be considered as a relevant target for the development of novel pharmacological tools and medical protocols involving the use of opioids.

Oral cancers are often severely painful and clinically difficult to manage. Few researchers have investigated the neurobiologic factors responsible for cancer pain; however, the study of oral cancer pain might inform us about the fundamental biology of cancer. The purpose of the present report was to summarize the clinical challenges inherent in oral cancer pain management, oral cancer pain mechanisms and mediators, and the convergence of the investigation of carcinogenesis and pain.

While intraosseous tumors of the pediatric sinonasal tract are rare and tend to be slow growing, they can be locally aggressive and have a tendency to recur. Due to the possibility of devastating outcomes secondary to mass effect, it is important for physicians to promptly diagnose and properly manage these tumors. We report an extremely rare case of a desmoplastic fibroma of the ethmoid sinus in a pediatric patient and review its clinical findings, methods of diagnosis, and treatment

PURPOSE: Facial fractures in the pediatric population have a significant impact on public health. Although some demographic data exists regarding the overall epidemiology of facial fractures, little attention has been paid to the patterns of facial fractures based on the etiology of the trauma. MATERIAL AND METHODS: The Kids' Inpatient Database 2000-2009 was utilized to analyze pediatric facial fractures. A total of 21,533 patients were identified. Associations of patient characteristics with outcomes of interest were assessed. RESULTS: The top three etiologies were motor vehicle accident (MVA), intentional trauma (IT), and falls. There was a decrease in the incidence of facial fractures due to MVAs and an increase in injuries due to IT and falls. Concomitant injuries were present in 58.8% and the mortality rate was 2%. The rate of concomitant injuries increased during study period. Age was significantly associated with concomitant injury, mortality, and LOS. CONCLUSION: The increasing rate of IT and falls with concomitant injury warrants special consideration to reduce undiagnosed accompanying injuries. Further programs should be put in place to protect children younger than 5 years of age, who have increased risk of concomitant injury and mortality following intentional trauma.

Endosteal dental implants have been utilized as anchors for dental and orthopedic rehabilitations for decades with one of the highest treatment success rates in medicine. Such success is due to the phenomenon of osseointegration where after the implant surgical placement, bone healing results into an intimate contact between bone and implant surface. While osseointegration is an established phenomenon, the route which osseointegration occurs around endosteal implants is related to various implant design factors including surgical instrumentation and implant macro, micro, and nanometer scale geometry. In an implant system where void spaces (healing chambers) are present between the implant and bone immediately after placement, its inherent bone healing pathway results in unique opportunities to accelerate the osseointegration phenomenon at the short-term and its maintenance on the long-term through a haversian-like bone morphology and mechanical properties.