Activation of the dorsal, but not the ventral, hippocampus relieves neuropathic pain in rodents

Abstract

Accumulating evidence suggests hippocampal impairment under the 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, optogenetic, and chemogenetic 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 2 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 N-Methyl-D-aspartate and μ-opioid receptors. In addition to analgesia, optogenetic stimulation of the DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where the DH was activated, a finding consistent with pain relief. Similar manipulations in the VH were ineffective. Using chemo-functional magnetic resonance imaging (fMRI), where awake resting-state fMRI was combined with viral vector-mediated chemogenetic activation (PSAM/PSEM89s) of DH neurons, we demonstrated changes of functional connectivity between the 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 back pain. Altogether, these results imply that downregulation of the DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of the DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, this study exhibits a novel causal role for the DH but not the VH in controlling neuropathic pain–related behaviors.

Knock-In Mouse Models to Investigate the Functions of Opioid Receptors in vivo

“…Indeed, the precise activation of neurons in the VTA of MOPr-eGFP/Cre mice triggered place avoidance, supporting previous results described by Tan et al (2012), Bailly et al (2020). The use of optogenetics has also been applied to the study of chronic pain, as recently reported by Wei et al (2021). In this article, the authors shed light on the implication of the dorsal (DH), but not the ventral (VH) hippocampus in the modulation of pain (Wei et al, 2021).…”

“…The use of optogenetics has also been applied to the study of chronic pain, as recently reported by Wei et al (2021). In this article, the authors shed light on the implication of the dorsal (DH), but not the ventral (VH) hippocampus in the modulation of pain (Wei et al, 2021). More specifically, photostimulation of DH neurons for approximately 3 h was shown to relieve tactile allodynia in the spared nerve injury (SNI) neuropathic chronic pain model (Wei et al, 2021).…”

“…In this article, the authors shed light on the implication of the dorsal (DH), but not the ventral (VH) hippocampus in the modulation of pain (Wei et al, 2021). More specifically, photostimulation of DH neurons for approximately 3 h was shown to relieve tactile allodynia in the spared nerve injury (SNI) neuropathic chronic pain model (Wei et al, 2021). Further experiments also suggested that the mechanism underlying the DH-mediated analgesic effects in SNI mice was dependent of N-Methyl-D-aspartate (NMDA) receptors, but also required the activation of MOPr (Wei et al, 2021).…”

Differential Rearrangement of Excitatory Inputs to the Medial Prefrontal Cortex in Chronic Pain Models

“…Thus, these data suggest that input-specific effects are central to the mPFC role in pain modulation. At the same time, the role of the ventral hippocampus in pain perception also remains unclear, because in a rodent model of early stage neuropathic pain neither optogenetic nor pharmacological activation of the ventral hippocampus produced analgesic effects (Wei et al, 2021). Multiple factors may explain these differences, including the specific pain model used, the pain duration, the strength, duration and pattern of the hippocampal stimulation, and the type of neurons stimulated.…”

PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus

“…Consistent with these, several experimental studies have found that direct hippocampal manipulation alters nociceptive behavior. Activation of the dorsal hippocampus reverses neuropathic pain through local excitatory and opioidergic mechanisms affecting dorsal hippocampus functional connectivity [30]. Direct injection of the local anesthetic like lidocaine to the dentate gyrus (DG) region of the hippocampus produces analgesia [31].…”