Faculty Bibliography

We have previously shown that the integrin beta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin beta6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin beta6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin beta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fyn and thus promotes oral cancer progression

Expression of beta 3 integrins is increased in invasive melanoma. In this study we show that K1735 cell proliferation is enhanced by the expression of either beta 3 or a constitutively active Src. We investigated possible modulators of FN matrix assembly and found that matrix metalloproteinase 2 (MMP2) was activated by alpha v beta 3. alpha v beta 3 integrin was localized to focal contacts whereas alpha v beta 5 was peripherally distributed. MMP2 was also activated by expression of CASrc. MMP2 activation inversely correlated with FN matrix assembly, in that it dramatically reduced the organization of a FN matrix. K1735 cell migration on VN and invasion through a reconstituted basement membrane were decreased in the presence of anti-MMP2 antibodies. These results demonstrate that the expression of the alpha v beta 3 complex modulates melanoma cell behavior including activation of Src, organization of the cytoskeleton, assembly of the extracellular matrix, cell motility, and activation of MMP2.

We report on the response of medically refractory neuropathic trigeminal pain in three patients to intravenous administration of a combination of the kappa-partial agonist opioid nalbuphine and the opioid antagonist naloxone. Each of the three patients had developed a painful peripheral neuropathy as a complication of chemical or mechanical injury to the trigeminal nerve. Each patient had been tried on a number of analgesics, including mu-opioids, and had not gained relief or was not able to tolerate side effects of the medications. Pain intensity was measured for 3 h following drug administration using a 10 cm visual analog scale. All three patients reported marked decrease in pain following administration of the nalbuphine and naloxone combination. These findings suggest a novel approach to the management for neuropathic pain.

We studied adaptations in nucleus accumbens opioidergic circuitry mediating noxious stimulus-induced antinociception (NSIA) in rats withdrawing from chronic morphine administration. Although the magnitude of NSIA in withdrawing rats was similar to that observed in naive rats despite the tolerance of withdrawing rats to the antinociceptive effects of acutely administered morphine, the involvement of nucleus accumbens opioid receptors in NSIA in withdrawing rats was different from previous observations in both naive and tolerant rats. In withdrawing rats intra-accumbens administration of the mu-opioid receptor antagonist Cys2, Tyr3, Orn5, Pen7 amide (CTOP), but not the delta-receptor antagonist naltrindole, blocked NSIA. Both antagonists blocked NSIA in the naive state, but neither was effective in tolerant rats. Also, intra-accumbens administration of the mu-agonist [D-Ala2, N-Me-Phe(4,) Gly5-ol]-enkephalin (DAMGO) alone was sufficient to induce antinociception in withdrawing rats, whereas a combination of both mu- and delta-receptor agonists (ie, DAMGO and D-Pen(2,5)-enkephalin [DPDPE], respectively) is required to induce antinociception in naive rats. The delta- agonist DPDPE was without effect in the withdrawing rat, alone or when combined with DAMGO. Thus, although the magnitude of NSIA does not differ significantly among the 3 states, it is mediated by both mu- and delta-receptors in the naive rat, mu- but not delta-receptors in the withdrawing rat, and neither receptor type in the morphine tolerant rat. These changes may result from different degrees of tolerance, with delta-receptors being the most sensitive; however, it is not known how these changes occur without affecting the magnitude of the resultant antinociception

