Stakeholder-driven transformative adaptation is needed for climate-smart nutrition security in sub-Saharan Africa.

Improving nutrition security in sub-Saharan Africa under increasing climate risks and population growth requires a strong and contextualized evidence base. Yet, to date, few studies have assessed climate-smart agriculture and nutrition security simultaneously. Here we use an integrated assessment framework (iFEED) to explore stakeholder-driven scenarios of food system transformation towards climate-smart nutrition security in Malawi, South Africa, Tanzania and Zambia. iFEED translates climate-food-emissions modelling into policy-relevant information using model output implication statements. Results show that diversifying agricultural production towards more micronutrient-rich foods is necessary to achieve an adequate population-level nutrient supply by mid-century. Agricultural areas must expand unless unprecedented rapid yield improvements are achieved. While these transformations are challenging to accomplish and often associated with increased greenhouse gas emissions, the alternative for a nutrition-secure future is to rely increasingly on imports, which would outsource emissions and be economically and politically challenging given the large import increases required.

In-Field Rainwater Harvesting Tillage in Semi-Arid Ecosystems: I Maize-Bean Intercrop Performance and Productivity.

The purpose of this study was to monitor and compare the growth and productivity of maize/beans sole and inter-cropping systems under conventional (CON) and in-field rainwater harvesting (IRWH) tillage practices. During the typical drought conditions of the 2018/19 growing season, seven homestead gardens of smallholder farmers (four in Paradys and three in Morago villages) in the Thaba Nchu rural communities of South Africa were selected for on-farm demonstration trials. Two tillage systems CON and IRWH as the main plot and three cropping systems as sub-treatment (sole maize and beans and intercropping) were used to measure crop growth and productivity parameters. The results showed that IRWH tillage had significantly higher above-ground dry matter for both sole maize (29%) and intercropped maize (27%) compared to CON treatments. The grain yield under both tillage systems showed that IRWH-Sole >> IRWH-Ic >> CON-Sole >> CON-Ic, with values ranging from 878.2 kg ha-1 to 618 kg ha-1 (p ≤ 0.05). The low harvest index values (0.21-0.38) could have been due to the effect of the drought during the growing season. The results of precipitation use efficiency (PUE) showed that the IRWH tillage was more effective at converting rainwater into maize biomass and grain yield compared to CON tillage. However, the different cropping systems did not show a consistent trend in PUE. During the growing season, the PUE for AGDM varied for different tillage and cropping system treatments in Morago and Paradys. For maize, it ranged between 10.01-6.07 and 9.93-7.67 kg ha-1, while for beans, it ranged between 7.36-3.95 and 7.07-3.89 kg ha-1 mm-1. The PUE for grain yield showed similar trends with the significantly highest values of PUE under IRWH tillage systems for the Morago sites, but there were no significant differences at the Paradys site in both tillage and cropping systems. There is a critical need, therefore, to devise alternative techniques to promote an increase in smallholders' productivity based on an improved ability to capture and use resources more efficiently.

In-Field Rainwater Harvesting Tillage in Semi-Arid Ecosystems: II Maize-Bean Intercrop Water and Radiation Use Efficiency.

