HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice.

Chronic pain is a significant health problem worldwide. Recent evidence has suggested that the ventral hippocampus is dysfunctional in humans and rodents, with decreased neuronal excitability and connectivity with other brain regions, parallel pain chronicity, and persistent nociceptive hypersensitivity. But the molecular mechanisms underlying hippocampal modulation of pain remain poorly elucidated. In this study, we used ex vivo whole-cell patch-clamp recording, immunofluorescence staining, and behavioral tests to examine whether hyperpolarization-activated cyclic nucleotide-gated channels 2 (HCN2) in the ventral hippocampal CA1 (vCA1) were involved in regulating nociceptive perception and CFA-induced inflammatory pain in mice. Reduced sag potential and firing rate of action potentials were observed in vCA1 pyramidal neurons from CFA-injected mice. Moreover, the expression of HCN2, but not HCN1, in vCA1 decreased in mice injected with CFA. HCN2 knockdown in vCA1 pyramidal neurons induced thermal hypersensitivity, whereas overexpression of HCN2 alleviated thermal hyperalgesia induced by intraplantar injection of CFA in mice. Our findings suggest that HCN2 in the vCA1 plays an active role in pain modulation and could be a promising target for the treatment of chronic pain.

A nociceptive neuronal ensemble in the dorsomedial prefrontal cortex underlies pain chronicity.

Pain chronicity involves unpleasant experience in both somatosensory and affective aspects, accompanied with the prefrontal cortex (PFC) neuroplastic alterations. However, whether specific PFC neuronal ensembles underlie pain chronicity remains elusive. Here we identify a nociceptive neuronal ensemble in the dorsomedial prefrontal cortex (dmPFC), which shows prominent reactivity to nociceptive stimuli. We observed that this ensemble shows distinct molecular characteristics and is densely connected to pain-related regions including basolateral amygdala (BLA) and lateral parabrachial nuclei (LPB). Prolonged chemogenetic activation of this nociceptive neuronal ensemble, but not a randomly transfected subset of dmPFC neurons, induces chronic pain-like behaviors in normal mice. By contrast, silencing the nociceptive dmPFC neurons relieves both pain hypersensitivity and anxiety in mice with chronic inflammatory pain. These results suggest the presence of specific dmPFC neuronal ensembles in processing nociceptive information and regulating pain chronicity.