Electrical stimulation of tooth pulp in humans. I. Relationships among physical stimulus intensities,psychological magnitude estimates and cerebral evoked potentials

Brief electrical pulses were applied to the pulp of individual pre-molar teeth of 14 healthy, adult volunteers via wire electrodes implanted and sealed in dentine. The sensation threshold was estimated in each individual by the Two-Alternative Forced-Choice Staircase (2AFCS) method. Seven, 5 or 4 stimulus intensities were employed which were equally spaced in a logarithmic scale between 10 μA above threshold and 500 μA. Magnitude estimates of the subjective intensity of the sensation produced by individual dental excitations were obtained. Cerebral tooth pulp-evoked potentials were simultaneously recorded in 11 subjects.The growth of psychological sensory magnitude with increasing strength of electrical stimulus conformed to the general psychophysical power law. Individual power function exponents varied from 0.204 to 0.907 with a mean of 0.475 and a standard deviation of 0.190. The amplitude of TPEPs, measured between components N135 and P293, also was a power function of stimulus intensity. The exponents of individual TPEP amplitude-intensity functions ranged from 0.055 to 0.362 with a mean of 0.144 and a standard deviation of 0.100. These last exponents were substantially smaller than those describing the growth of psychological magnitude estimates. Neither magnitude estimation nor TPEP amplitude-intensity functions displayed abrupt changes in slope which might accompany transition from one operating sensory mechanism to another and/or changes in qualities of subjective sensations from ‘innocuous’ to ‘uncomfortable’ to ‘painful.’The result of our psychophysical and electrophysiologic experiments indicate That: (1) albeit highly specialized both morphologically and functionally, human tooth pulp has certain fundamental properties in common with other sensory systems and (2) late midline TPEP components may provide measures of central events that, within a range of stimulus itensities, are associated with the perception of pain, but should not be looked upon as specific indicators of pain processes.     

Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study

PURPOSE: Cantuzumab mertansine (SB-408075; huC242-DM1) is a conjugate of the maytansinoid drug DM1 to the antibody huC242, which targets CanAg antigen. In previous studies, cantuzumab mertansine was considered safe and tolerable, but transaminitis precluded tolerance of higher doses. Based on those studies, it was suggested that treatment at intervals of the half-life of the intact immunoconjugate may allow a higher dose density. This provided the rationale for the three-times weekly treatment explored in this protocol. METHODS: Patients with advanced solid tumors and documented CanAg expression were treated with escalating doses of cantuzumab mertansine IV administered three-times a week in a 3 out of 4 weeks schedule. Plasma samples were assayed to determine pharmacokinetic parameters. RESULTS: Twenty patients (pts) with colon (11/20), rectal carcinomas (2/20), or other malignancies (7/20) were treated with doses ranging from 30 to 60 mg/m(2) per day of cantuzumab mertansine IV three-times a week. The maximum tolerated dose (MTD) was 45 mg/m(2), and the dose-limiting toxicity was grade 3 transaminitis. Hepatic, hematologic, and neurosensory effects occurred, but were rarely severe with repetitive treatment at doses of 45 mg/m(2). CONCLUSIONS: Treatment with cantuzumab mertansine at 45 mg/m(2) per day three-times weekly x 3-every-4-week schedule proved that a dose-intense treatment with an immunoconjugate can be safely administered. The pharmacokinetic profile of the intact immunoconjugate indicates that the linker is cleaved with a half-life of about 2 days, resulting in faster clearance of the maytansinoid relative to the antibody. Therefore, with the development of second-generation immunoconjugates, there is a need for improvement of the immunoconjugate linker to take full advantage of the slow clearance of full-length antibody molecules.     

5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism

5-HT(6) receptors are expressed in brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. This study examined the effects of acute systemic administration of two selective 5-HT(6) receptor antagonists Ro 04-6790 and SB-271046 (10 mg kg(-1) i.p.) on acquisition, consolidation, and retrieval in the novel object discrimination (NOD) task, a two-trial test of recognition memory in which rats exposed to two identical objects during a familiarisation trial can discriminate a novel from a familiar object during the subsequent choice trial, following inter-trial delays of up to 3 h. 5-HT(6) receptor antagonist administration 20 min prior to or immediately after the familiarisation trial, but not 20 min prior to the choice trial reversed the deficit in object discrimination produced by a 4 h inter-trial interval. The nootropic effects of the 5-HT(6) receptor antagonists in this task thus appear to involve enhanced consolidation. Pre-treatment with the non-competitive NMDA receptor antagonist MK-801 (0.05 mg kg(-1) i.p.) prevented the effect of Ro 04-6790 on delay-induced deficits in object discrimination. This suggests that the 5-HT(6) receptor antagonist-induced enhancement of consolidation involves increased central glutamatergic neurotransmission.     

