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Classical conditioning was suggested as a mechanism of placebo effects in the 1950s. It was then challenged by response expectancy theory, which proposed that classical conditioning is just one of the means by which expectancies are acquired and changed. According to that account, placebo effects induced by classical conditioning are mediated by expectancies. However, in most of the previous studies, either expectancies were not measured or classical conditioning was combined with verbal suggestions. Thus, on the basis of those studies, it is not possible to conclude whether expectancies are involved in placebo effects induced by pure classical conditioning. Two lines of recent studies have challenged the idea that placebo effects induced by classical conditioning are always mediated by expectancies. First, some recent studies have shown that a hidden conditioning procedure elicits both placebo analgesia and nocebo hyperalgesia, neither of which is predicted by expectancy. Second, there are studies showing that visual cues paired with pain stimuli of high or low intensity induce both placebo analgesia and nocebo hyperalgesia when they are presented subliminally without participants' awareness. The results of both lines of studies suggest that expectancy may not always be involved in placebo effects induced by classical conditioning and that conditioning may be a distinct mechanism of placebo effects. Thus, these results support the idea that placebo effects can be learned by classical conditioning either consciously or unconsciously. However, the existing body of evidence is limited to classically conditioned placebo effects in pain, that is, placebo analgesia and nocebo hyperalgesia.
Learn More >Allodynia refers to pain evoked by physiologically innocuous stimuli. It is a disabling symptom of neuropathic pain following a lesion within the peripheral or central nervous system. In fact, two different pathophysiological mechanisms of cold allodynia (ie, hypersensitivity to innocuous cold) have been proposed. The peripheral sensitization of nociceptive neurons can produce cold allodynia, which can be induced experimentally by a topical application of menthol. An alternative mechanism involves reduced inhibition of central pain processing by innocuous cold stimuli. A model to induce the latter type of allodynia is the conduction block of peripheral A-fiber input.
Learn More >: Chronic pain is a common comorbid complaint in traumatized refugees seeking treatment for posttraumatic stress disorder (PTSD) and depression. However, the effect of comorbid pain on treatment remains under investigated. : To investigate whether pre-treatment pain (severity/interference) predicts outcomes in a multimodal treatment targeting PTSD, depression, anxiety, somatic complaints, and health-related disability in refugees exposed to torture and organized violence. Additional predictors were gender, age, and number of treatment sessions. : Participants were active cases at a specialist outpatient clinic for tortured refugees (n = 276; 170 men, 106 women) who were either on a treatment waitlist (mean length = 7.4 months, SD = 4.5), in treatment (mean length = 12.2 months, SD = 6.5), or who completed treatment and had (or were waiting for) a follow-up assessment. Participants completed symptom measures at referral, pre- and post-treatment, and 9-month follow-up. Multi-level mixed modelling was used to assess whether outcomes at post-treatment and 9-months were predicted by pain, gender, age, or the number of treatment sessions. : Treatment yielded significant pre-to-post-treatment reductions in PTSD, depression, anxiety, and number of pain locations, but no reductions in pain severity/interference, or health-related disability, except for societal participation. Gains for PTSD, depression, and societal participation were maintained at the 9-month follow-up. Higher levels of pain interference (but not severity) predicted poorer outcomes (PTSD, depression, and anxiety). Age, gender and number of treatment sessions did not predict outcomes, except for a small negative effect of (older) age on PTSD. : A growing body of literature suggests that pain and PTSD symptoms interact in ways to increase the severity and impact of both disorders in refugee and non-refugee populations alike. The present study suggests interference from pain can lessen the effectiveness of standard multi-modal treatments for refugees.
Learn More >Chronic low back pain has been observed to decrease movement coordination. However, it is unclear whether the existing alteration of inter-hemispheric synchrony of intrinsic activity in patients with chronic low back-related leg pain (cLBLP). The present study aims to investigate the alteration of homotopic connectivity and its clinical association with the cLBLP patients.