The purpose of this study was to evaluate alternative management practices such as in-field rainwater harvesting (IRWH) and intercropping techniques through conducting on-farm demonstrations. Seven homestead gardens in Thaba Nchu rural communities in the central part of South Africa were selected as demonstration trials. Two tillage systems, conventional (CON) and IRWH, as the main plot, and three cropping systems as sub-plot (sole maize and beans and intercropping) were used to measure water use and radiation use parameters. The water productivity (WP) of various treatments was positively related to the radiation use efficiency (RUE), and the degree of associations varied for different tillage systems. The water use in IRWH was higher by 15.1%, 8.3%, and 10.1% over the CON for sole maize and beans and intercropping, respectively. Similarly, the intercropping system showed water use advantages over the solely growing crops by 5% and 8% for maize and by 16% and 12% for beans under IRWH and CON tillage, respectively. Maximum RUE was found for sole maize and beans under IRWH, higher by 13% and 55% compared to the CON tillage, respectively. The RUE under IRWH tillage was estimated to be 0.65 and 0.39 g DM MJ-1 in sole maize and intercropping, respectively. However, in sole and intercropped beans, the RUE showed higher values of 1.02 g DM MJ-1 and 0.73 g DM MJ-1, respectively. WP and RUE were associated with water deficits and proportional to lower radiation use. This relationship indicates that the intercepted radiation by plants for photosynthesis is directly related to the transpiration rate until radiation saturation occurs. Therefore, the higher water deficit and lesser efficiency in using the radiation available during the season can be improved by practicing IRWH techniques. Furthermore, in semi-arid areas, to enhance the efficiency of water and radiation usage in intercropping management, it is crucial to adjust plant population and sowing dates based on water availability and the onset of rainfall.

Agro-climatic sensitivity analysis for sustainable crop diversification; the case of Proso millet (Panicum miliaceum L.).

Current agricultural production depends on very limited species grown as monocultures that are highly vulnerable to climate change, presenting a threat to the sustainability of agri-food systems. However, many hundreds of neglected crop species have the potential to cater to the challenges of climate change by means of resilience to adverse climate conditions. Proso millet (Panicum miliaceum L.), one of the underutilised minor millets grown as a rainfed subsistence crop, was selected in this study as an exemplary climate-resilient crop. Using a previously calibrated version of the Agricultural Production Systems Simulator (APSIM), the sensitivity of the crop to changes in temperature and precipitation was studied using the protocol of the Coordinated Climate Crop Modelling Project (C3MP). The future (2040-2069) production was simulated using bias-corrected climate data from 20 general circulation models of the Coupled Model Intercomparison Project (CMIP5) under RCP4.5 and 8.5 scenarios. According to the C3MP analysis, we found a 1°C increment of temperature decreased the yield by 5-10% at zero rainfall change. However, Proso millet yields increased by 5% within a restricted climate change space of up to 2°C of warming with increased rainfall. Simulated future climate yields were lower than the simulated yields under the baseline climate of the 1980-2009 period (mean 1707 kg ha-1) under both RCP4.5 (-7.3%) and RCP8.5 (-16.6%) though these changes were not significantly (p > 0.05) different from the baseline yields. Proso millet is currently cultivated in limited areas of Sri Lanka, but our yield mapping shows the potential for expansion of the crop to new areas under both current and future climates. The results of the study, indicating minor impacts from projected climate change, reveal that Proso millet is an excellent candidate for low-input farming systems under changing climate. More generally, through this study, a framework that can be used to assess the climate sensitivity of underutilized crops was also developed.

Capturing epistemic reflexivity for teacher educators teaching about/to/for diversity in teacher education.

Internationally, there is a growing body of evidence which shows that newly graduated teachers do not feel prepared to teach the increasingly diverse student body in contemporary classrooms. However, to date, we have limited understanding of the ways in which teacher educators work with preservice teachers to enhance their knowledge about diversity and how to address the diverse needs of students in their classrooms. To further understand teacher educators' pedagogical decision making in the context of preparing preservice teachers for diverse classrooms, a way of capturing epistemic thinking in this space is required. The current study used the Epistemic Reflexivity Survey for Teacher Educators (ERS-TE) to explore the relationships between teacher educators' Epistemic Aims, Reliable epistemic processes (REPs), Criteria for Knowledge (Epistemic Ideals), Reflexivity (decision making) and Teaching Practices. Two hundred and eighty-six teacher educators across Australia and New Zealand completed the survey. Results indicated that epistemic aims related to understanding critical connections predicted engagement with reliable epistemic thinking processes, reflexivity, and teaching practices related to critical thinking and social justice. Findings are discussed in terms of implications for teacher educators' work with preservice teachers with respect to teaching about, to and for diversity.

Setting Preconception Care Priorities in Australia Using a Delphi Technique.

