Targeting the brain for pain relief
- Author(s): Juarez-Salinas, Dina Levi
- Advisor(s): Ohara, Peter T.
- et al.
The experience of pain involves both sensory discriminative and emotional features. As such pain can be regulated by an action on ascending spinal cord transmission pathways and on limbic brain regions that process the aversiveness of the pain experience. Loss of the latter is what constitutes pain relief. This thesis examined mechanisms through which the anticonvulsant, gabapentin, produces pain relief in models of nerve-injury induced neuropathic pain. The first studies used the conditioned place preference (CPP) paradigm to assay pain aversiveness and demonstrated that gabapentin is pain relieving by a supraspinal action, in the brain. However, as antagonists of noradrenergic signaling at the level of the spinal cord blocked the pain relieving effect of supraspinal gabapentin, we conclude that gabapentin must activate descending noradrenergic inhibitory controls to achieve this pain relief.
A second set of experiments focused on the rostral anterior cingulate cortex (rACC), in which its hyperexcitability in different neuropathic pain conditions contributes to the affective, but not the sensory discriminative features of chronic pain, in both rodents and humans. To develop long-term regulation of rACC activity, without surgical ablation, we transplanted embryonic precursor cells of cortical, GABAergic inhibitory interneurons derived from the medial ganglionic eminence (MGE) into the rACC of adult mice in which we had previously induced a chemotherapy (paclitaxel)-triggered neuropathic pain (mechanical hypersensitivity). Using the CPP model we asked whether MGE transplants into the rACC are pain relieving. In fact, the transplants blocked the animals’ preference for gabapentin, indicating that they no longer experienced ongoing pain. Importantly, the transplant did not reduce paclitaxel-induced mechanical hypersensitivity, indicating that there was no effect on the sensory discriminative component of the pain experience. Unexpectedly, the mice retained a preference for gabapentin when the transplant included both the rostral and posterior ACC (pACC). Apparently, inhibition of the pACC is pro-nociceptive and can block the behavioral effects of MGE transplantation in the rACC. We conclude that diverse brain areas are activated in the setting of neuropathic pain and the areas can influence rACC activity. Their identification will undoubtedly expand futures targets for long-term management of neuropathic pain.