The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyperalgesia rather than hypoalgesia during or immediately after receiving a conditioning stimulus. We observed that mice undergoing tonic inflammatory pain in the abdominal cavity (the conditioning stimulus) display hyperalgesia, not hypoalgesia, to noxious thermal stimulation (the test stimulus) applied to the hindpaw. In a series of parametric studies, we show that this hyperalgesia can be reliably observed using multiple conditioning stimuli (acetic acid and orofacial formalin), test stimuli (hindpaw and forepaw-withdrawal, tail-withdrawal, hot-plate, and von Frey tests) and genotypes (CD-1, DBA/2, and C57BL/6 mice and Sprague-Dawley rats). Although the magnitude of the hyperalgesia is dependent on the intensity of the conditioning stimulus, we find that the direction of effect is dependent on the effective test stimulus intensity, with lower-intensity stimuli leading to hyperalgesia and higher-intensity stimuli leading to hypoalgesia.

Background: Chronic pain has been shown to depend on nociceptive sensitization in the spinal cord, and while multiple mechanisms involved in the initiation of plastic changes have been established, the molecular targets which maintain spinal nociceptive sensitization are still largely unknown. Building upon the established neurobiology underlying the maintenance of long-term potentiation in the hippocampus, this present study investigated the contributions of spinal atypical protein kinase C (PKC) isoforms PKCi/k and PKMf and their downstream targets (p62/GluA1 and NSF/GluA2 interactions, respectively) to the maintenance of spinal nociceptive sensitization in male and female rats. Results: Pharmacological inhibition of atypical PKCs by ZIP reversed established allodynia produced by repeated intramuscular acidic saline injections in male animals only, replicating previously demonstrated sex differences. Inhibition of both PKCi/k and downstream substrates p62/GluA1 resulted in male-specific reversals of intramuscular acidic saline-induced allodynia, while female animals continued to display allodynia. Inhibition of NSF/GluA2, the downstream target to PKMf, reversed allodynia induced by intramuscular acidic saline in both sexes. Neither PKCi/k, p62/GluA1 or NSF/GluA2 inhibition had any effect on formalin response for either sex. Conclusion: This study provides novel behavioural evidence for the male-specific role of PKCi/k and downstream target p62/GluA1, highlighting the potential influence of ongoing afferent input. The sexually divergent pathways underlying persistent pain are shown here to converge at the interaction between NSF and the GluA2 subunit of the AMPA receptor. Although this interaction is thought to be downstream of PKMf in males, these findings and previous work suggest that females may rely on a factor independent of atypical PKCs for the maintenance of spinal nociceptive sensitization.

Background Chronic pain is a common public health problem with negative consequences for individuals and societies. Fortunately, interdisciplinary chronic pain management has been shown to be effective for improving patients’ outcomes and strongly recommended in clinical practice guidelines. Appropriate referral within the healthcare system based on individuals’ needs and available services is essential to optimise health-related outcomes and maximise resources. Clinical decision support systems have been shown to be effective for supporting healthcare professionals in different practices. However, there is no knowledge synthesis on clinical decision support systems for referral within chronic pain practice. We aim to identify the clinical decision support systems for referral within chronic pain practices and assess their content, effectiveness, harms, and validation parameters. Methods Using the methodology of Cochrane reviews, we will perform a systematic review and meta-analysis based on studies meeting the following criteria: Population, patients with chronic pain and/or healthcare professionals working in chronic pain; Intervention, clinical decision support systems for referral within chronic pain practice; Comparison, any other clinical tool, any usual care or practices; Outcomes, clinical outcomes of patients measuring how patients feel, function or survive including benefits, adverse effects, continuity of care, care appropriateness, care satisfaction, quality of life, healthcare professional performance, and cost outcomes; and Study design: randomized controlled trials, non-randomized controlled trials, before and after controlled studies and interrupted time series. We will search relevant literature with the support of an information specialist using Medline, Embase, PsycInfo, CINHAL, Web of Science and Cochrane Library from their inception onwards. Two reviewers will independently complete study selection, data extraction and risk of bias assessment. We will analyse data to perform both narrative syntheses and meta-analysis if appropriate. Discussion Findings of this review will contribute to enhancing chronic pain care and research. Clinical decision support systems identified as effective in this review can be investigated for implementation in clinical practice and impact on improving patient, clinical and health system outcomes. Clinical decision support systems not yet ready for implementation that require further improvement will also be identified. Systematic review registration PROSPERO registration: CRD42020158880.

IntroductionLinkages between health systems and communities may leverage community assets to address unmet needs and provide services for improved continuity and coordination of care. However, there are limited examples of specific strategies for such linkages for chronic disease management. Guided by a local need from stakeholders, this scoping review aims to clarify and map methods and strategies for linkages between communities and health systems across chronic diseases, to inform future implementation efforts.Methods and analysisThe scoping review will be conducted following Arksey and O’Malley’s methodological framework and latest Joanna Briggs Institute (JBI) guidelines, with continuous stakeholder engagement throughout. A structured literature search of records from January 2001 to April 2022 will be completed in MEDLINE/PubMed, CINAHL, EMBASE, PsycINFO, in addition to grey literature. Two reviewers will independently complete study selection following inclusion criteria reflecting population (chronic disease), concept (integrated care) and context (health systems and communities) and will chart the data. Data will be analysed using descriptive qualitative and quantitative methods, to map and operationalise the linkages between health systems and communities.Ethics and disseminationThe scoping review does not require ethics approval as it will examine and collect data from publicly available materials, and all stakeholder engagement will follow guidelines for patient and public involvement. Findings will be reported through a summarising list of considerations for different linkage strategies between health systems and community resources and implications for future research, practice and policy will be discussed and presented. The results will also be used to inform an integrated knowledge translation project to implement community-health system linkages to support chronic pain management.Registration number10.17605/OSF.IO/UTSN9.