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Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously-induced change in developmentally-imprinted excitatory neurotransmitter phenotype of these neurons to inhibitory has not yet been achieved. Here we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-Aminobutyric acid,) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) which persisted for minimum 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (such as sedation, motor weakness or loss of normal sensation) were seen between 2-13 months post-treatment in naive adult mice, pigs and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord- or peripheral nerve-injury induced neuropathic pain.