Martin Michaelis

Osteoarthritis — an untreatable disease?

Osteoarthritis is a painful and disabling disease that affects millions of patients. Its aetiology is largely unknown, but is most likely multi-factorial. Osteoarthritis poses a dilemma: it often begins attacking different joint tissues long before middle age, but cannot be diagnosed until it becomes symptomatic decades later, at which point structural alterations are already quite advanced. In this review, osteoarthritis is considered as a disease of the whole joint that may result from multiple pathophysiological mechanisms, one of which is the dysregulation of lipid homeostasis. No proven disease-modifying therapy exists for osteoarthritis and current treatment options for chronic osteoarthritic pain are insufficient, but new pharmacotherapeutic options are emerging.

Specific Inhibition of IκB Kinase Reduces Hyperalgesia in Inflammatory and Neuropathic Pain Models in Rats

Phosphorylation of IκB through IκB kinase (IKK) is the first step in nuclear factor κB (NF-κB) activation and upregulation of NF-κB-responsive genes. Hence, inhibition of IKK activity may be expected to prevent injury-, infection-, or stress-induced upregulation of various proinflammatory genes and may thereby reduce hyperalgesia and inflammation. In the present study, we tested this hypothesis using a specific and potent IKK inhibitor (S1627). In an IKK assay, S1627 inhibited IKK activity with an IC50 value of 10.0 ± 1.2 nm. In cell culture experiments, S1627 inhibited interleukin (IL)-1β-stimulated nuclear translocation and DNA-binding of NF-κB. Plasma concentration time courses after intraperitoneal injection revealed a short half-life of 2.8 hr in rats. Repeated intraperitoneal injections were, therefore, chosen as the dosing regimen. S1627 reversed thermal and mechanical hyperalgesia at 3× 30 mg/kg in the zymosan-induced paw inflammation model and reduced the inflammatory paw edema at 3× 40 mg/kg. S1627 also significantly reduced tactile and cold allodynia in the chronic constriction injury model of neuropathic pain at 30 mg/kg once daily. The drug had no effect on acute inflammatory nociception in the formalin test and did not affect responses to heat and tactile stimuli in naive animals. As hypothesized, S1627 prevented the zymosan-induced nuclear translocation of NF-κB in the spinal cord and the upregulation of NF-κB-responsive genes including cyclooxygenase-2, tumor necrosis factor-α, and IL-1β. Our data indicate that IKK may prove an interesting novel drug target in the treatment of pathological pain and inflammation.

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca(2+) channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the genes functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.

Modulation of CGRP and PGE2 release from isolated rat skin by alpha-adrenoceptors and kappa-opioid-receptors.

Norepinephrine (NE) reduces the release of neuropeptides from central terminals of primary afferent neurones by presynaptic inhibition. We investigated whether NE also affects stimulus-induced intracutaneous calcitonin gene-related peptide (CGRP) and secondary prostaglandin E2 (PGE2) release. For comparison, kappa-opioid effects were examined. Antidromic electrical nerve stimulation resulted in significant increases in the release of CGRP and PGE2. The PGE2 release was prevented by selective activation of alpha2-adrenoceptors whereas the CGRP release was not changed. In contrast, selective kappa-opioid receptor activation diminished electrically evoked release of both CGRP and PGE2. We conclude that NE affected stimulated PGE2 release via alpha2-adrenoceptors on cells other than cutaneous afferents while kappa-opioid receptors are expressed in peripheral terminals of cutaneous afferents and their activation reduced CGRP release and secondary PGE2 formation.

An anthology from Naunyn-Schmiedeberg's archives of pharmacology

Otto Schaumann (1891–1977) studied chemistry at the University of Vienna. He got his Ph.D. in 1914 and spent a post-doctorate at the Institute of Pharmacology under Hans Horst Meyer. From 1925–1946, he worked as head of a pharmacological laboratory at Farbwerke Hoechst, Frankfurt/ Main-Hochst (Fig. 1). In 1941, he wrote a habilitation thesis in medicine. Schaumann discovered the analgesic effects of Dolantin® (pethidine, meperidine) that was synthesized in 1932 as a potentially spasmolytic agent by the medicinal chemist Otto Eisleb (1887–1948) at Farbwerke Hoechst. He profiled the compound preclinically but, interestingly enough, also accompanied the clinical development of pethidine closely until and beyond its first launch as a parenteral injectable formulation in 1939 and the following launches as suppositories and drops in 1942, thus, already practicing translational science. Together with the pharmacologist Ernst Lindner, he was also involved in the discovery and the development of methadon (Polamidon® and LPolamidon®), synthesized by medicinal chemist Gustav Erhart at the Hoechst laboratories. Schaumann was, what seems to be today an endangered species, namely a “classical” experienced in vitro and in vivo pharmacologist, combining an excellent knowledge of systemic physiology, pathophysiology, and medicinal chemistry. In 1945, Schaumann left the company and worked from 1946–1962 as director of the Institute of Pharmacognosia in the Faculty of Philosophy and Natural Sciences at the University of Innsbruck, Austria. From his new position in Innsbruck, he still was very active in the further profiling of pethidine. Besides his scientific publications on analgesics, he also published articles on ephedrine, local anesthetics, hypophyseal hormones, and on the importance of an optimal pain reduction for a successful medical recovery (Heilanalgesie). In 1956, he also published a monograph on morphine and its derivatives (Schaumann 1957).