Acceptance and Adherence to COVID-19 Vaccination-The Role of Cognitive and Emotional Representations.

Vaccine hesitation is a topic of utmost importance, with the COVID-19 pandemic serving as a clear reminder of its timeliness. Besides evaluating COVID-19 vaccine acceptance in a sample of Portuguese people, this study aims at understanding cognitive and emotional representations related to vaccination, and their influence on vaccination hesitation. A cross-sectional online survey was conducted between 27 December 2020 and 27 January 2021. It assessed cognitive and emotional COVID-19 representations; vaccination status; cognitive and emotional representations of vaccination and perceived necessity and concerns about vaccines. Of 31 × 58 participants, 91% accepted taking a COVID-19 vaccine. Among several other significant findings, women (71.3%) more often considered that the pandemic affected their lives (p < 0.001) and were more often concerned with being infected (p < 0.001). Likewise, there were significantly more female participants concerned about taking a COVID-19 vaccine and its possible effects, when compared to the number of male participants (p < 0.001). The number of participants with a higher education level that were more worried about becoming infected was greater (p = 0.001), when compared with those less educated. Regarding age groups, people aged 18 to 24 had fewer concerned participants (9.6%), while the number of individuals aged 55 to 64 had the most (p < 0.001). Somewhat surprisingly, perceiving oneself as extremely informed about COVID-19 was not associated with greater vaccine acceptance (OR = 1.534 [1.160−2.029]; (p = 0.003)). Moreover, people aged 25 to 64 years old and with lower education level were more likely not to accept vaccination (OR = 2.799 [1.085−7.221]; (p = 0.033)). Finally, being more concerned about taking a vaccine lowers its acceptance (OR = 4.001 [2.518−6.356]; (p < 0.001)). Cognitive and emotional representations have a great impact and are reliable predictors of vaccine acceptance. Thus, it is of extreme importance that public health messages be adapted to the different characteristics of the population.

Portuguese Version of the Intentional Non-Adherence Scale: Validation in a Population of Chronic Pain Patients.

Objective: Despite the effectiveness of pain medicines, nonadherence to prescribed medication remains a major problem faced by healthcare systems. The aim of present study was to perform the translation, cultural adaptation, and validation of the Intentional Non-Adherence Scale (INAS) for the European Portuguese language in a sample of chronic pain patients. Methods: A Portuguese version of the INAS scale was constructed through a process of translation, back translation, and expert's panel evaluation. A total of 133 chronic pain patients were selected from two chronic pain clinics from tertiary hospitals in Porto, Portugal. The protocol interview included the assessment of pain beliefs (PBPI), beliefs about medicine (BMQ), medication adherence (MARS-P9), and two direct questions about adherence previously validated. Results: The internal consistency in all subscales was α = 0.902 for testing treatment; α = 0.930 for mistrust treatment; α = 0.917 for resisting treatment; and α = 0.889 for resisting illness. Exploratory and confirmatory factor analysis revealed a four-factor structure that explained 74% of the variance. The construct validity of the INAS was shown to be adequate, with the majority of the previously defined hypotheses regarding intercorrelations with other measures confirmed. Conclusion: The Portuguese version of INAS could be a valuable and available instrument for Portuguese researchers and clinicians to assess the intentional nonadherence determinants during the management of chronic pain.

Non-Adherence to Pharmacotherapy: A Prospective Multicentre Study About Its Incidence and Its Causes Perceived by Chronic Pain Patients.