GABAergic modulation of 5-HT7 receptor-mediated effects on 5-HT efflux in the guinea-pig dorsal raphe nucleus

5-HT(7) receptor mRNA and protein are localised in the dorsal raphe nucleus (DRN) on non-serotonergic neurones. The effect of 5-HT(7) receptor antagonism on 5-HT efflux was measured from guinea-pig DRN slices, using the technique of fast cyclic voltammetry. The 5-HT(7) receptor antagonist, SB-269970-A, significantly inhibited 5-HT efflux. The GABA(A) receptor agonist, muscimol, significantly inhibited 5-HT efflux, to a similar degree as SB-269970-A. In contrast, the GABA(A) receptor antagonist, bicuculline, significantly increased 5-HT efflux and attenuated the muscimol-induced inhibition. The muscimol and SB-269970-A effects were not additive and in the presence of bicuculline the SB-269970-A-induced inhibition of 5-HT efflux was attenuated. These data suggest that 5-HT(7) receptor antagonist-induced inhibition of 5-HT efflux occurs indirectly via activation of GABA(A) receptors. That is, 5-HT(7) receptors may be located on GABA interneurones and when activated decrease GABA release and hence decrease the inhibitory tone on 5-HT neurones, increasing 5-HT efflux in the DRN. Therefore, in the presence of GABAergic tone 5-HT(7) receptor antagonists would decrease 5-HT release from the DRN.     

Blockade of mesolimbic dopamine D<Subscript>3</Subscript> receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

Rationale The dopamine (DA) D₃ receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D₃ receptor blockade by the novel D₃ antagonist SB-277011A inhibits cocaines reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior.Objective In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior.Methods Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10–14 days, followed by a once-daily extinction session for 7–14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl--cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion.Results During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4±3.6 active lever-presses in last extinction session to 35.3±5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 g/0.5 l per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum.Conclusions The mesolimic DA D₃ receptor plays an important role in mediating stress-induced reinstatement.     

5-HT<Subscript>6</Subscript> receptor antagonists improve performance in an attentional set shifting task in rats

Rationale and objective Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to ‘shift attention’ between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT₆ receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT₆ receptor antagonists upon attentional set shifting in rats. Methods Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg⁻¹ bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts. Results Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05–0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05–0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01). Conclusion 5-HT₆ receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.     

5-HT2C receptor mediation of unconditioned escape behaviour in the unstable elevated exposed plus maze

Abstract Rationale and objectives. m-Chlorophenylpiperazine (mCPP) induces panic in humans and dose dependently increases unconditioned escape behaviour in a novel pre-clinical model of extreme anxiety in rats, the unstable elevated exposed plus maze (UEEPM). Numerous studies indicate that the anxiogenic effects of mCPP may be mediated by its action at the 5-HT_2C receptor. This study aimed to examine the involvement of the 5-HT_2C receptor in the unconditioned fear responses observed in the UEEPM (after an acute dose of mCPP) by pre-treatment with the selective 5-HT_2C receptor antagonist SB-242084. Methods. Male Hooded Lister rats received a single dose of SB-242084 (0.1–1.0 mg/kg IP) or vehicle 40 min pre-test followed by a single dose of mCPP (1.0 mg/kg IP) or saline 30 min before being exposed to the UEEPM for a period of 5 min. Subjects' behaviour was analysed to determine the effects of SB-242084 on mCPP-induced increases in escape behaviour. Results. mCPP alone increased animals' propensity to escape from the UEEPM despite producing marked decreases in locomotor/exploratory behaviour. SB-242084 dose dependently inhibited the increases in escape and hypolocomotor effects induced by mCPP. Conclusions. These results suggest that the escape-related behaviours exhibited by animals in the UEEPM are mediated, at least in part, by activation of the 5-HT_2C receptor subtype. Electronic Publication     

The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan

The mechanistically novel benzopyran derivative SB-220453, which is undergoing clinical evaluation in migraine, exhibits a high affinity for a selective, but not yet characterized, binding site in the human brain. It inhibits nitric oxide release and cerebral vasodilatation following cortical spreading depression as well as carotid vasodilatation induced by trigeminal nerve stimulation in the cat. The aim of our study was to investigate the contractile properties of SB-220453 on a number of human isolated blood vessels (coronary artery, saphenous vein and middle meningeal artery) as well as atrial and ventricular cardiac trabeculae. While sumatriptan induced marked contractions in three blood vessels investigated, SB-220453 was devoid of any effect. In atrial and ventricular cardiac trabeculae, neither SB-220453 nor sumatriptan displayed a positive or negative inotropic effect. Since SB-220453 did not contract the middle meningeal artery, we conclude that potential anti-migraine effects are not mediated via a direct cerebral vasoconstriction. The lack of activity of SB-220453 in coronary artery, saphenous vein and cardiac trabeculae demonstrates that the compound is unlikely to cause adverse cardiac side-effects.