| 1. |
- Aarnio, Mikko, et al.
(författare)
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Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl positron emission tomography and computed tomography
- 2022
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 163:3, s. 489-495
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.
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| 2. |
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| 3. |
- Agalave, Nilesh M., et al.
(författare)
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Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity
- 2021
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 162:2, s. 446-458
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Tidskriftsartikel (refereegranskat)abstract
- High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by liquid chromatography-mass spectrometry are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.
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| 4. |
- Agalave, Nilesh M, et al.
(författare)
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Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.
- 2014
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 155:9, s. 1802-1813
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. Subsequent to induction of collagen antibody-induced arthritis (CAIA), Hmgb1 mRNA and extranuclear protein levels were significantly increased in the lumbar spinal cord. Intrathecal (i.t.) injection of a neutralizing anti-HMGB1 monoclonal antibody or recombinant HMGB1 box A peptide (Abox), which each prevent extracellular HMGB1 activities, reversed CAIA-induced mechanical hypersensitivity. This occurred during ongoing joint inflammation as well as during the postinflammatory phase, indicating that spinal HMGB1 has an important function in nociception persisting beyond episodes of joint inflammation. Importantly, only HMGB1 in its partially oxidized isoform (disulfide HMGB1), which activates toll-like receptor 4 (TLR4), but not in its fully reduced or fully oxidized isoforms, evoked mechanical hypersensitivity upon i.t. injection. Interestingly, although both male and female mice developed mechanical hypersensitivity in response to i.t. HMGB1, female mice recovered faster. Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain.
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| 5. |
- Ahacic, K, et al.
(författare)
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Prevalence of musculoskeletal pain in the general Swedish population from 1968 to 2002 : Age, period, and cohort patterns
- 2010
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 151:1, s. 206-214
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Tidskriftsartikel (refereegranskat)abstract
- We examined age, period, and cohort patterns in musculoskeletalpainprevalence between 1968 and 2002 in the Swedishpopulation. A repeated nationally representative survey allowed cross-sectional comparisons of ages 18–75 (5 waves n ≈ 5000), and ages 77+ at later waves (2 waves n ≈ 500). Cross-sectional 10-year age group differences in 5 waves, time-lag differences between waves (shifts across time) for age groups, and within-cohort differences between waves for 10-year birth cohorts followed over time were analyzed using graphs and ordered logistic regressions. The outcome scale was based on the three items measuring slight or severe pain in back, shoulder, and joints during the past 12 months. Age–period–cohort models showed that painprevalence increased with age – mild or severe at all locations. Adjusted for the age-related increase, the cohorts followed over time did not show significant period change, except for cohorts born during 1940s. Beginning with the 1940s’ cohorts painprevalence increased over the period, and after baseline later cohorts also entered adulthood and the study with a higher painprevalence. The prevalence of pain in the adult population thus increased with the passage through age and time of the 1940s cohorts. While there were no pronounced cohort differences at baseline in 1968, results demonstrated strong age effects in pain. The results indicate that the prevalence of musculoskeletalpain among the oldest age groups may increase in the future, when more baby-boomers are entering their oldest ages.
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| 6. |
- Ahmed, Aisha S, et al.
(författare)
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Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis
- 2012
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 153:1, s. 18-26
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis is a degenerative joint disease with pain and loss of joint function as major pathological features. Recent studies show that proteasome inhibitors reduce pain in various pathological conditions. We evaluated the effects of MG132, a reversible proteasome inhibitor on pain and joint destruction in a rat model of osteoarthritis. Osteoarthritis was induced by intraarticular injection of monosodium iodoacetate into the rat knee. Knee joint stiffness was scored and nociception was evaluated by mechanical pressure applied to the respective hind paw. Knee joint destruction was assessed by radiological and histological analyses. Expression of matrix metalloproteinase-3 (MMP-3) was analyzed by quantitative reverse transcription polymerase chain reaction in the knee articular cartilage. Expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in the dorsal root ganglia (L4–L6) by quantitative reverse transcription polymerase chain reaction and in the knee joints by immunohistochemistry. Our results indicate that daily treatment of osteoarthritic rats with MG132 significantly increases their mobility while the swelling, pain thresholds, and pathological features of the affected joints were reduced. Furthermore, the upregulated expression of MMP-3, SP, and CGRP in the arthritic rats was normalized by MG132 administration. We conclude that the proteasome inhibitor MG132 reduces pain and joint destruction, probably by involving the peripheral nervous system, and that changes in SP and CGRP expression correlate with alterations in behavioural responses. Our findings suggest that nontoxic proteasome inhibitors may represent a novel pharmacotherapy for osteoarthritis.
