Chronic pain patients exhibit increased anxiety, depression, and deficits in learning and memory. Yet how persistent pain affects the key brain area regulating these behaviors, the hippocampus, has remained minimally explored. In this study we investigated the impact of spared nerve injury (SNI) neuropathic pain in mice on hippocampal-dependent behavior and underlying cellular and molecular changes. In parallel, we measured the hippocampal volume of three groups of chronic pain patients. We found that SNI animals were unable to extinguish contextual fear and showed increased anxiety-like behavior. Additionally, SNI mice compared with Sham animals exhibited hippocampal (1) reduced extracellular signal-regulated kinase expression and phosphorylation, (2) decreased neurogenesis, and (3) altered short-term synaptic plasticity. To relate the observed hippocampal abnormalities with human chronic pain, we measured the volume of human hippocampus in chronic back pain (CBP), complex regional pain syndrome (CRPS), and osteoarthritis patients (OA). Compared with controls, CBP and CRPS, but not OA, had significantly less bilateral hippocampal volume. These results indicate that hippocampus-mediated behavior, synaptic plasticity, and neurogenesis are abnormal in neuropathic rodents. The changes may be related to the reduction in hippocampal volume we see in chronic pain patients, and these abnormalities may underlie learning and emotional deficits commonly observed in such patients.

Neuropathic pain is a chronic pain that results from lesion or dysfunction of the nervous system. Depression and cognitive decline are often coupled to chronic pain, suggesting the involvement of cortical areas associated with higher cognitive functions. We investigated layer 2/3 pyramidal neurons in acute slices of the contralateral medial prefrontal cortex (mPFC) in the rat spared nerve injury (SNI) model of neuropathic pain and found morphological and functional differences between the mPFC of SNI and sham-operated animals. Basal, but not apical, dendrites of neurons from SNI rats are longer and have more branches than their counterparts in sham-operated animals; spine density is also selectively increased in basal dendrites of neurons from SNI rats; the morphological changes are accompanied by increased contribution to synaptic currents of the NMDA component. Interestingly, the NMDA/AMPA ratio of the synaptic current elicited in mPFC neurons by afferent fiber stimulation shows linear correlation with the rats' tactile threshold in the injured (but not in the contralateral) paw. Our results not only provide evidence that neuropathic pain leads to rearrangement of the mPFC, which may help defining the cellular basis for cognitive impairments associated with chronic pain, but also show pain-associated morphological changes in the cortex at single neuron level.

Fast and reliable activation of inhibitory interneurons is critical for the stability of cortical neuronal networks. Active conductances in dendrites may facilitate interneuron activation, but direct experimental evidence was unavailable. Patch-clamp recordings from dendrites of hippocampal oriens-alveus interneurons revealed high densities of voltage-gated sodium and potassium ion channels. Simultaneous recordings from dendrites and somata suggested that action potential initiation occurs preferentially in the axon with long threshold stimuli, but can be shifted to somatodendritic sites when brief stimuli are applied. After initiation, action potentials propagate over the somatodendritic domain with constant amplitude, high velocity, and reliability, even during high-frequency trains.

GABAergic interneurones differ from glutamatergic principal neurones in their ability to discharge high‐frequency trains of action potentials without adaptation. To examine whether Na⁺ channel gating contributed to these differences, Na⁺ currents were recorded in nucleated patches from interneurones (dentate gyrus basket cells, BCs) and principal neurones (CA1 pyramidal cells, PCs) of rat hippocampal slices. The voltage dependence of Na⁺ channel activation in BCs and PCs was similar. The slope factors of the activation curves, fitted with Boltzmann functions raised to the third power, were 11.5 and 11.8 mV, and the mid‐point potentials were −25.1 and −23.9 mV, respectively. Whereas the time course of Na⁺ channel activation (−30 to +40 mV) was similar, the deactivation kinetics (−100 to −40 mV) were faster in BCs than in PCs (tail current decay time constants, 0.13 and 0.20 ms, respectively, at −40 mV). Na⁺ channels in BCs and PCs differed in the voltage dependence of inactivation. The slope factors of the steady‐state inactivation curves fitted with Boltzmann functions were 6.7 and 10.7 mV, and the mid‐point potentials were −58.3 and −62.9 mV, respectively. The onset of Na⁺ channel inactivation at −55 mV was slower in BCs than in PCs; the inactivation time constants were 18.6 and 9.3 ms, respectively. At more positive potentials the differences in inactivation onset were smaller. The time course of recovery of Na⁺ channels from inactivation induced by a 30 ms pulse was fast and mono‐exponential (τ= 2.0 ms at −120 mV) in BCs, whereas it was slower and bi‐exponential in PCs (τ₁= 2.0 ms and τ₂= 133 ms; amplitude contribution of the slow component, 15%). We conclude that Na⁺ channels of BCs and PCs differ in gating properties that contribute to the characteristic action potential patterns of the two types of neurones.