Preconception health affects fertility, pregnancy, and future health outcomes but public awareness of this is low. Our aims were to rank priorities for preconception care (PCC), develop strategies to address these priorities, and establish values to guide future work in preconception healthcare in Australia. A Delphi technique involved two rounds of online voting and mid-round workshops. Inputs were a scoping review of PCC guidelines, a priority setting framework and existing networks that focus on health. During July and August, 2021, 23 multidisciplinary experts in PCC or social care, including a consumer advocate, completed the Delphi technique. Ten priority areas were identified, with health behaviors, medical history, weight, and reproductive health ranked most highly. Six strategies were identified. Underpinning values encompassed engagement with stakeholders, a life course view of preconception health, an integrated multi-sectorial approach and a need for large scale collaboration to implement interventions that deliver impact across health care, social care, policy and population health. Priority populations were considered within the social determinants of health. Health behaviors, medical history, weight, and reproductive health were ranked highly as PCC priorities. Key strategies to address priorities should be implemented with consideration of values that improve the preconception health of all Australians.

A qualitative investigation into clinical documentation: why do clinicians document the way they do?

BACKGROUND: Clinical documentation is a fundamental component of patient care. The transition from paper based to electronic medical records/electronic health records has highlighted a number of issues associated with documentation practices including duplication. Developing new ways to document the care provided to patients and in turn, persuading clinicians to accept a change, must be supported by evidence that a change is required. In Australia, there has been a limited number of studies exploring the clinical documentation practices and beliefs of clinicians. OBJECTIVE: To gain an in-depth understanding of clinician documentation practices. METHOD: A qualitative design using semi-structured interviews with clinicians (allied health professionals, doctors (physicians) and nurses) working in a tertiary-level hospital in South-East Queensland, Australia. RESULTS: Several themes emerged from the data: environmental factors, including departmental policy and systemic issues, and personal factors, including verification, clinical reasoning and experience influencing documentation practices. CONCLUSION: Our study identified that the documentation practices of clinicians are complex, being driven by both environmental and systemic factors and personal factors. This in turn leads to duplication and some redundancy. The documentation burden of duplication could be reduced by changes in policy, supported by multidisciplinary documentation procedures and electronic systems aligned with clinician workflows, while retaining some flexible documentation practices. The documentation practices of individuals, when considered from the perspective of enhancing quality care, are considered legitimate and therefore will continue to form part of the health (medical) record regardless of the format.

Circulating trace elements for the prediction of preeclampsia and small for gestational age babies.

INTRODUCTION: Poor gestational outcomes due to placental insufficiency can have lifelong consequences for mother and child. OBJECTIVE: There is a need for better methods of diagnosis, and elemental metabolomics may provide a means to determine the risk of gestational disorders. METHODS: This study used blood plasma samples collected at 36 weeks' gestation from women who later developed preeclampsia (n = 38), or small-for-gestational age babies (n = 91), along with matched controls (n = 193). Multi-element analysis was conducted by inductively coupled plasma mass spectrometer (ICP-MS), allowing simultaneous measurement of 28 elements. RESULTS: Women who later developed PE, exhibited significantly increased concentrations of K, Rb and Ba. For SGA pregnancies, there was a significant increase in Cu and a decrease in As concentrations. Despite significant differences in single elements, the elemental profile of groups indicated no clustering of control, PE, or SGA samples. Positive predicative values correctly identified approximately 60% of SGA and 70% of PE samples. CONCLUSION: This is the first-time elemental metabolomics has been used to predict SGA and PE at 36 weeks. Though significant changes were identified, routine clinical use may be limited but may contribute to a multi marker test. Future analysis should include other biomarkers, metabolic data or clinical measurements made throughout gestation.

Emergent Literacy Assessment in Children With Autism Spectrum Disorder Who Have Limited Verbal Communication Skills: A Tutorial.

