The positive allosteric GABAB receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic mice.
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.
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Khaled
K
Zemoura
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
William T
WT
Ralvenius
Discovery Neuroscience, F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Grenzacherstrasse 124, CH4070 Basel, Switzerland.
Pari
P
Malherbe
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Neuroscience Center Zurich (ZNZ), Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Drug Discovery Network Zurich (DDNZ), Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: benke@pharma.uzh.ch.
Dietmar
D
Benke
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000698:Analgesia / Q000379:methods*; D000818:Animals; D001418:Baclofen / Q000008:administration & dosage*; D001572:Benzofurans / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000008:administration & dosage*; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D018080:Receptors, GABA-B / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism
C532129:(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one; D001572:Benzofurans; D018757:GABA Modulators; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D001418:Baclofen
Allosteric modulation; GABA(B) receptor; Neuropathic pain; rac-BHFF