Noggin inhibits postoperative resynostosis in craniosynostotic rabbits

Inhibition of bone formation after surgery to correct craniosynostosis would alleviate the need for secondary surgeries and decrease morbidity and mortality. This study used a single dose of Noggin protein to prevent resynostosis and improve postoperative outcomes in a rabbit model of craniosynostosis. Introduction: Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures, which causes secondary deformations of the cranial vault, cranial base, and brain. Current surgical intervention involves extirpation of the fused suture to allow unrestricted brain growth. However, resynostosis of the extirpated regions often occurs. Several bone morphogenetic proteins (BMPs), well-described inducers of ossification, are involved in bone healing. This study tested the hypothesis that a postoperative treatment with Noggin, an extracellular BMP inhibitor, can inhibit resynostosis in a rabbit model of human familial nonsyndromic craniosynostosis. Materials and Methods: Thirty-one New Zealand white rabbits with bilateral coronal suture synostosis were divided into three groups: (1) suturectomy controls (n = 13); (2) suturectomy with BSA in a slow-resorbing collagen vehicle, (n = 8); and (3) suturectomy with Noggin in a slow-resorbing collagen vehicle (n = 10). At 10 days of age, a 3 x 15-mm coronal suturectomy was performed. The sites in groups 2 and 3 were immediately filled with BSA-loaded gel or Noggin-loaded gel, respectively. Serial 3D-CT scan reconstructions of the defects and standard radiographs were obtained at 10, 25, 42, and 84 days of age, and the sutures were harvested for histological analysis. Results: Radiographic analysis revealed that Noggin-treated animals had significantly greater coronal suture marker separation by 25 days and significantly greater craniofacial length at 84 days of age compared with controls. 3D-CT analysis revealed that Noggin treatment led to significantly greater defect areas through 84 days and to increased intracranial volumes at 84 days of age compared with other groups. Histological analysis supported CT data, showing that the untreated and BSA-treated groups had significant healing of the suturectomy site, whereas the Noggin-treated group had incomplete wound healing. Conclusions: These data support our hypothesis that inhibition of BMP activity using Noggin may prevent postoperative resynostosis in this rabbit model. These findings also suggest that Noggin therapy may have potential clinical use to prevent postoperative resynostosis in infants with craniosynostosis. © 2007 American Society for Bone and Mineral Research

Inhibitory inputs from rostromedial tegmental nucleus regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse

The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activatio