OBJECTIVE: Pharmacological interventions remain the cornerstone of chronic pain treatment; however, nearly 40% of the prescription medicines are not taken as prescribed. The present study aims at understanding and describing non-adherence from the perspective of chronic pain patients during a 1-year follow-up study. METHODS: A cohort of 950 consecutive patients referred to a first consultation in Multidisciplinary Chronic Pain Clinics was followed with a standardized protocol for 1 year. This included assessment of pain characteristics; prescribed medication; therapeutic adherence; effectiveness of treatment, non-adherence and its perceived reasons; clinical outcomes and quality of life. We used a mixed methods approach, including qualitative and quantitative analyses. RESULTS: Forty-nine percent of the 562 patients who responded to all assessments during follow-up were adherent after 1 year of chronic pain treatment. The core associations between each "non-adherence reason" and Anatomical Therapeutic Chemical Code (ATC) group were perceived side effects (p=0.019) and delayed start (p=0.022) for narcotic analgesics (opioids); perceived non-efficacy (p=0.017) and delayed start (p=0.004) for antiepileptics and anticonvulsants; perceived low necessity (p=0.041) and delayed start (p=0.036) for analgesics antipyretics; change in prescriptions because of a new clinical condition for antidepressants (p=0.024); high concerns (p=0.045) and change in prescriptions because of a new clinical condition (p<0.001) for non-steroidal anti-inflammatory drugs; delayed start (p=0.016) and financial constraints (p=0.018) for other medications. DISCUSSION: This study emphasizes the patient's perspective regarding non-adherence to pharmacological treatment of chronic pain, providing valuable and novel information to be used in future interventions to help patients make an informed choice about their adherence behavior.

Improving perioperative pain management: a preintervention and postintervention study in 7 developing countries.

INTRODUCTION: The burden of untreated postoperative pain is high. OBJECTIVE: This study assessed feasibility of using quality improvement (QI) tools to improve management of perioperative pain in hospitals in multiple developing countries. METHODS: The International Pain Registry and Developing Countries working groups, from the International Association for the Study of Pain (IASP), sponsored the project and PAIN OUT, a QI and research network, coordinated it, and provided the research tools. The IASP published a call about the project on its website. Principal investigators (PIs) were responsible for implementing a preintervention and postintervention study in 1 to 2 surgical wards in their hospitals, and they were free to choose the QI intervention. Trained surveyors used standardized and validated web-based tools for collecting findings about perioperative pain management and patient reported outcomes (PROs). Four processes and PROs, independent of surgery type, assessed effectiveness of the interventions. RESULTS: Forty-three providers responded to the call; 13 applications were selected; and PIs from 8 hospitals, in 14 wards, in 7 countries, completed the study. Interventions focused on teaching providers about pain management. Processes improved in 35% and PROs in 37.5% of wards. CONCLUSIONS: The project proved useful on multiple levels. It offered PIs a framework and tools to perform QI work and findings to present to colleagues and administration. Management practices and PROs improved on some wards. Interpretation of change proved complex, site-dependent, and related to multiple factors. PAIN OUT gained experience coordinating a multicentre, international QI project. The IASP promoted research, education, and QI work.

Portuguese version of the Medication Adherence Report Scale (MARS-9): Validation in a population of chronic pain patients.

AIM: The aim of present study was to perform the translation, cultural adaptation, and validation of the Medication Adherence Report Scale (MARS-P9) for the European Portuguese language in a sample of chronic pain patients. METHODS: A Portuguese version of the nine-item MARS (©Professor Rob Horne) scale (MARS-P9) was constructed through a process of translation, back translation, and experts' panel evaluation. A total of 141 chronic pain patients were subsequently evaluated at four time assessments during a 1-year pain medication treatment. The protocol interview included the assessment of pain intensity and interference (BPI), clinical outcomes and quality of life (S-TOPS), and MARS-P9. RESULTS: The internal consistency coefficient was acceptable for the total scale (α = 0.84). Exploratory factor analysis revealed a two-factor structure (intentional and unintentional nonadherence) that explained 61% of the variance. Convergent and discriminant validity were demonstrated by correlations between MARS scores and pain interference (r = 0.180, P ≤ 0.01) and S-TOPS (r = 0.242, P ≤ 0.05). CONCLUSION: MARS-P9 has been shown to be an adequate instrument for Portuguese researchers and clinicians to assess the pattern of adherence during the management of chronic pain.

