[Show abstract][Hide abstract] ABSTRACT: The hippocampus has been shown to undergo significant changes in rodent models of neuropathic pain; however, the role of the hippocampus in human chronic pain and its contribution to pain chronification has remained unexplored. Here we examine hippocampal processing during a simple visual attention task. We used functional MRI to identify intrinsic and extrinsic hippocampal functional connectivity (synchronous neural activity) comparing sub-acute back pain (SBP, back pain 1-4 months) and chronic back pain (CBP, back pain >10 years) to control subjects (CON). Both groups showed more extensive hippocampal connectivity than CON. We then examined the evolution of hippocampal connectivity longitudinally in SBP patients who recovered (SBPr, back pain decreases >20% in one year) and those with persistent pain (SBPp). We found that SBPp and SBPr have distinct changes in hippocampal-cortical connectivity over one year; specifically, SBPp subjects showed large decreases in connectivity with medial prefrontal cortex (HG-mPFC). Furthermore, in SBP patients the strength of HG-mPFC reflected variations in back pain over the year. These relationships were replicated when examined in a different task performed by SBP patients (rating fluctuations of back pain), indicating that functional connectivity of the hippocampus changes robustly in sub-acute pain, and the nature of these changes depends on whether or not patients recover from SBP. The observed reorganization of processing within the hippocampus and between the hippocampus and the cortex seems to contribute to the transition from sub-acute to chronic pain, and may also underlie learning and emotional abnormalities associated with chronic pain.
Journal of Neurophysiology 12/2013; · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies found that neuron specific enolase promoter (Nse-BMP4) transgenic mice have increased expression of the nociceptive mediator, substance P and exaggerated local injury responses associated with heterotopic ossification (HO). It is of interest great to know the pain responses in these mice and how the opioid signaling is involved in the downstream events such as mast cell (MC) activation.
This study utilized a transgenic mouse model of HO in which BMP4 is expressed under the control of the Nse-BMP4. The tactile sensitivity and the cold sensitivity of the mice were measured in a classic inflammatory pain model (carrageenan solution injected into the plantar surface of the left hind paw). The MC activation and the expression profiles of different components in the opioid signaling were demonstrated through routine histology and immunohistochemistry and Western blotting, in the superficial and deep muscle injury models.
We found that the pain responses in these mice were paradoxically attenuated or unchanged, and we also found increased expression of both Methionine Enkephalin (Met-Enk), and the μ-opioid receptor (MOR). Met-Enk and MOR both co-localized within activated MCs in limb tissues. Further, Nse-BMP4;MOR(-/-) double mutant mice showed attenuated MC activation and had a significant reduction in HO formation in response to injuries.
These observations suggest that opioid signaling may play a key role in MC activation and the downstream inflammatory responses associated with HO. In addition to providing insight into the role of MC activation and associated injury responses in HO, these findings suggest opioid signaling as a potential therapeutic target in HO and possibly others disorders involving MC activation.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neuroscience 04/2012; 32(17):5747-56. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigated how individual differences in anxiety modulate the neural response to errors and performance feedback. The design included false feedback on some trials in order to test the hypothesis that anxious people show stronger neural reactions to feedback that is worse than expected. Participants completed a trial-and-error learning task that required learning the correct key to press in response to face images. EEG was recorded during the task, and the response-locked error-related negativity (ERN) and feedback-locked ERN were computed to measure neural responses to error commission and feedback. As expected, errors produced a response-locked ERN and false feedback produced a feedback-locked ERN in the group as a whole. High levels of trait worry predicted a disproportionately larger ERN following false feedback, but did not predict the magnitude of the response-locked ERN following errors. These results imply that worry-prone people react more strongly to violations of expectations, rather than to errors themselves.
Cognition and Emotion 01/2010; 24(3):465-479. · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A meta-analysis of predictors of nonmarital romantic relationship dissolution was conducted, including data collected from 37,761 participants and 137 studies over 33 years. Individual, relationship, and external variables were investigated, and results suggest that commitment, love, inclusion of other in the self, and dependence were among the strongest predictors of dissolution. Other relational variables such as satisfaction, perceptions of alternatives, and investments were modest predictors of breakup, and the external factor of social network support was also a robust predictor. Personality measures were found to have limited predictive utility, with small effects found for dimensions relational in nature (e.g., adult attachment orientations). Theoretical and methodological implications are discussed within the context of future research on nonmarital relationship dissolution.
Personal Relationships 01/2010; · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been recently demonstrated that pain behavior in the mouse can be modulated by the presence of a conspecific, but what remains unclear is whether such pain behavior can serve the function of soliciting social approach. Using a novel social approach paradigm, we tested mice in various dyadic or triadic conditions, including "jailed" mice-some in pain via intraperitoneal injection of 0.9% acetic acid-and test mice free to approach or avoid the jailed mice. We observed a sex-specific effect whereby female, but not male, test mice approached a familiar same-sex conspecific in pain more frequently than an unaffected familiar or unfamiliar, but affected, conspecific. Despite a substantial literature emphasizing oxytocin's role in affiliative and pair-bonding behavior, this effect was also observed in female mice lacking the oxytocin receptor, suggesting that pain-related social approach may not be mediated by oxytocin. Furthermore, we found that the frequency of contact by the test mouse was negatively correlated with the pain behavior of the jailed mouse, suggesting that proximity of a familiar unaffected conspecific may have analgesic properties.
Social neuroscience 10/2009; 5(2):163-70. · 3.17 Impact Factor
[Show abstract][Hide abstract] 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.