Christof Pertl

Assessment of differential blockade by amitriptyline and its N-methyl derivative in different species by different routes

Background Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. Methods The Na+ channel–blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH3 cells. Various functions (motor, nociception, proprioception–ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). Results In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mm N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. Conclusions Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.

Effects of local anesthesia on substance P and CGRP content of the human dental pulp.

The aim of the study was to determine immunoreactive Substance P (iSP) and immunoreactive calcitonin gene-related peptide (iCGRP) content in the human dental pulp and whether local anesthesia has an effect on the neuropeptide content. Dental pulps were obtained from patients, who underwent surgical extraction of all 4 impacted wisdom teeth under general isoflurane gas anesthesia. There was a very high interindividual variation in tissue content, with small variation in levels found in teeth from the same patient. Pulps obtained from lower teeth without local anesthesia contained an average of 131 +/- 62 fmol/mg protein of iCGRP and 15 +/- 9 fmol/mg iSP (n = 10). With additional mandibular block anesthesia the values were 194 +/- 71 fmol/mg iCGRP (statistically significant, p = 0.0356, Mann-Whitney-rank-sum-test) and 12 +/- 3.6 fmol/mg iSP. The results suggest that local anesthesia attenuates neuropeptide release in the human dental pulp during surgical extraction.

Histology and intramandibular course of the inferior alveolar nerve

The morphology of the inferior alveolar nerve is a very important factor for all surgical procedures in the mandibular region. The aim of this anatomical and histological study was to describe the intramandibular course and the microscopic histology of the inferior alveolar nerve in the dissected human cadaver. Twenty partially dentulous hemimandible specimens from human cadavers were dissected and embalmed, and the findings were interpreted by standard and histological imaging. The result of this study showed that the inferior alveolar nerve comprises two larger nerves that are separately wrapped in perineural sheaths and spirally twisted around each other. The mental nerve exits through the mental foramen in the premolar region and the dental nerve continues from the premolar region as the incisive nerve in the incisive canal. These findings provide relevant data for clinical dentistry, especially when planning oral and dental operative treatment procedures in the mandibular region.

Role of microchimerism in the pathogenesis of oral lichen planus

Objective:  Microchimerism of persistent fetal cells has been implicated in some cell‐mediated autoimmune diseases. This study examines the hypothesis that fetal microchimerism plays a role in the pathogenesis of lichen planus (LP) affecting the oral cavity.

Secretoneurin, a novel neuropeptide, in the human dental pulp

Secretoneurin is a neuropeptide that is stored in and released from primary afferent neurones. By radioimmunoassay and immunohistochemistry, secretoneurin was here demonstrated in the human dental pulp and localized in varicose nerve fibres that were frequently associated with blood vessels. No significant correlation was found between the levels of immunoreactive secretoneurin and immunoreactive calcitonin-gene related peptide. The results suggest that primary afferent neurones of the human dental pulp contain secretoneurin, which may influence local inflammatory responses if it is released together with other neuropeptides.

Lack of effect of a selective vasopressin V1A receptor antagonist, SR 49,059, on potentiation by vasopressin of adrenoceptor-mediated pressor responses in the rat mesenteric arterial bed

1 The vasopressin receptor subtype involved in the enhancement by vasopressin of adrenoceptor‐mediated vasoconstriction was investigated in rat isolated perfused mesenteric arteries. 2 [Arg8]vasopressin (1–10 nm) dose‐dependently increased the perfusion pressure and enhanced the pressor response to the adrenoceptor agonist methoxamine (40 nmol) or electrical stimulation of periarterial nerves (16 Hz), at the concentration of 10 nm of [Arg8]vasopressin up to 4 and 3 fold, respectively. 3 During prolonged exposure (45 min) the direct vasoconstrictor effect of [Arg8]vasopressin (10 nm) rapidly declined whereas the potentiation of methoxamine‐induced vasoconstriction was maintained. 4 The selective vasopressin V1A receptor antagonist SR 49,059 (1–3 nm) and the non‐selective V1A/B and oxytocin receptor antagonist [deamino‐Pen1,Tyr(Me)2,Arg8]vasopressin (15–45 nm) inhibited the direct vasoconstrictor action of [Arg8]vasopressin but had no effect on the enhancement of the pressor response to methoxamine or electrical stimulation. 5 The V1B receptor agonist [deamino‐Cys1,β‐(3‐pyridyl)‐D‐Ala2,Arg8]vasopressin (100–1000 nm) and the V2 receptor agonist [deamino‐Cys1,D‐Arg8]vasopressin (1–10 nm) were devoid of any pressor activity and did not potentiate methoxamine‐evoked vasoconstriction. In contrast, [1‐triglycyl,Lys8]vasopressin (100–1000 nm) potentiated the methoxamine responses without per se inducing vasoconstriction. 6 In arteries precontracted with methoxamine (7.5 μm) pressor responses to [Arg8]vasopressin (3–10 nm) were not inhibited by a dose of SR 49,059 (3 nm) which abolished the peptides vasoconstrictor effect under control conditions. 7 These data show that the direct vasoconstrictor effect of [Arg8]vasopressin is mediated by V1A receptors while the enhancement of adrenoceptor‐mediated pressor responses is insensitive to V1A, V1B, and oxytocin receptor antagonists and is not mimicked by selective agonists of V1B and V2 receptors. In conclusion, an unusual interaction of vasopressin with V1A receptors, or even the existence of a novel receptor subtype, has to be considered.