Effectiveness of Opioids for Chronic Noncancer Pain: A Two-Year Multicenter, Prospective Cohort Study With Propensity Score Matching.

Opioid use in chronic non cancer pain (CNCP) is still controversial regarding their effectiveness and safety. We conducted a 2-year prospective cohort study in 4 multidisciplinary chronic pain clinics to assess long-term opioid effectiveness in CNCP patients. All adult CNCP patients consecutively admitted to their first consultation were recruited. Demographic and clinical data were collected, and propensity score matching was used to adjust for differences between opioid users and nonusers. The Brief Pain Inventory and the Short version of Treatment Outcomes in Pain Survey were used to measure pain outcomes and quality of life. A total of 529 subjects were matched and included in our analysis. Rate of prescription opioid use was 59.7% at baseline, which increased to 70.3% over 2 years, of which 42.7% of the prescriptions were for strong opioids. Opioid users reported no improvement regarding pain symptoms, physical function, emotional function, and social/familiar disability. Opioid users reported higher satisfaction with care and outcomes at 1 year of follow-up, but at 2 years, they only reported improvement in satisfaction with outcomes. Opioids have shown limited effectiveness in long-term CNCP management, as opioid users presented no improvements regarding functional outcomes and quality of life. These findings emphasize the need for proper selection and outcome assessment of CNCP patients prescribed opioids. PERSPECTIVE: This study adds important additional evidence concerning the controversial use of opioids in CNCP management. Opioid users presented no improvement regarding pain relief, functional outcomes and quality of life over 2 years of follow-up. Therefore, our results support and highlight the limited effectiveness of opioids in long-term CNCP management.

A Two-Year Prospective Multicenter Study of Opioid Therapy for Chronic Noncancer Pain: Prescription Trends and Predictors.

OBJECTIVES: Opioid use in chronic pain has increased worldwide in recent years. The aims of this study were to describe the trends and patterns of opioid therapy over two years of follow-up in a cohort of chronic noncancer pain (CNCP) patients and to assess predictors of long-term opioid use and clinical outcomes. METHODS: A prospective cohort study with two years of follow-up was undertaken in four multidisciplinary chronic pain clinics. Demographic data, pain characteristics, and opioid prescriptions were recorded at baseline, three, six, 12, and 24 months. RESULTS: Six hundred seventy-four CNCP patients were recruited. The prevalence of opioid prescriptions at baseline was 59.6% (N = 402), and 13% (N = 86) were strong opioid prescriptions. At 24 months, opioid prescription prevalence was as high as 74.3% (N = 501), and strong opioid prescription was 31% (N = 207). Most opioid users (71%, N = 479) maintained their prescription during the two years of follow-up. Our opioid discontinuation was very low (1%, N = 5). Opioid users reported higher severity and interference pain scores, both at baseline and after two years of follow-up. Opioid use was independently associated with continuous pain, pain location in the lower limbs, and higher pain interference scores. CONCLUSIONS: This study describes a pattern of increasing opioid prescription in chronic pain patients. Despite the limited improvement of clinical outcomes, most patients keep their long-term opioid prescriptions. Our results underscore the need for changes in clinical practice and further research into the effectiveness and safety of chronic opioid therapy for CNPC.

Impact of the economic crisis on pain research: a bibliometric analysis of pain research publications from Ireland, Greece, and Portugal between 1997 and 2017.

