Accumulating evidence suggests hippocampal impairment under chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here we enhanced hippocampal activity by pharmacological, opto- and chemo-genetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH), hippocampus induces analgesia in two rodent models of neuropathic pain (SNI and SNL), and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by NMDA and μ-opioid receptors. In addition to analgesia, optogenetic stimulation of DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where DH was activated, a finding consistent with pain relief. Similar manipulations in VH were ineffective. Using chemo-fMRI, where awake resting-state fMRI was combined with viral vector mediated chemogenetic activation (PSAM/PSEM) of DH neurons, we demonstrated changes of functional connectivity between DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans, and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic backpain. Altogether, these results imply that downregulation of DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, the present study exhibits a novel causal role for the DH but not VH in controlling neuropathic pain-related behaviors.

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