Maria Virginia Centeno

Abnormalities in Hippocampal Functioning with Persistent Pain

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.

D-cycloserine reduces neuropathic pain behavior through limbic NMDA-mediated circuitry.

Abstract Human brain imaging studies suggest that chronic neuropathic pain has a strong emotional component that is mediated by medial prefrontal cortex (mPFC) activity; in rodents, the mPFC is involved in emotional and cognitive aspects of behavior, including the extinction of Pavlovian fear conditioning. Together, these findings suggest that the cortex may modulate the memory trace of pain. As d‐cycloserine (DCS), a partial agonist of the NMDA receptor, can enhance learning and potentiate the extinction of acquired fear, in the present study we tested its efficacy in neuropathic pain behavior. In rats with spared nerve injury (SNI), repeated daily oral administration of DCS reduced mechanical sensitivity of the injured limb in a dose‐dependent manner; this effect continued for weeks after the cessation of DCS treatment. In addition, re‐exposure to DCS further enhanced antinociceptive behavior. Repeated oral DCS administration also reduced cancer chemotherapy drug‐induced neuropathic pain behavior. Infusions of DCS directly into the mPFC (especially within prelimbic cortex) or the amygdala (but not into thalamus, insula, or occipital cortex) acutely induced antinociception in SNI rats. The antinociceptive effect of intra‐mPFC DCS infusions was mimicked by NMDA and glycine, and blocked by HA 966. In the mPFC of SNI rats, NR2B expression was down‐regulated; however, this effect was reversed with repeated oral DCS. Lastly, infusions of DCS into mPFC reversed place avoidance behavior induced by mechanical stimulation of the injured paw in SNI rats. These findings indicate that limbic NMDA‐mediated circuitry is involved in long‐term reduction in neuropathic pain behavior.

Chronic neuropathic pain-like behavior correlates with IL-1β expression and disrupts cytokine interactions in the hippocampus.

Summary IL‐1β expression in the contralateral hippocampus coincides with neuropathic pain behavior in rats, and the correlations between hippocampal IL‐1β and IL‐1ra or IL‐6 are lost. ABSTRACT We have proposed that neuropathic pain engages emotional learning, suggesting the involvement of the hippocampus. Because cytokines in the periphery contribute to induction and maintenance of neuropathic pain but might also participate centrally, we used 2 neuropathic pain models, chronic constriction injury (CCI) and spared nerve injury (SNI), to investigate the temporal profile of hippocampal cytokine gene expression in 2 rat strains that show different postinjury behavioral threshold sensitivities. SNI induced long‐lasting allodynia in both strains, while CCI induced allodynia with time‐dependent recovery in Sprague Dawley (SD) and no allodynia in Wistar Kyoto (WK) rats. In WK rats, only SNI induced sustained upregulation of hippocampal interleukin (IL)‐1β, while IL‐6 expression was transiently increased and no significant changes in IL‐1ra expression were detected. Conversely, in SD rats, SNI resulted in sustained and robust increased hippocampal IL‐1β expression, which was only transient in rats with CCI. In this strain, IL‐6 expression was not affected in any of the 2 injury models and IL‐1ra expression was significantly increased in rats with SNI or CCI at late phases. We found that the degree and development of neuropathic pain depend on the specific nerve injury model and rat strain; that hippocampal IL‐1β mRNA levels correlate with neuropathic pain behavior; that, in contrast to sham‐operated animals, there are no correlations between hippocampal IL‐1β and IL‐1ra or IL‐6 in neuropathic rats; and that alterations in cytokine expression are restricted to the hippocampus contralateral to the injury side, again implying that the observed changes reflect nociception.

Role of nucleus accumbens in neuropathic pain: Linked multi-scale evidence in the rat transitioning to neuropathic pain

Summary In a rodent neuropathic pain model, combined fMRI and PCR assessment revealed reorganization of nucleus accumbens, while interruption of accumbens activity diminished neuropathic pain. ABSTRACT Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross‐sectionally), in an animal model of neuropathic pain (spared nerve injury [SNI]). We observed interrelated changes: (1) In resting‐state functional magnetic resonance imaging (fMRI), functional connectivity of the NAc to dorsal striatum and cortex was reduced 28 days (but not 5 days) after SNI; (2) Contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and &kgr;‐opioid receptors decreased 28 days after SNI; (3) In SNI (but not sham), covariance of gene expression was upregulated at 5 days and settled to a new state at 28 days; and (4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain‐like behavior.