Background and aims The recent economic crisis started in the USA in 2008 but quickly had worldwide impact. Ireland, Greece, and Portugal were in economic distress in 2009 and received rescue monetary packages from the European Union (EU) and the International Monetary Fund (IMF) in the following years. Meanwhile, the economic recovery has begun for those countries, but at different paces. The aim of the present study was to evaluate if the economic crisis influenced pain research outcomes, by performing a bibliometric analysis based on the ISI Web of Science to evaluate the evolution of the scientific production and performance in the field of pain research between 1997 and 2017. Methods Articles search was conducted using the ISI Web of Science, search keywords "pain or nocicep*", between 1997 and 2017, and one author affiliated in an Irish, Greek or Portuguese institution. The total number of published articles per country, total citations, h-index, document types and authors' institution were tabulated to determine the quantity and quality of the publications in this field. Results The search retrieved 2,368 publications over the 20 years' period, increasing from 26 in 1997 to 230 in 2017. The number of Irish publications per year increased steadily along the studied period, while the number of Greek publications stabilized from 2008 onward and Portuguese publications started to increase only in 2007 but declined slightly after 2014. In total, Irish authors published 1,143 articles, Greek authors 624 and Portuguese authors 618. There were nine articles with more than 100 citations, and Irish publications had a higher h-index (52) than Greek's (45) or Portuguese's (36) publications. Ireland had the highest number of pain publications per capita, but in 2016 Portugal had the lowest cost per publication, as measured by the GDP per capita per publication (in 1997 Portugal had the highest cost). The three major research fields of the publications were neurosciences/neurology (19%), general internal medicine (16%) and anaesthesiology (13%), and the affiliation institutions were mostly universities or universities hospitals. Conclusions The number of Irish, Greek, and Portuguese pain publications increased between 1997 and 2017, but at different paces. It appears that the economic crisis had no impact on the rate of pain publications in Ireland, had a delayed impact in Portugal, and affected mostly Greek pain scientific research. This may be related to the fact that Greece was the country that received more rescue packages and where the economic crisis was deepest and lasted longer. Implications Economics and scientific production have a mutual influence: usually research investment decreases in recession times (reducing grants and scientific employment), but health scientific production can improve health and quality of life and also benefit the economy. So in crisis periods, governments should create means to protect and foster scientific work.

Glial activation in the collagenase model of nociception associated with osteoarthritis.

Background Experimental osteoarthritis entails neuropathic-like changes in dorsal root ganglia (DRG) neurons. Since glial activation has emerged as a key player in nociception, being reported in numerous models of neuropathic pain, we aimed at evaluating if glial cell activation may also occur in the DRG and spinal cord of rats with osteoarthritis induced by intra-articular injection of collagenase. Methods Osteoarthritis was induced by two injections, separated by three days, of 500 U of type II collagenase into the knee joint of rats. Movement-induced nociception was evaluated by the Knee-Bend and CatWalk tests during the following six weeks. Glial fibrillary acidic protein (GFAP) expression in satellite glial cells of the DRG was assessed by immunofluorescence and Western Blot analysis; the pattern of GFAP and activating transcription factor-3 (ATF-3) expression was also compared through double immunofluorescence analysis. GFAP expression in astrocytes and IBA-1 expression in microglia of the L3-L5 spinal cord segments was assessed by immunohistochemistry and Western Blot analysis. The effect of the intrathecal administration of fluorocitrate, an inhibitor of glial activation, on movement-induced nociception was evaluated six weeks after the first collagenase injection. Results GFAP expression in satellite glial cells of collagenase-injected animals was significantly increased six weeks after osteoarthritis induction. Double immunofluorescence showed GFAP upregulation in satellite glial cells surrounding ATF-3-positive neurons. In the spinal cord of collagenase-injected animals, an ipsilateral upregulation of GFAP and IBA-1 was also observed. The inhibition of glial activation with fluorocitrate decreased movement- and loading-induced nociception. Conclusion Collagenase-induced knee osteoarthritis leads to the development of nociception associated with movement of the affected joint and to the activation of glial cells in both the DRG and the spinal cord. Inhibition of glial cell activation by fluorocitrate decreases these osteoarthritis-associated nociceptive behaviours. These results suggest that glial cell activation may play a role in the development of chronic pain in this experimental model of osteoarthritis.

Chemotherapy-induced peripheral neuropathy after neoadjuvant or adjuvant treatment of breast cancer: a prospective cohort study.