Purpose Children with autism spectrum disorder (ASD) are at increased risk of experiencing difficulties with the development of literacy, including the emergent literacy skills recognized to underpin conventional literacy success. Comprehensive assessment is essential. Characteristics of ASD can make assessment challenging, and this can be compounded when children are unable to demonstrate their skills using spoken language. The purpose of this clinical tutorial is to outline the process of emergent literacy assessment for children with ASD who have limited verbal communication skills. A case example of a 5-year-old boy is presented. Method Pertinent literature is reviewed around the literacy profiles of children with ASD, the subgroup of children with ASD who have limited verbal communication skills, key components of emergent literacy, and previous research examining the emergent literacy abilities of children with ASD. The case report is described in depth and emphasizes the key factors to consider when designing an assessment battery and protocol. Results The case example information is interpreted, and its application is discussed. Key outcomes are highlighted including a greater understanding of the child's literacy strengths and needs and the implications for individualized instruction. Conclusion The clinical tutorial highlights the need for a comprehensive, well-planned assessment approach that involves all members of the educational team, and that is considerate to the needs of the individual child and responsive to their communication needs.

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

ErbB1-dependent signalling and vesicular trafficking in primary afferent nociceptors associated with hypersensitivity in neuropathic pain.

Effective analgesic treatment for neuropathic pain remains an unmet need, so previous evidence that epidermal growth factor receptor inhibitors (EGFRIs) provide unexpected rapid pain relief in a clinical setting points to a novel therapeutic opportunity. The present study utilises rodent models to address the cellular and molecular basis for the findings, focusing on primary sensory neurons because clinical pain relief is provided not only by small molecule EGFRIs, but also by the anti-EGFR antibodies cetuximab and panitumumab, which are unlikely to access the central nervous system in therapeutic concentrations. We report robust, rapid and dose-dependent analgesic effects of EGFRIs in two neuropathic pain models, matched by evidence with highly selective antibodies that expression of the EGFR (ErbB1 protein) is limited to small nociceptive afferent neurons. As other ErbB family members can heterodimerise with ErbB1, we investigated their distribution, showing consistent co-expression of ErbB2 but not ErbB3 or ErbB4, with ErbB1 in cell bodies of nociceptors, as well as providing evidence for direct molecular interaction of ErbB1 with ErbB2 in situ. Co-administration of selective ErbB1 and ErbB2 inhibitors produced clear evidence of greater-than-additive, synergistic analgesia; highlighting the prospect of a unique new combination therapy in which enhanced efficacy could be accompanied by minimisation of side-effects. Peripheral (intraplantar) administration of EGF elicited hypersensitivity only following nerve injury and this was reversed by local co-administration of selective inhibitors of either ErbB1 or ErbB2. Investigating how ErbB1 is activated in neuropathic pain, we found evidence for a role of Src tyrosine kinase, which can be activated by signals from inflammatory mediators, chemokines and cytokines during neuroinflammation. Considering downstream consequences of ErbB1 activation in neuropathic pain, we found direct recruitment to ErbB1 of an adapter for PI 3-kinase and Akt signalling together with clear Akt activation and robust analgesia from selective Akt inhibitors. The known Akt target and regulator of vesicular trafficking, AS160 was strongly phosphorylated at a perinuclear location during neuropathic pain in an ErbB1-, ErbB2- and Akt-dependent manner, corresponding to clustering and translocation of an AS160-partner, the vesicular chaperone, LRP1. Exploring whether neuronal ion channels that could contribute to hyperexcitability might be transported by this vesicular trafficking pathway we were able to identify Nav1.9, (Nav1.8) and Cav1.2 moving towards the plasma membrane or into proximal axonal locations - a process prevented by ErbB1 or Akt inhibitors. Overall these findings newly reveal both upstream and downstream signals to explain how ErbB1 can act as a signalling hub in neuropathic pain models and identify the trafficking of key ion channels to neuronal subcellular locations likely to contribute to hyperexcitability. The new concept of combined treatment with ErbB1 plus ErbB2 blockers is mechanistically validated as a promising strategy for the relief of neuropathic pain.

