Modulation of Chronic Pain Spinal a2 and a3 GABAa Receptors

The canonical circuits of GABAergic control of principal cells also applies to circuits in the spinal cord with particular reference to sensory pain processing. Using the point-mutated mice described earlier, spinal a2 (and a3) GABAA receptors were identified as powerful gatekeepers of pain (Knabl et al. 2008). The experimental a2/a3 receptor ligand L-838 417 (Table 2) was highly effective in suppressing inflammatory and neuropathic pain, yet devoid of unwanted sedation and motor impairment. Most importantly, in contrast to ► morphine, L-838417 failed to show any ► tolerance in analgesic efficacy, as tested over nine days. The a2/a3 receptor ligand reduced not only the nociceptive input, but also reduced the activity in brain areas associated with the associative-emotional component of pain (fMRI) (Knabl et al. 2008). Similarly, NS11394, acting as ► partial agonist at a2 and a3 receptors and as almost full agonist at a5 receptors, was effective in rat models of inflammatory and neuropathic pain (Table 2) (Mirza et al. 2008). These results provide a rational basis for a new class of drugs for the treatment of chronic inflammatory and neuropathic pain, based on a pain-related inhibitory interneuron network in brain and spinal cord.

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