Abstract
Neuropathic pain is a debilitating condition that is often refractory to treatment. The network of neural substrates for pain transmission and control within the brain is complex and remains poorly understood. Through a combination of neuronal tracing, optogenetics, chemogenetics, electrophysiological recordings, and behavioral assessment, we demonstrate that activation of layer 5 pyramidal neurons in the ventrolateral orbitofrontal cortex (vlOFC) attenuates mechanical and thermal hypersensitivity and cold allodynia in mice with neuropathic pain induced by spared nerve injury (SNI). These vlOFC output neurons project to the posterior ventrolateral periaqueductal gray (vlPAG) region and receive inputs from the ventromedial thalamus (VM). Specific optogenetic and chemogenetic activation of the vlOFC-vlPAG and the VM-vlOFC circuits inhibits hypersensitivity associated with neuropathy. Thus, we reveal a modulatory role of the vlOFC and its projections to the vlPAG circuit in the processing of hypersensitive nociception.
Highlights
Neuropathic pain causes sensory and emotional suffering and is poorly managed by existing therapies
Co-staining of c-fos with mCherry-expressing neurons revealed that clozapine N-oxide (CNO) induces robust activation of hM3Dq-expressing glutamatergic neurons in the ventrolateral orbitofrontal cortex (vlOFC) compared with the saline and virus control groups (Figures 1D and 1E)
The mechanical thresholds in these mice were unaltered by CNO-induced activation or inhibition of GABAergic neurons (Figures 1F and 1G)
Summary
Neuropathic pain causes sensory and emotional suffering and is poorly managed by existing therapies. The parabrachial nucleus (PBN) (Chiang et al, 2019), central amygdala (CeA) (Wilson et al, 2019), thalamus (Meda et al, 2019), nucleus accumbens (NAc) (Baliki et al, 2010), ventral tegmental area (VTA) (Waung et al, 2019), periaqueductal gray (PAG) (Huang et al, 2019), and rostroventral medulla (RVM) (Ossipov et al, 2010) relay ascending and descending pain signals, whereas the somatosensory cortex (primary [S1]/secondary [S2]) (Liu et al, 2018), prefrontal cortex (PFC) (Huang et al, 2019; Zhang et al, 2015), anterior cingulate cortex (ACC) (Johansen et al, 2001), insular cortex (IC) (Lu et al, 2016), and orbitofrontal cortex (OFC) (Tang et al, 2009) are involved in processing sensory and affective components of pain (Singh et al, 2020).
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