PURPOSE: The purposes of this study were to estimate the incidence of chemotherapy-induced peripheral neuropathy (CIPN) and to identify its main determinants and impact in patient-reported outcomes. METHODS: We performed a prospective cohort study including 296 patients with incident breast cancer submitted to chemotherapy, followed for 1 year. Patients with incident CIPN were reevaluated 6 months after this diagnosis. Relative risks (RR) with 95 % confidence intervals (95 % CI) were computed to quantify the relation between different clinical characteristics and the occurrence of CIPN, using Poisson regression. The variation of patient-reported outcomes between baseline and 1-year follow-up assessments was compared between patients with and without CIPN. RESULTS: The cumulative incidence of CIPN in the first year after diagnosis was 28.7 % (95 % CI 23.8-34.1), and more than 80 % of the patients were still symptomatic after 6 months. Among the latter, there was a significant decrease in the median total neuropathy score, clinical version (7 versus 4) between the two periods. In multivariable analysis, the risk of CIPN was higher for treatment with docetaxel (cumulative doses ≤300 mg/m(2), RR = 6.96, 95 % CI 2.53-19.10; >300 mg/m(2), RR = 13.32; 95 % CI 4.11-43.14). Alcohol consumption and diabetes were not significantly associated with CIPN. There were no significant differences in the variation of patient-reported outcomes between the baseline and 1-year follow-up evaluations. CONCLUSIONS: CIPN was frequent in this contemporary cohort of early-stage breast cancer patients and was strongly associated with docetaxel-based regimens. Symptoms persisted for at least 6 months in most patients, but severity was low and CIPN had no impact on patient-reported outcomes.

The economic impact of chronic pain: a nationwide population-based cost-of-illness study in Portugal.

In addition to its high frequency and relevant individual and social impact, chronic pain (CP) has been shown to be a major contributor to increased healthcare utilisation, reduced labour productivity, and consequently large direct and indirect costs. In the context of a larger nationwide study, we aimed to assess the total annual direct and indirect costs associated with CP in Portugal. A population-based study was conducted in a representative sample of the Portuguese adult population. The 5,094 participants were selected using random digit dialling and contacted by computer-assisted telephone interviews. Questionnaires included the brief pain inventory and pain disability index. Estimates were adequately weighted for the population. From all CP subjects identified, a subsample (n = 562) accepted to participate in this economic study. Mean total annualised costs per CP subject of €1,883.30 were observed, amounting to €4,611.69 million nationally, with 42.7% direct and 57.3% indirect costs, and corresponding to 2.71% of the Portuguese annual GDP in 2010. Only socio-demographic variables were significantly and independently associated with CP costs, and not CP severity, raising the possibility of existing inequalities in the distribution of healthcare in Portugal. The high economic impact of CP in Portugal was comprehensively demonstrated. Given the high indirect costs observed, restricting healthcare services is not a rational response to these high societal costs; instead improving the quality of CP prevention and management is recommended.

Intra-articular injection of collagenase in the knee of rats as an alternative model to study nociception associated with osteoarthritis.

INTRODUCTION: Animal models currently used in osteoarthritis-associated pain research inadequately reproduce the initiating events and structural pathology of human osteoarthritis. Conversely, intra-articular injection of collagenase is a structurally relevant model, as it induces articular degeneration both by digesting collagen from cartilage and by causing articular instability, thereby reproducing some of the main events associated with osteoarthritis onset and development. Here, we evaluated if the intra-articular injection of collagenase can be an alternative model to study nociception associated with osteoarthritis. METHODS: Osteoarthritis was induced by two intra-articular injections of either 250 U or 500 U of collagenase into the left knee joint of adult male Wistar rats. A six weeks time-course assessment of movement- and loading-induced nociception was performed by the Knee-Bend and CatWalk tests. The effect of morphine, lidocaine and diclofenac on nociceptive behaviour was evaluated in animals injected with 500 U of collagenase. Joint histopathology was scored for both doses throughout time. The expression of transient receptor potential vanilloid 1 (TRPV1) in ipsilateral dorsal root ganglia (DRG) was evaluated. RESULTS: An increase in nociceptive behaviour associated with movement and loading of affected joints was observed after intra-articular collagenase injection. With the 500 U dose of collagenase, there was a significant correlation between the behavioural and the histopathological osteoarthritis-like structural changes developed after six weeks. One week after injection of 500 U collagenase, swelling of the injected knee and inflammation of the synovial membrane were also observed, indicating the occurrence of an early inflammatory reaction. Behavioural changes induced by the 500 U dose of collagenase were overall effectively reversed by morphine and lidocaine. Diclofenac was effective one week after injection. TRPV1 expression increased six weeks after 500 U collagenase injection. CONCLUSION: We conclude that the intra-articular injection of 500 U collagenase in the knee of rats can be an alternative model for the study of nociception associated with osteoarthritis, since it induces significant nociceptive alterations associated with relevant osteoarthritis-like joint structural changes.

