The journal of pain : official journal of the American Pain Society
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The knee osteoarthritis (KOA) model is a convenient and coherent archetype that is frequently used in pharmaceutical trials of drugs with analgesic and/or anti-inflammatory properties; yet, little is known about its specific pathophysiology. The presumed chronic inflammatory etiology of osteoarthritis suggests that nociceptive processes and neurogenic inflammation predominate in this condition. However, most chronic pain conditions are associated with changes in peripheral and central processing. Recent data corroborate this as an important mechanism in KOA. We compared psychophysical characteristics (including thermal Quantitative Sensory Testing); thermal, mechanical, and functional wind-up; thermal and mechanical aftersensations; and pressure algometry of 37 subjects with KOA with 35 age- and sex-matched controls. A third of the KOA subjects demonstrated hypoesthesia to vibration and the 4.56 von Frey fiber, yet few showed allodynia in their worse knee. The majority of subjects had abnormalities to pinprick (41% were hyperalgesic and 27% were hypoesthetic). Compared to controls, the more painful knee was hypoesthetic to cold detection and had greater thermal wind-up, lower pressure-pain thresholds, thermal and mechanical aftersensations, and twice the pain ratings of controls after stair climb. Substantial intraindividual differences were found in KOA subjects and controls for mechanical wind-up and algometric thresholds. ⋯ These results develop the KOA model and suggest mechanistic hypotheses. Certain of these tests may ultimately prove to be responsive, quasi-objective, and quantitative outcomes for research and lend empirical support to the notion of measurable sensitization in osteoarthritis.
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Pain is associated with stimulation of some behaviors (eg, withdrawal reflexes) but depression of many other behaviors (eg, feeding, locomotion, positively reinforced operant behavior). Drugs that block reuptake of serotonin, norepinephrine, and/or dopamine are widely used to treat depression, and they have also emerged as useful drugs for treatment of pain. This study compared effects of selective and mixed-action inhibitors of serotonin, norepinephrine, and/or dopamine reuptake in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute acid served as a noxious stimulus to stimulate a writhing response or depress intracranial self-stimulation (ICSS) in Sprague Dawley rats. Selective reuptake inhibitors of serotonin (citalopram, clomipramine) and norepinephrine (nisoxetine, nortriptyline) and a mixed-action reuptake inhibitor of serotonin and norepinephrine (milnacipran) blocked acid-stimulated writhing but failed to block acid-induced depression of ICSS. Selective dopamine reuptake inhibitors (RTI-113 [3ß-(4-chlorophenyl)tropane-2ß-carboxylic acid phenyl ester hydrochloride], bupropion) and a triple reuptake inhibitor of dopamine, serotonin, and norepinephrine (RTI-112 [3ß-(3-methyl-4-chlorophenyl)tropane-2ß-carboxylic acid methyl ester hydrochloride]) blocked both acid-stimulated writhing and acid-induced depression of ICSS, although these drugs also produced an abuse-related facilitation of ICSS in the absence of the noxious stimulus. These results support further consideration of dopamine reuptake inhibitors as candidate analgesics, although abuse liability remains a concern. ⋯ Monoamine reuptake inhibitors are used to treat depression and some forms of pain. This study examined effects of monoamine reuptake inhibitors in a preclinical assay of pain-related behavioral depression. The results support further consideration of dopamine reuptake inhibitors as candidate analgesics under selected circumstances, although abuse liability remains a concern.
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Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex-related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. ⋯ This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism.
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Review Meta Analysis
Inserting needles into the body: a meta-analysis of brain activity associated with acupuncture needle stimulation.
Acupuncture is a therapeutic treatment that is defined as the insertion of needles into the body at specific points (ie, acupoints). Advances in functional neuroimaging have made it possible to study brain responses to acupuncture; however, previous studies have mainly concentrated on acupoint specificity. We wanted to focus on the functional brain responses that occur because of needle insertion into the body. An activation likelihood estimation meta-analysis was carried out to investigate common characteristics of brain responses to acupuncture needle stimulation compared to tactile stimulation. A total of 28 functional magnetic resonance imaging studies, which consisted of 51 acupuncture and 10 tactile stimulation experiments, were selected for the meta-analysis. Following acupuncture needle stimulation, activation in the sensorimotor cortical network, including the insula, thalamus, anterior cingulate cortex, and primary and secondary somatosensory cortices, and deactivation in the limbic-paralimbic neocortical network, including the medial prefrontal cortex, caudate, amygdala, posterior cingulate cortex, and parahippocampus, were detected and assessed. Following control tactile stimulation, weaker patterns of brain responses were detected in areas similar to those stated above. The activation and deactivation patterns following acupuncture stimulation suggest that the hemodynamic responses in the brain simultaneously reflect the sensory, cognitive, and affective dimensions of pain. ⋯ This article facilitates a better understanding of acupuncture needle stimulation and its effects on specific activity changes in different brain regions as well as its relationship to the multiple dimensions of pain. Future studies can build on this meta-analysis and will help to elucidate the clinically relevant therapeutic effects of acupuncture.