The positive allosteric GABAB receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic mice

NEUROPHARMACOLOGY

卷:108

Article

Zemoura, Khaled¹  Ralvenius, William T.¹  Malherbe, Pari²  Benke, Dietmar^1,3,4 

[1] Univ Zurich, Inst Pharmacol & Toxicol, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[2] F Hoffmann La Roche & Cie AG, Discovery Neurosci, pRED, Grenzacherstr 124, CH-4070 Basel, Switzerland

[3] Neurosci Ctr Zurich ZNZ, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[4] DDNZ, Winterthurerstr 190, CH-8057 Zurich, Switzerland

关键词: Allosteric modulation;    GABA(B) receptor;    Neuropathic pain;    rac-BHFF;   

DOI  :  10.1016/j.neuropharm.2016.04.028

来源: Elsevier

【 摘 要 】

Neuropathic pain is associated with impaired inhibitory control of spinal dorsal horn neurons, which are involved in processing pain signals. The metabotropic GABA(B) 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 GABA(B)ergic tone regulating the sensitivity to mechanical stimuli. Surprisingly, rac-BHFF displayed no analgesic activity in neuropathic mice although GABA(B) receptor expression was not affected in the dorsal horn as shown by quantitative receptor autoradiography. However, activation of spinal GABA(B) 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 GABA(B) receptors. However, allosteric modulators would be well suited as an add-on to reduce the dose of baclofen required to achieve analgesia. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free