BACKGROUND: An explanation for the predominance of injuries to lingual nerves over those to inferior alveolar nerves as a result of inferior alveolar nerve blocks may be due to the nerves' fascicular pattern. A unifascicular nerve may be injured more easily than a multifascicular nerve. METHODS: The authors unilaterally dissected lingual and inferior alveolar nerves from 12 cadavers. They cut the specimens 2 millimeters above the lingula for both the lingual nerve and inferior alveolar nerve and opposite the site of the middle of the third molar for the lingual nerve, and they counted the number of fascicles at each site. RESULTS: For the lingual nerve at the lingula, the mean number of fascicles was three (range, one to eight). Four of the 12 nerves (33 percent) were unifascicular at this point. Opposite the third molar, the lingual nerve had a mean of 20 fascicles (range, six to 39). In every case, there were more fascicles in the third molar region than above the lingula in the same nerve. At the lingula, the inferior alveolar nerve had a mean of 7.2 fascicles (range, three to 14). CONCLUSION: This study may explain the observation that when an inferior alveolar nerve block causes permanent nerve impairment, the lingual nerve is affected about 70 percent of the time and the inferior alveolar nerve is affected only 30 percent of the time. In 33 percent of cases, the lingual nerve had only one fascicle at the lingula; a unifascicular nerve may be injured more easily than a multifascicular one. CLINICAL IMPLICATIONS: There is no known way to avoid the remote possibility of nerve damage resulting from an inferior alveolar nerve block. The lingual nerve may be predominantly affected because of its fascicular pattern

PURPOSE: The purpose of this project was to evaluate a novel technique for inducing osteogenesis through periosteal distraction in a rabbit model. MATERIALS AND METHODS: A periosteal distraction device was rigidly fixed to the lateral surface of the mandible in 10 adult rabbits. Periosteal distraction was started 7 days after placement of the periosteal distraction device. The periosteum was distracted 7 mm over 15 days. The unoperated, contralateral side of the mandible served as the control. The animals were killed at postoperative days 28, 35, 42, and 56. The specimens were then fixed, decalcified, and stained with hematoxylin and eosin. Histologic examination and histomorphometric analysis were performed on all specimens. RESULTS: Nine of 10 periosteal distraction devices remained rigidly fixed to the lateral surface of the mandible. On postoperative day 28, the histologic specimen from the experimental side showed periosteal proliferation and an increase in the number of osteoblasts. On postoperative days 35, 42, and 56, the experimental side showed an increase in the number of osteocytes per unit area, collagen fibers parallel to the vector of distraction, islands of osteoblasts surrounded by newly formed bone, and maturation of bone. An average of 2.86 +/- 0.56 mm of new bone height was formed. CONCLUSION: We report on a novel technique for generating bone by periosteal distraction. Our histologic analysis showed proliferation of the periosteum, an increase in the number of osteoblasts and osteogenesis

We investigated the effect of chronic administration of morphine on noxious stimulus-induced antinociception (NSIA) produced by intraplantar capsaicin injection. In the untreated (naive) rat, we previously found that NSIA depends on activation of dopamine, nicotinic acetylcholine, and mu- and delta-opioid receptors in nucleus accumbens. Rats chronically implanted with subcutaneous morphine pellets demonstrated tolerance to the antinociceptive effects of acute systemic morphine administration but did not show cross-tolerance to NSIA. Morphine pretreatment, however, significantly reduced NSIA dependence on intra-accumbens opioid receptors but not on dopamine or nicotinic acetylcholine receptors. As observed in naive rats, intra-accumbens microinjection of either the dopamine receptor antagonist flupentixol or the nicotinic receptor antagonist mecamylamine blocked NSIA in rats tolerant to the antinociceptive effects of morphine, but, in contrast to naive rats, intra-accumbens microinjection of either the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7 amide or the delta-receptor antagonist naltrindole failed to block NSIA. These findings suggest that although NSIA is dependent on nucleus accumbens opioid receptors in the naive state, this dependence disappears in rats tolerant to the antinociceptive effects of morphine, which may account for the lack of NSIA cross-tolerance. In separate experiments, intra-accumbens extracellular dopamine levels were measured using microdialysis. Dopamine levels increased after either capsaicin or systemic morphine administration in naive rats but only after capsaicin administration in morphine pretreated rats. Thus, intra-accumbens dopamine release paralleled antinociceptive responses in naive and morphine pretreated rats