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Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy (spared nerve injury, SNI) and neuronal activity in the mPFC was monitored using the immediate early gene, c-Fos, and electrophysiological recordings. mPFC eCB concentrations were determined using mass spectrometry while behavioral and electrophysiological experiments were employed to evaluate role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI and our results indicate that this resulted in loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression.Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model includes widespread central nervous system dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Whereas manipulation of the endocannabinoid (eCB) signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here we show that activity dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.
Learn More >Research on intersectionality and chronic pain disparities is very limited. Intersectionality explores the interconnections between multiple aspects of identity and provides a more accurate picture of disparities. This study applied a relatively novel statistical approach (i.e., Latent Class Analysis; LCA) to examine chronic pain disparities with an intersectional identity approach. Cross-sectional data were analyzed using pre-treatment data from the Learning About My Pain (LAMP) trial, a randomized comparative effectiveness study of group-based psychosocial interventions (PCORI Contract #941, Beverly Thorn, PI; clinicaltrials.gov identifier NCT01967342) for patients receiving care for chronic pain at low-income clinics in rural and suburban Alabama. LCA results suggested a 5-class model. In order to easily identify each class, the following labels were created: Older Adults (OA), Younger Adults (YA), Severe Disparity (SD), Older/Black/African-American (OB), and Working Women (WW). The latent disparity classes varied by pre-treatment chronic pain functioning. Overall, the SD group had the lowest levels of functioning, and the WW group had the highest levels of functioning. Although younger and with higher literacy levels, the YA group had similar levels of pain interference and depressive symptoms to the SD group (p's < .05). The YA group also had higher pain catastrophizing than the OA group (p < .005). Results highlighted the importance of the interactions between the multiple factors of socioeconomic status, age, and race in the experience of chronic pain. The intersectional identity theory approach through LCA provided an integrated picture of chronic pain disparities in a highly understudied and underserved population.
Learn More >Clinically, posttraumatic stress disorder (PTSD) and chronic pain are highly comorbid conditions, but the underlying mechanisms of and therapeutic strategies against PTSD-related pain remain unclear. Our previous studies suggested that dysregulation of neuroinflammation contributes to the development of stress-induced hyperalgesia. Recent studies reported that angiotensin II was a 'stress-related hormone', and could induce glial activation by stimulating the type 1 receptor (AT1R). In the present study, we aimed to investigate whether AT1R blockade could attenuate mechanical allodynia induced by PTSD-like stress. Adult male rats were exposed to single prolonged stress (SPS) to establish a model of PTSD-pain comorbidity. Our results showed that SPS exposure increased the levels of angiotensin II in the hippocampus, prefrontal cortex (PFC) and spinal cord; intraperitoneal injection of losartan attenuated SPS-induced mechanical allodynia, and suppressed SPS-induced glial activation (both microglia and astrocytes) and proinflammatory cytokine expression in the PFC and spinal cord, but not in the hippocampus. We further showed that intrathecal injection of losartan also exerted anti-hyperalgesic effect and suppressed SPS-induced glial activation and proinflammatory cytokine expression in the spinal cord. These results indicated that AT1R blockade by losartan attenuated mechanical allodynia induced by PTSD-like stress, and this may be attributed to the suppression of glial activation and proinflammatory cytokine expression in the spinal cord. Although further research is warranted to verify our findings in female rodents and to assess pharmacological effects of AT1R blockade in PFC and hippocampus, our study suggested the therapeutic potential of targeting AT1R in the treatment of PTSD-related chronic pain.
Learn More >Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.
Learn More >Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects.
Learn More >We assessed the longitudinal association of suicide attempts by moderate to severe pain and insomnia prior to and following the initiation of pain services among veterans.
Learn More >Chemotherapy-induced peripheral neuropathy ((CI)PN) becomes chronic in 30% of cancer patients. Knowledge of predictors of chronic (CI)PN and related impairments in health-related quality of life (HRQoL) is lacking. We examined the role of optimism in chronic (CI)PN severity and associated HRQoL in colorectal cancer (CRC) patients up to two years after diagnosis.
Learn More >Comorbid chronic pain and depression are increasingly becoming a concerning public problem, but the underlying mechanisms remain unclear. Here, we demonstrate that pain-related depression-like behaviors are induced in a rat model of chronic constriction injury (CCI). Using this model, we found that chronic neuropathic pain decreased the activity and expression of sirtuin 1 (SIRT1, an NAD-dependent deacetylase) in the central nucleus of the amygdala (CeA). In addition, the pharmacologic activation of SIRT1 in the CeA could alleviate the depression-like behaviors associated with chronic pain while relieving sensory pain. Accordingly, adeno-associated virus (AAV)-mediated SIRT1 overexpression in the CeA produced a positive effect on the easement of chronic pain and comorbid depression. Taken together, these findings highlight the role of SIRT1 in the CeA in chronic pain and depression states and reveal that the upregulation of SIRT1 may be a potential therapy for the treatment of pain-depression comorbidities.
Learn More >Reliably identifying good placebo responders has pronounced implications for basic research on, and clinical applications of, the placebo response. Multiple studies point to direct verbal suggestibility as a potentially valuable predictor of individual differences in placebo responsiveness, but previous research has produced conflicting results on this association.
Learn More >Slow, deep breathing (SDB) is a common pain self-management technique. Stimulation of the arterial baroreceptors and vagal modulation are suggested, among others, as potential mechanisms underlying the hypoalgesic effects of SDB. We tested whether adding an inspiratory load to SDB, which results in a stronger baroreceptor stimulation and vagal modulation, enhances its hypoalgesic effects. Healthy volunteers performed SDB (controlled at 0.1 Hz) with and without an inspiratory threshold load. Controlled breathing (CB) at a normal frequency (0.23 Hz) was used as an active control. Each condition lasted 90 s, included an electrical pain stimulation on the hand, and was repeated four times in a randomized order. Pain intensity, self-reported emotional responses (arousal, valence, dominance), and cardiovascular parameters (including vagally-mediated heart rate variability) were measured per trial. A cover story was used to limit the potential effect of outcome expectancy. Pain intensity was slightly lower during SDB with load compared with normal-frequency CB, but the effect was negligible (Cohens d < 0.2), and there was no other difference in pain intensity between the conditions. Heart rate variability was higher during SDB with/without load compared with normal-frequency CB. Using load during SDB was associated with higher heart rate variability, but less favorable emotional responses. These findings do not support the role of baroreceptor stimulation or vagal modulation in the hypoalgesic effects of SDB. Other mechanisms, such as attentional modulation, warrant further investigation.
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