The α2/α3GABAA receptor modulator TPA023B alleviates not only the sensory but also the tonic affective component of chronic pain in mice

Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn alpha 2/alpha 3GABA(A)Rs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain. Here, we investigated the effects of the alpha 2/alpha 3GABA(A)R subtype-selective modulator TPA023B on the tonic aversive component of pain in mice with peripheral inflammation or neuropathy. In neuropathic mice with a chronic constriction injury of the sciatic nerve, TPA023B not only reversed hyperalgesia to tactile and heat stimuli but also was highly effective in the conditioned place preference test. In the formalin test, TPA023B not only reduced licking of the injected paw but also reversed facial pain expression scores in the mouse grimace scale assay. Taken together, our results demonstrate that alpha 2/alpha 3GABA(A) receptor subtype-selective modulators not only reduce nociceptive withdrawal responses but also alleviate the tonic aversive components of chronic pain.

Automated summary

The study explored the effects of alpha 2/alpha 3GABA(A) receptor subtype-selective modulators in alleviating neuropathic or inflammatory pain, showing significant modulation of pain behaviors.