The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain

We examined adaptations in nucleus accumbens (NAc) neurons in mouse and rat peripheral nerve injury models of neuropathic pain. Injury selectively increased excitability of NAc shell indirect pathway spiny projection neurons (iSPNs) and altered their synaptic connectivity. Moreover, injury-induced tactile allodynia was reversed by inhibiting and exacerbated by exciting iSPNs, indicating that they not only participated in the central representation of pain, but gated activity in ascending nociceptive pathways.

Identifying directed links in large scale functional networks: application to brain fMRI

BackgroundBiological experiments increasingly yield data representing large ensembles of interacting variables, making the application of advanced analytical tools a forbidding task. We present a method to extract networks of correlated activity, specifically from functional MRI data, such that: (a) network nodes represent voxels, and (b) the network links can be directed or undirected, representing temporal relationships between the nodes. The method provides a snapshot of the ongoing dynamics of the brain without sacrificing resolution, as the analysis is tractable even for very large numbers of voxels.ResultsWe find that, based on topological properties of the networks, the method provides enough information about the dynamics to discriminate between subtly different brain states. Moreover, the statistical regularities previously reported are qualitatively preserved, i.e. the resulting networks display scale-free and small-world topologies.ConclusionOur method expands previous approaches to render large scale functional networks, and creates the basis for an extensive and -due to the presence of mixtures of directed and undirected links- richer motif analysis of functional relationships.

The Emotional Brain as a Predictor and Amplifier of Chronic Pain

Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain—that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances.

Resting-sate functional reorganization of the rat limbic system following neuropathic injury

Human brain imaging studies from various clinical cohorts show that chronic pain is associated with large-scale brain functional and morphological reorganization. However, how the rat whole-brain network is topologically reorganized to support persistent pain-like behavior following neuropathic injury remains unknown. Here we compare resting state fMRI functional connectivity-based whole-brain network properties between rats receiving spared nerve injury (SNI) vs. sham injury, at 5 days (n = 11 SNI; n = 12 sham) and 28 days (n = 11 SNI; n = 12 sham) post-injury. Similar to the human, the rat brain topological properties exhibited small world features and did not differ between SNI and sham. Local neural networks in SNI animals showed minimal disruption at day 5, and more extensive reorganization at day 28 post-injury. Twenty-eight days after SNI, functional connection changes were localized mainly to within the limbic system, as well as between the limbic and nociceptive systems. No connectivity changes were observed within the nociceptive network. Furthermore, these changes were lateralized and in proportion to the tactile allodynia exhibited by SNI animals. The findings establish that SNI is primarily associated with altered information transfer of limbic regions and provides a novel translational framework for understanding brain functional reorganization in response to a persistent neuropathic injury.

Predictive Dynamics of Human Pain Perception

While the static magnitude of thermal pain perception has been shown to follow a power-law function of the temperature, its dynamical features have been largely overlooked. Due to the slow temporal experience of pain, multiple studies now show that the time evolution of its magnitude can be captured with continuous online ratings. Here we use such ratings to model quantitatively the temporal dynamics of thermal pain perception. We show that a differential equation captures the details of the temporal evolution in pain ratings in individual subjects for different stimulus pattern complexities, and also demonstrates strong predictive power to infer pain ratings, including readouts based only on brain functional images.

Prefrontal cortex and spinal cord mediated anti-neuropathy and analgesia induced by sarcosine, a glycine-T1 transporter inhibitor ☆

ABSTRACT Sarcosine is a competitive inhibitor of glycine type 1 transporter. We hypothesized that it may have analgesic and anti‐neuropathic efficacy by a dual action: affecting neurotransmission in the prefrontal cortex as well as within the spinal cord. In rats with spared nerve injury (SNI) oral sarcosine reduced mechanical sensitivity for the injured limb (anti‐neuropathy or anti‐allodynia) as well as for the uninjured limb (analgesia), showing better dose efficacy for the injured limb. Intrathecal administration of sarcosine was more effective in reducing mechanical sensitivity for the uninjured paw. In contrast, prefrontal cortex infusions of sarcosine acutely reduced mechanical sensitivity for the injured paw. Repeated daily oral sarcosine induced anti‐neuropathy, observed only after days of repeated treatment; this long‐term effect disappeared a few days after treatment cessation. The findings indicate that manipulating glycine‐T1 transporter at multiple central sites can induce acute analgesia, as well as acute and long‐term reduction in neuropathic pain behavior. Analgesic effects seem primarily mediated through spinal cord circuitry while anti‐neuropathic effects seem mediated through prefrontal cortex circuitry, most likely through distinct molecular pathways. The results suggest that such an approach may provide a novel venue for treating clinical pain conditions.