Middleton, J. | bioRxiv Science

bioRxiv2021

Chronic THC vapor rescues inflammation-related thermal hyperalgesia and causes cell type-specific modifications in vlPAG neurons

AbstractIn an effort to reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain. We tested chronic THC vapor inhalation effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., ventrolateral periaqueductal gray [vlPAG]) neuronal function, in adult male and female Wistar rats with chronic inflammatory pain (CFA treatment). We report that chronic THC vapor inhalation rescues both thermal hyperalgesia and mechanical hypersensitivity in males treated with CFA, but only thermal hyperalgesia in CFA females. Most of the anti-hyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure. We also report that chronic THC vapor inhalation modulates intrinsic and synaptic properties of vlPAG neurons, including reductions in action potential firing rate and spontaneous inhibitory synaptic transmission in males, and that these effects occur specifically in neurons that respond to current input with a "delayed" firing phenotype. Treatment with CFA led to increased firing rate and increased sIPSC amplitude in vlPAG neurons of female rats, and chronic THC vapor rescued sIPSC amplitudes to control levels - these effects were specific to vlPAG neurons categorized as having an "onset" firing phenotype. Ongoing work is exploring sex-specific mechanisms (e.g., CB1 receptor) of THC vapor rescue effects in the vlPAG of rats treated with CFA, and further exploring the vlPAG cell types impacted by CFA treatment and chronic THC vapor inhalation. Significance StatementMany adults in the U.S. with pain self-medicate with THC and cannabis, and many humans use e-cigarette type devices filled with cannabis extracts to self-administer THC and other constituents of the marijuana plant. Until recently, most rodent studies of THC effects on brain and behavior have used injection procedures and male rats. Here, we tested the effect of chronic THC vapor inhalation on pain-related behaviors and midbrain neural circuit function in adult male and female Wistar rats. As predicted, chronic THC vapor inhalation rescued chronic inflammatory pain effects on behavior and midbrain neuronal function.

neuroscience↗

bioRxiv2021

Tick hazard in the South Downs National Park (UK): species, distribution, key locations for future interventions, site density, habitats

BackgroundThe South Downs National Park (SDNP) is the UKs most visited National Park, and a foci of tick-borne Lyme disease. A range of human pathogens have been detected in UK ticks and related hosts, and the first presumed autochthonous cases of tick-borne encephalitis and babesiosis were recorded in 2019-20. SDNPs key objectives include conserving wildlife and encouraging enjoyment of the countryside, so interventions are needed that reduce hazard without negatively affecting ecosystem health. To be successful these require knowledge of site hazards, and we aimed to provide this to enable action. MethodsBritish Deer Society volunteers submitted ticks removed from deer. Key potential intervention sites were selected and ticks collected by drag-sampling six 50 m2 transects per site, in most cases twice yearly for two years. Ticks were identified in-lab (sex, life stage, species), hazard measured as tick presence, Density of Ticks (all life stages, DOT), and Density of Nymphs (DON). Sites and habitat types were analysed for association with hazard. Distribution across SDNP was mapped in a Geographic Information System (GIS), by combining and comparing our fieldwork results with records from five other data sources (recent and historic). Results87 Ixodes ricinus (all but one adults, 82%F) were removed from 14 deer (Dama dama n=10; Capreolus capreolus n=3; 1 not recorded; tick burden, 1-35) at 12 locations (commonly woodland). Five potential key intervention sites were identified and drag-sampled 2015-16, collecting 623 ticks (238 on-transects): 53.8% nymphs, 42.5% larvae, 3.7% adults (13M, 10F). Ticks were present on-transects at all sites drag-sampled (I.ricinus at three, Haemaphysalis punctata at two). The Mens (TM, the quietist site for human visitors) had the highest DOT at 30/300 m2 (DON=30/300 m2), followed by Queen Elizabeth Country Park (QECP, the busiest) at 22/300 m2 (12/300 m2), Cowdray Estate (CE) at 8/300 m2 (6/300 m2), and Seven Sisters Country Park (SSCP) at 1/300 m2 (1/300 m2). Ditchling Beacon Nature Reserve (DBNR) was sampled 2016 only (one adult H.punctata collected). Woodland had significantly higher hazard than grazed downland, but ticks were present at all downland sites drag-sampled. GIS mapping showed I.ricinus identified in 33/37 of SDNPs 10 km2 grid squares, Ixodes hexagonus 10/37, H.punctata 7/37, Dermacentor reticulatus 1/37. ConclusionsMapping shows tick hazard is broadly distributed across SDNP. Ixodes ricinuswas most common, though the seeming range expansion of H.punctata is concerning, particularly as it seems to thrive better on grazed downland than I.ricinus. Site specific recommendations include: management of small high hazard plots with heavy visitor numbers (QECP); signage on post-visit precautions (all sites); repellent impregnated clothing for deerstalkers (CE); flock trials to control H.punctata (SSCP, DBNR). Further research at TM, which has high tick density, may contribute to knowledge on ecological dynamics underlying infection density, and the potential use of predator re-introduction/protection as a public health intervention. Ecological research on H.punctata would aid control. The SDNP Authority is ideally placed to link and champion site-based and regional policies to reduce hazard, whilst avoiding or reducing conflict between public health and ecosystem health.

ecology↗