Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity.

UNLABELLED: This investigation used capsaicin to selectively lesion unmyelinated sensory neurons in rats. Neuronal lesioning induced a loss of trabecular integrity, reduced bone mass and strength, and depleted neuropeptides in nerve and bone. These data suggest that capsaicin-sensitive sensory nerves contribute to trabecular bone integrity. INTRODUCTION: Familial dysautomia is an autosomal recessive disease in which patients suffer from unmyelinated sensory neuron loss, reduced BMD, and frequent fractures. It has been proposed that the loss of neurotransmitters synthesized by unmyelinated neurons adversely affects bone integrity in this hereditary syndrome. The purpose of this study was to determine whether small sensory neurons are required for the maintenance of bone integrity in rats. MATERIALS AND METHODS: Ten-month-old male Sprague-Dawley rats were treated with either capsaicin or vehicle. In vivo DXA scanning and micro CT scanning, and histomorphometry were used to evaluate BMD, structure, and cellular activity. Bone strength was measured in distal femoral sections. Body weight and gastrocnemius/soleus weights were measured and spontaneous locomotor activity was monitored. Peroneal nerve morphometry was evaluated using light and electron microscopy. Substance P and calcitonin gene-related peptide (CGRP) content in the sciatic nerve and proximal tibia were determined by enzyme immunoassay (EIA). Substance P signaling was measured using a sciatic nerve stimulation extravasation assay. RESULTS: Four weeks after capsaicin treatment, there was a loss of BMD in the metaphyses of the tibia and femur. In the proximal tibia, the osteoclast number and surface increased, osteoblast activity and bone formation were impaired, and trabecular bone volume and connectivity were diminished. There was also a loss of bone strength in the distal femur. No changes occurred in body weight, 24-h grid-crossing activity, weight bearing, or muscle mass after capsaicin treatment, indicating that skeletal unloading did not contribute to the loss of bone integrity. Capsaicin treatment destroyed 57% of the unmyelinated sensory axons, reduced the substance P and CGRP content in the sciatic nerve and proximal tibia, and inhibited neurogenic extravasation. CONCLUSION: These results support the hypothesis that capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. Capsaicin-sensitive neurons have efferent functions in the tissues they innervate, effects mediated by transmitters released from the peripheral nerve terminals. We postulate that the deleterious effects of capsaicin treatment on trabecular bone are mediated by reductions in local neurotransmitter content and release.

A substance P receptor (NK1) antagonist enhances the widespread osteoporotic effects of sciatic nerve section.

The long-term effects of sciatic nerve section on bone mineral density (BMD) were studied using dual-energy X-ray absorptiometry (DEXA) in skeletally mature rats. Unilateral sciatic neurectomy caused the rapid loss of cancellous bone in the proximal and distal femur and tibia in the ipsilateral hindlimb and, to a lesser extent, in the contralateral intact hindlimb. The reduction in BMD rapidly progressed for 4 weeks after sciatic section and then gradually stabilized with no evidence of recovery at 12 weeks. The development of osteoporosis in the contralateral intact hindlimb was a novel finding. There was no evidence of disuse in the normal contralateral hindlimb after unilateral sciatic section; grid-crossing activity over a 24-h interval was unchanged and there was no reduction in weight bearing on the contralateral normal hindpaw during the stance phase of ambulation. Unilateral peripheral nerve lesions have well-documented effects on substance P content and function in the corresponding contralateral intact nerve. We hypothesized that after sciatic section a reduction in substance P signaling might contribute to bone loss in the contralateral hindlimb. Daily administration of the substance P receptor (NK1) antagonist LY303870 for 2 weeks caused significant loss of cancellous bone in the denervated and the contralateral hindlimb, evidence that substance P signaling sustained bone density after nerve section. After sciatic neurectomy there was a 33% reduction in sciatic nerve stimulation-evoked extravasation in the contralateral intact hindlimb, indicating transmedian inhibition of substance P signaling after nerve injury. Furthermore, there was a 50% reduction in the substance P content in both tibias after unilateral sciatic section. Collectively, these data support the hypothesis that a widespread reduction in substance P content in bone contributes to the osteoporotic effects of sciatic neurectomy and that residual substance P signaling maintains bone integrity after nerve section in both the denervated and contralateral intact hindlimb.

Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I.

Wrist and ankle fractures are the most frequent causes of complex regional pain syndrome (CRPS type I). The current study examined the temporal development of vascular, nociceptive and bony changes after distal tibial fracture in rats and compared these changes to those observed after cast immobilization in intact normal rats. After baseline testing the right distal tibial was fractured and the hindlimb casted. A control group was simply casted without fracturing the tibia. After 4 weeks the casts were removed and the rats retested. Subsequent testing was performed at 6, 8, 10, 16, and 20 weeks after onset of treatment. Distal tibial fracture or cast immobilization alone generated chronic hindlimb warmth, edema, spontaneous protein extravasation, allodynia, and periarticular osteoporosis, changes resembling those observed in CRPS. Hindlimb warmth and allodynia resolved much more quickly after cast immobilization than after fracture. Previously we observed that the substance P receptor (NK(1)) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II. Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870. Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870. Collectively, these data support the hypotheses that the distal tibial fracture model simulates CRPS, immobilization alone can generate a syndrome resembling CRPS, and substance P signaling contributes to the vascular and nociceptive changes observed in these models.

Randomized trial demonstrates that extended-release epidural morphine may provide safe pain control for lumbar surgery patients.

BACKGROUND: Safe and effective postoperative pain control remains an issue in complex spine surgery. Spinal narcotics have been used for decades but have not become commonplace because of safety or re-dosing concerns. An extended release epidural morphine (EREM) preparation has been used successfully in obstetric, abdominal, thoracic, and extremity surgery done with epidural anesthesia. This has not been studied in open spinal surgery. METHODS: Ninety-eight patients having complex posterior lumbar surgery were enrolled in a partially randomized clinical trial (PRCT) of low to moderate doses of EREM. Surgery included levels from L3 to S1 with procedures involving combinations of decompression, instrumented arthrodesis, and interbody grafting. The patients were randomized to receive either 10 or 15 mg of EREM through an epidural catheter placed under direct vision at the conclusion of surgery. Multiple safety measures were employed to prevent or detect respiratory depression. Postoperative pain scores, narcotic utilization, and adverse events were recorded. RESULTS: There were no significant differences between the two groups as to supplemental narcotic requirements, pain scores, or adverse events. There were no cases of respiratory depression. The epidural narcotic effect persisted from 3 to 36 hours after the injection. CONCLUSION: By utilizing appropriate safety measures, EREM can be used safely for postoperative pain control in lumbar surgery patients. As there was no apparent advantage to the use of 15 mg, the lower 10 mg dose should be used.

Murine model of oligotrophic tibial nonunion.

OBJECTIVES: This study aimed to use modified distraction osteogenesis techniques to develop a reliable mouse fracture nonunion model with an oligotrophic phenotype. METHODS: Twenty-six 10- to 14-week-old C57BL/6 male mice underwent a proximal diaphyseal tibial osteotomy with a 2-mm bone resection. An external fixation device was applied to the tibia using cerclage wires. A total of 2.25 mm of distraction was applied over 3 days, resulting in an average distraction gap of 4.28 mm. Plain radiographs were taken at regular intervals until euthanasia at 7 (n = 9), 10 (n = 13), or 12 (n = 4) weeks. After euthanasia, all samples were fixed in formalin, scanned with microcomputed tomography, decalcified in formic acid, prepared in paraffin, and stained with Alcian blue/Mayer's hematoxylin. RESULTS: In the distraction groups, five mice were prematurely euthanized as a result of wound complications stemming from loss of distal fixation. Of the remaining 21, two healed, resulting in a 90% nonunion rate. These nonunions radiographically resembled clinical nonunions with tapered, cone-like fracture ends and histologically demonstrated evidence of attempted healing as seen with cartilage capping. Additionally, the plain radiographic appearance of those nonunions from mice euthanized at 10 and 12 weeks did not change over the final 4 to 6 weeks. CONCLUSIONS: The use of 2-mm tibial resection osteotomy with 2-mm distraction provides a predictable model for fracture nonunion in mice with the oligotrophic phenotype closely resembling the clinical correlate. This model offers a promising means for characterization of the molecular events that occur during the development of fracture nonunion and for evaluation of noninvasive methods of nonunion rescue.