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| 7. |
- Aili, Katarina, 1980-, et al.
(författare)
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Long-term trajectories of chronic musculoskeletal pain: a 21-year prospective cohort latent class analysis
- 2021
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Ingår i: Pain. - Philadelphia, PA : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 162:5, s. 1511-1520
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Tidskriftsartikel (refereegranskat)abstract
- Our knowledge of the prevalence, impact, and outcomes of chronic pain in the general population is predominantly based on studies over relatively short periods of time. The aim of this study was to identify and describe trajectories of the chronic pain status over a period of 21 years. Self-reported population data (n = 1858) from 5 timepoints were analyzed. Pain was categorized by: no chronic pain (NCP), chronic regional pain (CRP), and chronic widespread pain (CWP). Latent class growth analysis was performed for identification of trajectories and logistic regression analysis for identification of predictors for pain prognosis. Five trajectories were identified: (1) persistent NCP (57%), (2) migrating from NCP to CRP or CWP (5%), (3) persistent CRP or migration between CRP and NCP (22%), (4) migration from CRP to CWP (10%), and (5) persistent CWP (6%). Age, sleeping problems, poor vitality, and physical function at baseline were associated with pain progression from NCP. Female gender, seeking care for pain, lack of social support, poor physical function, vitality, and mental health predicted poor pain prognosis among those with CRP. In conclusion, chronic pain was common in the population including 6% reporting persistent CWP, although the majority persistently reported NCP. Most people had stable pain status, but some had ongoing change in pain status over time including people who improved from chronic pain. It was possible to identify clinically relevant factors, characterizing trajectories of chronic pain development, that can be useful for identifying individuals at risk and potential targets for intervention.
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| 8. |
- Alier, Kwai, et al.
(författare)
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Selective stimulation of GalR1 and GalR2 in rat substantia gelatinosa reveals a cellular basis for the anti- and pro-nociceptive actions of galanin
- 2008
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 137:1, s. 138-146
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Tidskriftsartikel (refereegranskat)abstract
- Galanin modulates spinal nociceptive processing by interacting with two receptors, GalR1 and GalR2. The underlying neurophysiological mechanisms were examined by whole-cell recording from identified neurons in the substantia gelatinosa of young adult rats. GalR1 was activated with a 'cocktail' containing the GalR1/2 agonist, AR-M 961 (0.5 mu M), in the presence of the GalR2 antagonist, M871 (1.0-2.5 mu M). GalR2 was activated with the selective agonist, AR-M 1896 (0.5-1.0 mu M). Application of the 'GalR1 agonist cocktail' often activated an inwardly-rectifying conductance in delay firing (excitatory) and tonically firing (inhibitory) neurons. This conductance was not activated by AR-M 1896 which instead decreased or increased an outwardly-rectifying conductance at voltages positive to -70 rnV. Despite this variability in its actions on current-voltage relationships, AR-M 1896 very consistently decreased membrane excitability, as measured by cumulative action potential latency in response to a depolarizing current ramp. This strong GalR2-mediated effect was seen in neurons where membrane conductance was decreased, and where membrane excitability might be predicted to increase. GalR2 was also located presynaptically, as AR-M 1896 increased the interevent interval of spontaneous EPSCs in both delay and tonic cells. By contrast, the 'GalR1 agonist cocktail' had little effect on spontaneous EPSCs, suggesting that presynaptic terminals do not express GalR1. These diverse actions of GalR1 and GalR2 activation on both inhibitory and excitatory neurons are discussed in relation to the known spinal antinociceptive and pro-nociceptive actions of galanin, to the possible association of GalR1 with the inhibitory G-protein, G(i/o) and to report that GalR2 activation suppresses Ca(2+) channel currents.
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| 9. |
- Amandusson, Åsa, 1974-, et al.
(författare)
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Estrogen-induced alterations of spinal cord enkephalin gene expression
- 1999
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Ingår i: Pain. - : Elsevier. - 0304-3959 .- 1872-6623. ; 83:2, s. 243-248
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Tidskriftsartikel (refereegranskat)abstract
- Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.
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| 10. |
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