Dirk Denzer

Cannabinoid CB1 receptor upregulation in a rat model of chronic neuropathic pain

Abstract Although cannabinoids are known to be more effective analgesics against chronic rather than acute pain, the mechanism underlying this phenomenon is still unclear. We report now that contralateral thalamic cannabinoid CB 1 receptors are upregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a rat model of chronic neuropathic pain, and hypothesize that cannabinoid CB 1 receptor upregulation contributes to the increased analgesic efficacy of cannabinoids in chronic pain conditions.

Pharmacological sensitivity and gene expression analysis of the tibial nerve injury model of neuropathic pain

The tibial nerve injury model is a novel, surgically uncomplicated, rat model of neuropathic pain based on a unilateral transection (neurotomy) of the tibial branch of the sciatic nerve. The aim of the present study was to describe some behavioral and molecular features of the model, and to test its sensitivity to a number of drugs which are currently used for the treatment of neuropathic pain. The model was characterized by a pronounced mechanical allodynia which was present in all subjects and a less robust thermal hyperalgesia. Mechanical allodynia developed within 2 weeks post-surgery and was reliably present for at least 9 weeks. Neurotomized rats showed no autotomy and their body weight developed normally. Gene expression in ipsilateral L5 dorsal root ganglia, analyzed by quantitative polymerase chain reaction (PCR), showed a pronounced up-regulation of galanin and vasointestinal peptide (VIP). This up-regulation developed rapidly (within 1 to 2 days following neurotomy) and remained present for at least 12 days. On the other hand, expression of calcitonin gene-related peptide (CGRP) and substance P mRNA was down-regulated 12 days following neurotomy. Mechanical allodynia was completely reversed by morphine [minimal effective dose (MED): 8 mg/kg, i.p.] and partially reversed by carbamazepine (MED: 64 mg/kg, i.p.), baclofen (MED: 3 mg/kg, i.p.) and amitriptyline (trend for efficacy at 32 mg/kg, i.p.), but not by gabapentin (50-100 mg/kg, i.p.). The finding that the tibial nerve injury model shows a robust and persistent mechanical allodynia which is sensitive to a number of established analgesics, as well as a gene expression profile which is compatible with that obtained in other models of neuropathic pain, further supports its validity as a reliable and surgically uncomplicated model for the study of neuropathic pain.

Novel Analgesic Triglycerides from Cultures of Agaricus macrosporus and Other Basidiomycetes as Selective Inhibitors of Neurolysin

The agaricoglycerides are a new class of fungal secondary metabolites that constitute esters of chlorinated 4-hydroxy benzoic acid and glycerol. They are produced in cultures of the edible mushroom, Agaricus macrosporus, and several other basidiomycetes of the genera Agaricus, Hypholoma, Psathyrella and Stropharia. The main active principle, agaricoglyceride A, showed strong activities against neurolysin, a protease involved in the regulation of dynorphin and neurotensin metabolism (IC50=200 nM), and even exhibited moderate analgesic in vivo activities in an in vivo model. Agaricoglyceride monoacetates (IC50=50 nM) showed even stronger in vitro activities. Several further co-metabolites with weaker or lacking bioactivities were also obtained and characterized. Among those were further agaricoglyceride derivatives, as well as further chlorinated phenol derivatives such as the new compound, agaricic ester. The characteristics of the producer organisms, the isolation of bioactive metabolites from cultures of A. macrosporus, their biological activities, and preliminary results on their occurrence in basidiomycetes, are described.

Metabotropic glutamate mGlu1 receptor mRNA expression in dorsal root ganglia of rats after peripheral nerve injury.

Although cerebral and spinal metabotropic glutamate mGlu(1) receptors are thought to be involved in nociception and in the development/maintenance of chronic pain, it is still unclear to what extent mGlu(1) receptors are present in the dorsal root ganglia of peripheral sensory afferents, and whether their expression is affected during development of chronic pain. It was found in the present study that mGlu(1) receptor messenger RNA (mRNA) is present in rat L5 dorsal root ganglia and that it is strongly downregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a model of chronic neuropathic pain. However, as sham-operated animals showed a similar downregulation, it is suggested that peripheral tissue damage is sufficient to result in a reduction of peripheral mGlu(1) receptor expression.