Accepted

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Structural approaches to promoting health focus on policies and practices affecting health at the community level and concentrate on systems and forces of society, including distribution of power, that foster disadvantage and diminish health and well-being. In this paper we advocate consideration of structural approaches to explore macro level influences on the burden of persistent pain on society. We argue that health promotion is an appropriate discipline to ameliorate painogenic environments and that a "settings approach" offers a crucial vehicle to do this. We encourage consideration of socio-ecological frameworks to explore factors affecting human development at individual, interpersonal, organizational, societal, and environmental levels because persistent pain is multifaceted and complex and unlikely to be understood from a single level of analysis. We acknowledge criticisms that the structural approach may appear unachievable due to its heavy reliance on inter-sectoral collaboration. We argue that a settings approach may offer solutions because it straddles "practical" and cross-sectorial forces impacting on the health of people. A healthy settings approach invests in social systems where health is not the primary remit and utilises synergistic action between settings to promote greater health gains. We offer the example of obesogenic environments being a useful concept to develop strategies to tackle childhood obesity in school-settings, community-settings, shops, and sports clubs; and that this settings approach has been more effective than one organisation tackling the issue in isolation. We argue that a settings approach should prove useful for understanding painogenic environments and tackling the burden of persistent pain.

People living with opioid use disorder and those experiencing other types of substance misuse are part of a public health crisis in the United States. Rates of opioid misuse, overdose, and opioid-related deaths within different subpopulations show where prevention efforts must focus. Through concerted efforts, aligned with common goals, a statewide community-based educational organization (Michigan State University Extension) has demonstrated ability to acquire multi-year funding from varied sources of state and federal funds that has produced robust support for statewide projects and collaborations. Researchers, educators, public health program managers, and other practitioners can benefit from learning how three funded initiatives in one state resulted in improved awareness and access for individuals and healthcare organizations. By sharing our implementation of health educational programs and presentations, other states' can adopt these evidence-based strategies for similar outreach. Cooperative Extension in Michigan delivers program series and one-time education to the public on the self-management of chronic conditions and pain, mindfulness for stress reduction, anger management, and opioid misuse prevention, treatment, and recovery. These evidence- and research-based health programs implemented by Extension staff teach participants common aspects of prevention such as self-management care, communication skills, self-efficacy, and goal setting or personal health action plans. Education aims to reduce dependency on opioids, prevent opioid misuse and share non-pharmacological solutions to pain management for those living with chronic conditions or at risk for developing dependence. The funded initiatives targeted rural residents, older adults, health care providers, and people living with chronic pain who may have access to prescription opioids. In addition to direct education, projects supported local communities with the development of coalitions, including the training of community partners to become program facilitators thereby increasing community capacity for prevention programs, and through the creation of patient referrals from healthcare settings to community-based education. In rural areas, Cooperative Extension plays a crucial role in connecting community resources to address healthy aging, and chronic disease or chronic pain self-management education. Community partners engaged in public health education and promotion, and healthcare providers alike may not be aware that Cooperative Extension plays a vital role in providing community-based health education.

Opioid tolerance, opioid-induced hyperalgesia during repeated opioid administration, and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static (15 mg/kg, 5 days) or an escalating tolerance paradigm (10-40 mg/kg, 4 days). Systemic treatment with an AC1 inhibitor, ST03437 (2.5-10 mg/kg, IP), reduced morphine-induced hyperalgesia in mice. Lumbar intrathecal administration of a viral vector incorporating a short-hairpin RNA targeting reduced morphine-induced hypersensitivity compared to control mice. In contrast, acute morphine antinociception, along with thermal paw withdrawal latencies, motor performance, exploration in an open field test, and burrowing behaviors were not affected by intrathecal knockdown. Knockdown of by intrathecal injection also decreased inflammatory mechanical hyperalgesia and increased burrowing and nesting activity after intraplantar administration of Complete Freund's Adjuvant (CFA) one-week post-injection.