Prolonged Analgesia by Spinal Cord Stimulation Following a Spinal Injury Associated With Activation of Adult Neural Progenitors.

OBJECTIVES: Responses of spinal progenitors to spinal cord stimulation (SCS) following spinal cord injury (SCI) in rats were assessed to reveal their potential contribution to SCS-induced analgesia. METHODS: Spinal epidural electrodes were implanted in rats at T12 rostral to a quadrant dorsal horn injury at T13. Further groups additionally received either a microlesion to the dorsolateral funiculus (DLF) or gabapentin (10 mg/kg). SCS was performed at 25 Hz for 10 minutes on day 4 (early SCS) and at 10 Hz for 10 minutes on day 8 (late SCS) after injury. Paw withdrawal threshold (PWT) was measured before injury, 30 minutes before or after SCS, and before cull on day 14, followed by immunostaining assessment. RESULTS: Paw withdrawal thresholds in uninjured animals (51.0 ± 4.0 g) were markedly reduced after SCI (17.3 ± 2.2 g). This was significantly increased by early SCS (38.5 ± 5.2 g, P < 0.01) and further enhanced by late SCS (50.9 ± 1.9 g, P < 0.01) over 6 days. Numbers of neural progenitors expressing nestin, Sox2, and doublecortin (DCX) in the spinal dorsal horn were increased 6 days after SCS by 6-fold, 2-fold, and 2.5-fold, respectively (P < 0.05 to 0.01). The elevated PWT evoked by SCS was abolished by DLF microlesions (48.9 ± 2.6 g vs. 19.0 ± 3.9 g, P < 0.01) and the number of nestin-positive cells was reduced to the level without SCS (P < 0.05). Gabapentin enhanced late SCS-induced analgesia from 37.0 ± 3.9 g to 54.0 ± 0.8 g (P < 0.01) and increased gamma-aminobutyric acid (GABA)-ergic neuronal marker vesicular GABA transporter-positive newborn cells 2-fold (P < 0.01). CONCLUSIONS: Spinal progenitor cells appear to be activated by SCS via descending pathways, which may be enhanced by gabapentin and potentially contributes to relief of SCI-induced neuropathic pain.

Feasibility of a community pharmacy antimicrobial stewardship intervention (PAMSI): an innovative approach to improve patients' understanding of their antibiotics.

BACKGROUND: Community pharmacy staff have an opportunity to play a pivotal role in antimicrobial stewardship (AMS) due to their expertise in medicines and accessibility to patients. OBJECTIVES: To develop and test the feasibility of a pharmacy AMS intervention (PAMSI) to increase community pharmacy staff's capability, opportunity and motivation to check antibiotic appropriateness and provide self-care and adherence advice when dispensing antibiotics. METHODS: The PAMSI was centred around an Antibiotic Checklist, completed by patients and pharmacy staff, to facilitate personalized advice to the patient, based on their reported knowledge. An educational webinar for staff and patient-facing materials were also developed. Staff and patients completing Antibiotic Checklists were invited to provide feedback via questionnaires. RESULTS: In February 2019, 12 community pharmacies in England trialled the intervention. Forty-three pharmacy staff evaluated the educational webinar and reported increases in their understanding, confidence, commitment and intention to use the tools provided to give adherence and self-care advice. Over 4 weeks, 931 Antibiotic Checklists were completed. Staff reported being more focused on giving advice and able to address patients' knowledge gaps (mainly: likely symptom duration; alcohol and food consumption advice; possible side effects from antibiotics; returning unused antibiotics to the pharmacy), resulting in increased self-reported effective and meaningful conversations. CONCLUSIONS: Implementation of a PAMSI is feasible and effectively promotes AMS. Pharmacy staff and commissioners should consider this within their AMS plans. An optional digital format of the Antibiotic Checklist should be explored, for patients who are not collecting their antibiotic prescriptions themselves, and to save printing costs.