Chronic pain and health services utilization: is there overuse of diagnostic tests and inequalities in nonpharmacologic treatment methods utilization?

BACKGROUND: Few studies have described patterns and determinants of health services utilization (HSU) in chronic pain (CP) subjects. We aimed to describe these, in particular, regarding medical consultations (MCs), diagnostic tests (DTs), pain medicines (PMs) and nonpharmacologic treatment methods (NTM) utilization. METHODS: A cross-sectional nationwide study was conducted in a representative sample of the Portuguese population. The 5094 participants were selected using random digit dialling and were contacted by computer-assisted telephone interviews. Questionnaires included the brief pain inventory and pain disability index. Estimates were adequately weighted for the population. RESULTS: Prevalence of CP and CP with moderate to severe disability was 36.7% and 10.8%, respectively. Most CP subjects were being managed/treated by health professionals (81%) and had high levels of HSU. More than half of them had used imaging DT in the previous 6 months. Main factors associated with HSU were as follows: pain-related disability, intensity, duration, and depressive symptoms for MC utilization; sex, pain-related disability, and duration for PM utilization; and education level and depression diagnosis for NTM utilization. CONCLUSIONS: The main drivers behind HSU are pain severity, psychological distress, and socio-economic determinants. An important set of benchmarks are presented regarding HSU in CP subjects, comprising useful tools for public health policy and decision-making. Results presented may suggest possible inequalities in the access to NTM, and interventions to improve access are encouraged. Moreover, possible indirect evidence of imaging DT overuse is presented, and it is recommended that their use in CP subjects should more closely follow existing guidelines.

The challenges of pain management in primary care: a pan-European survey.

BACKGROUND: The OPENMinds Primary Care group is a group of European primary care physicians (PCPs) with an interest in pain management, formed to improve the understanding and management of chronic pain in primary care. OBJECTIVE: A survey was conducted to assess the challenges of chronic nonmalignant pain (CNMP) management in primary care in Europe, focusing particularly on pain assessment, opioid therapy, and educational needs. METHODS: A questionnaire was developed for online use by PCPs in 13 European countries (Belgium, Denmark, France, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the UK). RESULTS: A total of 1309 PCPs completed the questionnaire, approximately 100 from each country. Most PCPs (84%) perceived CNMP to be one of the most challenging conditions to treat, yet a low priority within healthcare systems. Only 48% of PCPs used pain assessment tools, and 81% considered chronic pain and its impact on quality of life to be underassessed in primary care. PCPs were less confident about prescribing strong opioids for CNMP than for use in cancer pain. Most PCPs (84%) considered their initial training on CNMP was not comprehensive, with 89% recognizing a need for more education on the topic. CONCLUSION: These findings reveal that PCPs in Europe find CNMP a challenge to treat. Areas to address with training include underuse of pain assessment tools and lack of confidence in use of opioid therapy. Guidelines on CNMP management in primary care would be welcomed. The insights gained should provide the basis for future initiatives to support primary care management of chronic pain.

