The positive allosteric GABA(B) receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic mice
| Autor: | Dietmar Benke, William T. Ralvenius, Pari Malherbe, Khaled Zemoura |
|---|---|
| Přispěvatelé: | University of Zurich, Benke, Dietmar |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Baclofen Allosteric modulator 2804 Cellular and Molecular Neuroscience 10050 Institute of Pharmacology and Toxicology 610 Medicine & health Pharmacology BHFF GABAB receptor Mice 03 medical and health sciences chemistry.chemical_compound Cellular and Molecular Neuroscience 0302 clinical medicine Allosteric Regulation medicine Animals GABA Modulators Benzofurans Dose-Response Relationship Drug business.industry 3. Good health Mice Inbred C57BL 030104 developmental biology Metabotropic receptor 3004 Pharmacology Receptors GABA-B chemistry nervous system GABA-B Receptor Agonists Hyperalgesia Neuropathic pain Nociceptor Neuralgia 570 Life sciences biology Analgesia Sciatic Neuropathy medicine.symptom business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neuropharmacology |
| DOI: | 10.1016/j.neuropharm.2016.04.028 |
| Popis: | Neuropathic pain is associated with impaired inhibitory control of spinal dorsal horn neurons, which are involved in processing pain signals. The metabotropic GABAB receptor is an important component of the inhibitory system and is highly expressed in primary nociceptors and intrinsic dorsal horn neurons to control their excitability. Activation of GABAB receptors with the orthosteric agonist baclofen effectively reliefs neuropathic pain but is associated with severe side effects that prevent its widespread application. The recently developed positive allosteric GABAB receptor modulators lack most of these side effects and are therefore promising drugs for the treatment of pain. Here we tested the high affinity positive allosteric modulator rac-BHFF for its ability to relief neuropathic pain induced by chronic constriction of the sciatic nerve in mice. rac-BHFF significantly increased the paw withdrawal threshold to mechanical stimulation in healthy mice, indicating an endogenous GABABergic tone regulating the sensitivity to mechanical stimuli. Surprisingly, rac-BHFF displayed no analgesic activity in neuropathic mice although GABAB receptor expression was not affected in the dorsal horn as shown by quantitative receptor autoradiography. However, activation of spinal GABAB receptors by intrathecal injection of baclofen reduced hyperalgesia and its analgesic effect was considerably potentiated by co-application of rac-BHFF. These results indicate that under conditions of neuropathic pain the GABAergic tone is too low to provide a basis for allosteric modulation of GABAB receptors. However, allosteric modulators would be well suited as an add-on to reduce the dose of baclofen required to achieve analgesia. |
| Databáze: | OpenAIRE |
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