Faculty Bibliography

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

Escherichia coli grows over a wide range of pHs (pH 4.4 to 9.2), and its own metabolism shifts the external pH toward either extreme, depending on available nutrients and electron acceptors. Responses to pH values across the growth range were examined through two-dimensional electrophoresis (2-D gels) of the proteome and through lac gene fusions. Strain W3110 was grown to early log phase in complex broth buffered at pH 4.9, 6.0, 8.0, or 9.1. 2-D gel analysis revealed the pH dependence of 19 proteins not previously known to be pH dependent. At low pH, several acetate-induced proteins were elevated (LuxS, Tpx, and YfiD), whereas acetate-repressed proteins were lowered (Pta, TnaA, DksA, AroK, and MalE). These responses could be mediated by the reuptake of acetate driven by changes in pH. The amplified proton gradient could also be responsible for the acid induction of the tricarboxylic acid (TCA) enzymes SucB and SucC. In addition to the autoinducer LuxS, low pH induced another potential autoinducer component, the LuxH homolog RibB. pH modulated the expression of several periplasmic and outer membrane proteins: acid induced YcdO and YdiY; base induced OmpA, MalE, and YceI; and either acid or base induced OmpX relative to pH 7. Two pH-dependent periplasmic proteins were redox modulators: Tpx (acid-induced) and DsbA (base-induced). The locus alx, induced in extreme base, was identified as ygjT, whose product is a putative membrane-bound redox modulator. The cytoplasmic superoxide stress protein SodB was induced by acid, possibly in response to increased iron solubility. High pH induced amino acid metabolic enzymes (TnaA and CysK) as well as lac fusions to the genes encoding AstD and GabT. These enzymes participate in arginine and glutamate catabolic pathways that channel carbon into acids instead of producing alkaline amines. Overall, these data are consistent with a model in which E. coli modulates multiple transporters and pathways of amino acid consumption so as to minimize the shift of its external pH toward either acidic or alkaline extreme.

Oral squamous cell carcinoma (SCC) is characterized by invasive growth and the propensity for distant metastasis. The expression of specific adhesion receptors promotes defined interactions with the specific components found within the extracellular matrix (ECM). We previously showed that the alpha v beta 6 fibronectin receptor is highly expressed in oral SCC. Here we forced expression of the beta 6 subunit into poorly invasive SCC9 cells to establish the SCC9 beta 6 cell line and compared these two cell lines in several independent assays. Whereas adhesion to fibronectin was unaffected by the expression of beta 6, migration on fibronectin and invasion through a reconstituted basement membrane (RBM) were both increased. Function-blocking antibodies to alpha v beta 6 (10D5) reduced both migration on fibronectin and invasion through an RBM, whereas anti-alpha 5 antibodies were effective only in suppressing migration on fibronectin, not invasion. Expression of beta 6 also promoted tumor growth and invasion in vivo and modulated fibronectin matrix deposition. When grown as a co-culture with SCC9 cells, peritumor fibroblasts (PTF) organized a dense fibronectin matrix. However, fibronectin matrix assembly was decreased in co-cultures of SCC9 beta 6 cells and PTF and this decrease was reversed by the addition of function-blocking anti-alpha v beta 6 antibodies. The expression of beta 6 also resulted in increased levels of matrix metalloproteinase 3. Addition of the general MMP inhibitor GM6001 to SCC9 beta 6/PTF co-cultures dramatically increased fibronectin matrix assembly in a similar fashion as incubation with anti-alpha v beta 6 antibodies. These results demonstrate that expression of beta 6 (1) increases oral SCC cell motility and growth in vitro and in vivo; (2) negatively affects fibronectin matrix assembly; and (3) stimulates the expression and activation of MMP3. We suggest that the integrin alpha v beta 6 is a key component of oral SCC invasion and metastasis through modulation of MMP-3 activity

We previously demonstrated that noxious peripheral stimulation (e.g. subdermal capsaicin injection in the hind paw) produces antinociception that is mediated by opioid receptors in nucleus accumbens. The current study used the trigeminal jaw-opening nociceptive reflex responses in the rat to assess the role of intra-accumbens mu-, delta- and kappa-opioid receptors in the antinociceptive effect of noxious stimulation and intra-accumbens opioid agonism. Whilst intra-accumbens injection of either the mu-receptor-selective antagonist Cys2,Tyr3,Orn5,Pen7amide (CTOP) or the delta-receptor-selective antagonist naltrindole blocked capsaicin-induced antinociception, neither the selective mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO; 150 or 300 ng) nor the selective delta-agonist D-Pen2,5-enkephalin (DPDPE; 150 or 300 ng) alone induced antinociception. Simultaneous injection of DAMGO and DPDPE (150 ng each), however, produced significant antinociception. Capsaicin-induced antinociception was not blocked by the selective kappa-receptor antagonist nor-binaltorphimine, but was blocked by the kappa-agonist U69,593. U69,593 also antagonized the antinociceptive effect of the DAMGO/DPDPE combination. Thus, in nucleus accumbens, mu- and delta- but not kappa-opioid receptors contributed to capsaicin-induced antinociception; selective activation of individual receptor subtypes was insufficient, but coactivation of mu- and delta-opioid receptors induced antinociception, and kappa-receptors appeared to play an antianalgesic role in nucleus accumbens

PURPOSE: This study evaluated the use of enucleation and cryosurgery in the management of odontogenic keratocysts. PATIENTS AND METHODS: This study involved a retrospective review of 26 patients. All of the patients received a combination of enucleation and cryosurgery. Postoperative follow-up consisted of clinical and radiographic examinations. RESULTS: Before enucleation and cryotherapy, 22 of the 26 patients had received previous treatment consisting of enucleation alone. The average time from initial treatment to recurrence was 6.2 years. Twenty-three cases occurred in the mandible, 22 in the posterior (proximal to the canine), and 1 in the anterior mandible. Three cases involved the maxilla. Three of the 26 patients (11.5%) developed a recurrence after treatment. The average time from treatment to recurrence in these 3 patients was 1.6 years (range, 1.2 to 1.9 years). The remaining 23 patients (88.5%) had no evidence of clinical or radiographic recurrence. The average time of follow-up was 3.5 years (range, 2.0 to 10.0 years). CONCLUSIONS: Based on these results, the combination of enucleation and liquid nitrogen cryotherapy may offer patients improved therapy in the management of odontogenic keratocysts