Phenotypic alterations of neurons that innervate osteoarthritic joints in rats.

OBJECTIVE: Pain is a prominent feature of osteoarthritis (OA). To further understand the primary mechanisms of nociception in OA, we studied the expression of the phenotype markers calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), and neurofilament 200 (NF200) in sensory neurons innervating the OA knee joint in rats. METHODS: OA was induced in rats by intraarticular injection of 2 mg of mono-iodoacetate (MIA) into the knee. Neurons innervating the joint were identified by retrograde labeling with fluorogold in dorsal root ganglia (DRG) and colocalized with neurochemical markers by immunofluorescence. The total number of DRG cells was determined by stereologic methods in Nissl-stained sections. RESULTS: A 37% decrease in the number of fluorogold-backlabeled cells was observed in rats with OA when compared with control rats, even though no decrease in the total number of cells was observed. However, an increase in the number of medium/large cell bodies and a decrease in the number of the smallest cells were observed, suggesting the occurrence of perikarya hypertrophy. The percentage of CGRP-positive cells increased significantly, predominantly in medium/large cells, suggesting the occurrence of a phenotypic switch. Colocalization of CGRP and NF200 revealed no significant changes in the percentage of double-labeled cells, but an increase in the number of medium/large double-labeled cells was observed. No differences in the expression of either IB4 or NF200 were observed in fluorogold-backlabeled cells. CONCLUSION: These results indicate that MIA-induced OA causes an up-regulation of CGRP in different subpopulations of primary afferent neurons in DRG due to a phenotypic switch and/or cell hypertrophy which may be functionally relevant in terms of the onset of pain in this pathologic condition.

Assessment of movement-evoked pain in osteoarthritis by the knee-bend and CatWalk tests: a clinically relevant study.

UNLABELLED: Although there are several reports on pain behavioral tests in rat models of knee osteoarthritis (OA), most of them focus on the paw. The aim of this study was to investigate pain-related behaviors on the affected knee joint, the primary source of nociception, in animals with mono-iodoacetate-induced OA, using the knee-bend (which provides information on movement pain) and pin-prick tests, and to evaluate nociception elicited by walking using the CatWalk test. The von Frey and Randall-Selitto tests applied to the paw allowed us to compare our study results with previous studies. A further aim was to compare the behavioral nociceptive responses of the most used doses of mono-iodoacetate, 2 and 3 mg. Knee-bend score of OA animals was higher than those of control animals throughout the study (P < .05). At every time point, the ipsilateral hind-paw load of OA rats, as measured by the CatWalk test, was lower than that of control rats (P < .05), and paw withdraw threshold to von Frey filaments was also decreased (P < .01). No changes were observed in pin-prick and Randall-Selitto tests. Results obtained with the 2 doses of mono-iodoacetate were similar. The knee-bend and CatWalk tests are effective for evaluating movement-related nociception, a hallmark of clinical OA, which was present throughout the experimental period. PERSPECTIVE: Behavioral characterization of models of OA pain is important and useful for use in future studies to test pharmacological treatments. Furthermore, it is important to find methods that correlate better with the human symptoms of OA.

GABA(B2) receptor subunit mRNA decreases in the thalamus of monoarthritic animals.