Learn More >The thalamus is a key region for the transmission of nociceptive information in the central modulation of pain and has been studied in the setting of numerous chronic pain conditions. Brain-derived neurotrophic factor (BDNF) is considered an important modulator for mediating nociceptive pathways in chronic pain. The present study aimed to investigate whether there was thalamus-related abnormal functional connectivity or relevant serum BDNF level alterations during periovulation in long-term primary dysmenorrhea (PDM). Thalamic subregions were defined according to the Human Brainnetome Atlas. Functional connectivity analyses were performed in 36 patients in the periovulatory phase and 29 age-, education-, and gender-matched healthy controls. Serum BDNF levels were evaluated by enzyme-linked immunosorbent assay and a significantly higher BDNF level was detected in PDM patients. Compared with HCs, PDM patients had abnormal functional connectivity of thalamic-subregions, mainly involving with prefrontal cortex, sensorimotor cortex, and temporal cortex. In addition, the functional connectivity of thalamic-subregions showed significant interactive effect correlated with serum BDNF level between PDM and HCs. It has been suggested that there were maladaptive or adoptive alteration associated with chronic menstrual pain even without the ongoing menstrual pain. BDNF might play a role in the development and chronicity of central nervous system dysfunction. These findings provided more accurate information about the involvement of the thalamus in the pathophysiology of PDM.
Learn More >Growing evidence indicates that neuropathic pain is frequently accompanied by cognitive impairments, which aggravate the quality of life of chronic pain patients. Here, we investigated whether acupuncture treatments can improve cognitive dysfunction as well as allodynia induced by neuropathic pain in mice. One week after the left partial sciatic nerve ligation (PSNL), acupuncture treatments on the acupoints GB30-GB34 (AP1), HT7-GV20 (AP2), or control points (CP) were performed for 4 weeks. Notably, the significant attenuations of mechanical allodynia and cognitive impairment were observed in the AP1 group, but not in PSNL, AP2, or CP groups. A random decision forest classifier based on the pain and cognitive functions displayed that the acupuncture group was clearly segregated from the other groups. We also demonstrated that acupuncture restored the reduced field excitatory post-synaptic potentials and was able to elevate the expression levels of glutamate receptors (NR2B and GluR1) in the hippocampus. Moreover, the expressions of Ca/calmodulin-dependent protein kinase II and synaptic proteins (pPSD-95 and pSyn-1) were enhanced by acupuncture treatment. These results suggest that acupuncture can enhance hippocampal long-term action through the regulation of the synaptic efficacy and that acupuncture may provide a viable option for managing both pain and cognitive functions associated with chronic neuropathic pain.
Learn More >Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescence-activated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.
Learn More >Sub-anesthetic ketamine is frequently used as an analgesic to reduce perioperative opioid consumption and has also been shown to have antidepressant effects. Side effects of ketamine include dizziness, diplopia, nystagmus, and psychomimetic effects. It is unclear what clinical factors may be associated with ketamine-related adverse drug events (ADEs).
Learn More >Increasing physical function is a challenging, yet imperative goal of pain management programs. Physical activity can improve physical function, but uptake is low due to chronic pain misconceptions, poor pain management skills, and doing too much too soon.
Learn More >Migraine is a very common, multifactorial, and recurrent central nervous system disorder that causes throbbing headache, photophobia, phonophobia, nausea, and disability. Migraine occurs more often in females, and its complex physiopathology is not yet fully understood. An increasing number of gastrointestinal disorders have been linked to the occurrence of migraine suggesting that gut microbiota might play a pivotal role in migraine through the gut-brain axis. In the present work, we performed a metagenome-wide association study (MWAS) to determine the relationship between gut microbiota and migraine by analyzing 108 shotgun-sequenced fecal samples obtained from elderly women who suffer from migraine and matched healthy controls. Notably, the alpha diversity was significantly decreased in the migraine group at species, genus, and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous levels. Firmicutes, especially the "unfriendly" spp., were significantly enriched in the migraine group. Conversely, the healthy controls held more beneficial microorganisms, such as , and . For functional modules, the migraine group was enriched in gut-brain modules (GBMs) including kynurenine degradation and γ-aminobutyric acid (GABA) synthesis. However, the healthy controls held higher gut metabolic modules (GMMs) including glycolysis, homoacetogenesis, and GBMs including quinolinic acid degradation and -adenosyl methionine (SAM) synthesis. The differences in gut microbiota composition and function between the migraine and healthy groups provided new information as well as novel therapeutic targets and strategies for migraine treatment, which could help to improve the early diagnosis of the disease, as well as the long-term prognosis and the life quality of patients suffering from migraine.
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