Playworlds and Executive Functions in Children: Theorising with the Cultural-Historical Analytical Lenses.

This paper provides a theorisation of developmental conditions to support executive functions (working memory, inhibition and shifting) in children in playworlds settings, where children and teachers play together in collectively created imaginary situations. Vygotsky's general law of development of psychological functions constitutes the general frame for the analysis of the process of development of executive functions (EF) in playworlds, and the theoretical concepts of drama, social situation of development and perezhivanie are used as analytical tools to examine opportunities of playworlds to support children executive functions.

The development of children's epistemic beliefs across the early years of elementary school.

BACKGROUND: A growing body of research shows that the beliefs we hold about the nature of knowing and knowledge (epistemic beliefs) may mediate moral reasoning. However, a limitation of much of the research in the area of epistemic beliefs is the lack of a longitudinal approach. AIMS: The study investigated longitudinal changes in Australian elementary school children's beliefs about knowing and knowledge (epistemic beliefs) across three judgement domains (personal taste, ambiguous facts, and moral values). SAMPLE: The participants in this longitudinal study were tracked from Year 1 through to Year 3 of primary school. In Year 1, there were 169 participants (83 boys, 86 girls) aged 6-7 years (M = 6.7, SD = 0.32). In Year 2, there were 156 participants (79 boys, 77 girls), and in Year 3, there were 129 participants (65 boys, 64 girls). METHODS: Using vignettes that reflected each of the three judgement domains, children were interviewed about the beliefs held by two puppet characters. The interviews took place each year across the early years of elementary education in Year 1, Year 2, and Year 3. RESULTS: Findings revealed that children's epistemic beliefs in each of the judgement domains became more subjectivist over time but that the age at which this occurred differed according to the judgement domain in question. CONCLUSIONS: We argue that it is important for teachers to pay attention to children's beliefs about the nature of knowledge and knowing in the process of scaffolding their reasoning about moral values for active citizenship.

Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial.

OBJECTIVE: Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. METHODS: In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. RESULTS: The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). CONCLUSIONS: This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

A Targeted Mutation Disrupting Mitochondrial Complex IV Function in Primary Afferent Neurons Leads to Pain Hypersensitivity Through P2Y1 Receptor Activation.

As mitochondrial dysfunction is evident in neurodegenerative disorders that are accompanied by pain, we generated inducible mutant mice with disruption of mitochondrial respiratory chain complex IV, by COX10 deletion limited to sensory afferent neurons through the use of an Advillin Cre-reporter. COX10 deletion results in a selective energy-deficiency phenotype with minimal production of reactive oxygen species. Mutant mice showed reduced activity of mitochondrial respiratory chain complex IV in many sensory neurons, increased ADP/ATP ratios in dorsal root ganglia and dorsal spinal cord synaptoneurosomes, as well as impaired mitochondrial membrane potential, in these synaptoneurosome preparations. These changes were accompanied by marked pain hypersensitivity in mechanical and thermal (hot and cold) tests without altered motor function. To address the underlying basis, we measured Ca2+ fluorescence responses of dorsal spinal cord synaptoneurosomes to activation of the GluK1 (kainate) receptor, which we showed to be widely expressed in small but not large nociceptive afferents, and is minimally expressed elsewhere in the spinal cord. Synaptoneurosomes from mutant mice showed greatly increased responses to GluK1 agonist. To explore whether altered nucleotide levels may play a part in this hypersensitivity, we pharmacologically interrogated potential roles of AMP-kinase and ADP-sensitive purinergic receptors. The ADP-sensitive P2Y1 receptor was clearly implicated. Its expression in small nociceptive afferents was increased in mutants, whose in vivo pain hypersensitivity, in mechanical, thermal and cold tests, was reversed by a selective P2Y1 antagonist. Energy depletion and ADP elevation in sensory afferents, due to mitochondrial respiratory chain complex IV deficiency, appear sufficient to induce pain hypersensitivity, by ADP activation of P2Y1 receptors.