Many studies have implicated GABA(B) receptors in pain transmission mechanisms, especially in the spinal cord. In the thalamus, mRNA expression of the GABA(B(1b)) isoform was shown to be regulated in relay nuclei in response to chronic noxious input arising from experimental monoarthritis. GABA(B(1a)) and GABA(B2) mRNA expression was here determined by in situ hybridisation in the brain of control, 2, 4, 7 and 14 days monoarthritic rats, to evaluate whether this expression was regulated by chronic noxious input in thalamic nuclei. mRNA labelling was analysed quantitatively in the ventrobasal complex, posterior, central medial/central lateral and reticular thalamic nuclei; the thalamic visual relay and dentate gyrus were examined for control. No mRNA expression was detected for GABA(B(1a)) in control and monoarthritic animals. Similarly, GABA(B2) mRNA was not found in the reticular nucleus. However, GABA(B2) mRNA expression was observed in the ventrobasal complex, posterior and central medial/central lateral nuclei of control animals. A significant decrease of 42% at 2 days and 27% at 4 days of monoarthritis was observed in the ventrobasal complex contralaterally, when compared with controls, returning to basal levels at 7 days of monoarthritis. In the ipsilateral posterior nucleus, there was a significant decrease of 38% at 2 days of monoarthritis. No significant changes were observed in central medial/central lateral nuclei. The data suggest that GABA(B2) mRNA expression in the ventrobasal complex and posterior nucleus is regulated by noxious input and that GABA(B) receptors might play a role in the plasticity of these relay nuclei during chronic inflammatory pain.

Differential expression of GABA(B(1b)) receptor mRNA in the thalamus of normal and monoarthritic animals.

GABA(B) receptors have been implicated in the plastic changes occurring in the spinal cord during the development of chronic inflammatory pain. In this study, we evaluated whether the expression of GABA(B(1b)) receptor mRNA is regulated supraspinally, namely in the thalamus, as part of the response to chronically enhanced noxious input arising from experimental monoarthritis (MA). In situ hybridization with [(35)S]-labelled oligonucleotide probes was performed in sections of control, 2, 4, 7 and 14 days MA rats' brains (n = 6/group). The distribution of GABA(B(1b)) mRNA was determined bilaterally in the ventrobasal complex (VB), posterior (Po), centromedial/centrolateral (CM/CL) and reticular (Rt) thalamic nuclei. The amount of GABA(B(1b)) mRNA was expressed as times fold of background values. In normal animals, values of mRNA expression were very similar in VB, Po and CM/CL, ranging from 2.2 +/- 0.2 to 2.7 +/- 0.4 (mean +/- S.E.M.) times higher than background levels. No expression of GABA(B(1b)) mRNA was found in the Rt of control or MA animals. A significant decrease of 26% at 4 days, and 37% at 7 days of MA, was observed in the VB contralateral to the affected joint. On the contrary, in the Po there was a significant bilateral increase at 2 days (38% contralaterally, 25% ipsilaterally), returning to basal levels at 4 days MA. No significant changes were observed in CM/CL. These results suggest that the expression of GABA(B(1b)) in the VB and Po is regulated by noxious input, and might contribute to the functional changes that occur in the thalamus during chronic inflammatory pain.

Effects of Kelatorphan and morphine before and after noxious stimulation on immediate-early gene expression in rat spinal cord neurons.

Expression of the immediate-early genes (IEG) c-FOS, NGF1-A and c-JUN was induced by noxious thermal stimulation in neurons of the rat spinal cord dorsal horn. Intravenous injection of Kelatorphan (5, 10 and 20 mg/kg), an inhibitor of multiple enkephalin-degrading enzymes, 20 min before noxious stimulation reduced the overall number of dorsal horn neurons expressing c-FOS and NGF1-A by up to 20-30%. While c-FOS expression was suppressed in superficial and deep laminae of the spinal cord, NGF1-A and c-JUN was only suppressed in superficial laminae. Morphine (5, 7.5 and 10 mg/kg) produced a dose-dependent reduction of c-FOS expression by up to 70% only when injected before noxious stimulation. Morphine injected 10 min after the noxious treatment was virtually ineffective. The depressant effect of Kelatorphan and morphine could be prevented by prior application of the opioid antagonist naloxone. Naloxone itself slightly increased the overall number of c-FOS-positive neurons in all laminae of the spinal cord. The present data support the existence of a tonic release of endogenous opioid peptides at the spinal level and show that inhibition of their peptidase-induced degradation modulates IEG expression in dorsal horn neurons of the rat. The finding that opioid agonists were ineffective when applied after stimulation underline the necessity of pre-emptive analgesia to prevent long-term activity-dependent changes in spinal cord neurons.