Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia

Prepregnancy Diabetes and Perinatal Mental Illness: A Population-Based Latent Class Analysis

This is an accepted manuscript of an article published in the American Journal of Epidemiology.We examined the risk of any perinatal mental illness associated with prepregnancy diabetes and identified how diabetes duration, complexity, and intensity of care affect this risk. We performed a population-based study of women aged 15-49 years with (n = 14,186) and without (n = 843,818) prepregnancy diabetes who had a singleton livebirth (Ontario, Canada, 2005-2015) and no recent mental illness. Modified Poisson regression estimated perinatal mental illness risk between conception and 1 year postpartum in women with versus without diabetes and in diabetes groups, defined by a latent class analysis of diabetes duration, complexity, and intensity-of-care variables, versus women without diabetes. Women with diabetes were more likely than those without to develop perinatal mental illness (18.1% vs. 16.0%; adjusted relative risk = 1.11, 95% confidence interval: 1.07, 1.15). Latent classes of women with diabetes were: uncomplicated and not receiving regular care (59.7%); complicated, with longstanding diabetes, and receiving regular care (16.4%); and recently diagnosed, with comorbidities, and receiving regular care (23.9%). Perinatal mental illness risk was elevated in all classes versus women without diabetes (adjusted relative risks: 1.09-1.12), but results for class 2 were nonsignificant after adjustment. Women with diabetes could benefit from preconception and perinatal strategies to reduce their mental illness risk.We gratefully acknowledge the Connaught New Researcher Award and the Canadian Institutes of Health Research (Project Grant program # 376290) for their support of this study

Incidence of Pregnancy-Associated Cancer in Two Canadian Provinces: A Population-Based Study

Pregnancy-associated cancer—that is diagnosed in pregnancy or within 365 days after delivery—is increasingly common as cancer therapy evolves and survivorship increases. This study assessed the incidence and temporal trends of pregnancy-associated cancer in Alberta and Ontario—together accounting for 50% of Canada’s entire population. Linked data from the two provincial cancer registries and health administrative data were used to ascertain new diagnoses of cancer, livebirths, stillbirths and induced abortions among women aged 18–50 years, from 2003 to 2015. The annual crude incidence rate (IR) was calculated as the number of women with a pregnancy-associated cancer per 100,000 deliveries. A nonparametric test for trend assessed for any temporal trends. In Alberta, the crude IR of pregnancy-associated cancer was 156.2 per 100,000 deliveries (95% CI 145.8–166.7), and in Ontario, the IR was 149.4 per 100,000 deliveries (95% CI 143.3–155.4). While no statistically significant temporal trend in the IR of pregnancy-associated cancer was seen in Alberta, there was a rise in Ontario (p = 0.01). Pregnancy-associated cancer is common enough to warrant more detailed research on maternal, pregnancy and child outcomes, especially as cancer therapies continue to evolve.Medicine, Faculty ofNon UBCObstetrics and Gynaecology, Department ofReviewedFacult

Erratum: Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia