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As the effects of baclofen on primary afferent activity
As the effects of baclofen on primary afferent activity are not reproduced by GABAA receptor agonists like muscimol and isoguvacine, this ionotropic receptor may play minimal role in the modulation of primary afferent activity. However, it is important to note that post-synaptic GABAA receptors remain critical for mediating GABA-induced analgesia and indeed some benzodiazepine that are GABA mimetic drugs at the GABAA receptors exert analgesic effects. In the case of systemic diazepam, the site of action appears to be the spinal cord where GABAA receptor subunits α2 and α3 are responsible for analgesic effects (Knabl et al., 2008, Knabl et al., 2009).
GABAB1 knock out mice which lack GABA acridine orange receptor and functional GABAB receptors display reduced sensitivity to hot and mechanical nociceptive stimulation and confirm the existence of a GABAB-mediated tone of pain and the possibility that GABAB modulators would act synergistically with endogenous GABA.
Under inflammatory pain conditions such as in rat models of monoarthritic inflammatory pain, GABA is up-regulated in dorsal horn superficial laminae (Castro-Lopes et al., 1992) and down-regulated in the ventrobasal thalamus (Zhang et al., 2017) and animals are less sensitive to the analgesic effect of systemic baclofen (Castro et al., 1999, Malcangio and Bowery, 1994). Recent evidence indicates that GABA-mediated inhibitory activity is decreased in the dorsal horn after peripheral inflammation and contributes to reduced inhibition under persistent pain conditions (Takazawa et al., 2017).
Whilst selective deletion of peripheral GABAB1 receptor subunit in sensory neurons indicated no major role in inflammatory pain (Gangadharan et al., 2009), both GABAB receptor activation in the spinal cord and ventrolateral thalamus contribute to the anti-nociceptive effect of baclofen (Buritova et al., 1996, Potes et al., 2006). Recently, GABA expression has been identified in sensory neurons which also express the GABAB1 receptor subunit in close juxtaposition with TRPV1 receptors. A fascinating possibility is that GABA via activation of GABAB1 autoreceptor can attenuate sensitization of TRPV1 receptor in nociceptors (Hanack et al., 2015). A strategy which has yielded significant success evolved around the development of positive allosteric modulators, or PAMs. PAMs provide an opportunity for selectivity as these molecules become operative only in the presence of the endogenous agonist, when they display the positive enhancing effect on receptor activation. The rationale herein would be to positive modulate GABAB receptor activity only at synapses where GABA is released. Of importance, PAMs can enhance activity of orthosteric agonists like baclofen. Congruently, ADX71441, a compound developed very recently, showed limited muscle relaxant activity but significant anti-nociceptive activity in the inflammatory phase of the monoiodoacetate model of osteoarthritis (Kalinichev et al., 2017).
In neuropathic pain conditions, GABAergic inhibitory control at the level of the spinal cord is significantly reduced and contributes to increased excitation and central sensitization of pain transmission. Such loss of inhibition is the result of several possible mechanisms including death of inhibitory neurons (Castro-Lopes et al., 1992, Ibuki et al., 1996, Moore et al., 2002, Yowtak et al., 2013) but see (Polgár and Todd, 2008), diminished neuronal activity and decreased release of GABA (Leitner et al., 2013, Lever et al., 2003, Schoffnegger et al., 2006). Despite the reduced endogenous GABAergic tone, baclofen exerts anti-nociceptive effects in neuropathic animals and intraspinal transplantation of cortical precursors of GABAergic interneurons from the medial ganglionic eminence (MGE approach) which can release GABA, can reverse neuropathic allodynia (Bráz et al., 2015). Notably, MGE approach is effective in chemotherapy-induced pain models in which GABA levels are not altered (Bráz et al., 2015). In addition, still in models of chemotherapy-induced neuropathy, significant up-regulation of GABAB receptors in sensory neurons mediates the sustained analgesic effect of the opioid oxycodone (Thibault et al., 2014).