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N-methyl-D-aspartate receptors (NMDARs) are excitatory ionotropic glutamate receptors expressed throughout the CNS, including in the spinal dorsal horn. The GluN2 subtypes of NMDAR subunit, which include GluN2A, GluN2B, and GluN2D in the dorsal horn, confer NMDARs with structural and functional variability, enabling heterogeneity in synaptic transmission and plasticity. Despite essential roles for NMDARs in physiological and pathological pain processing, the distribution and function of these specific GluN2 isoforms across dorsal horn laminae remain poorly understood. Surprisingly, there is a complete lack of knowledge of GluN2 expression in female rodents. We, therefore, investigated the relative expression of specific GluN2 variants in the dorsal horn of lumbar (L4/L5) spinal cord from both male and female rats. In order to detect synaptic GluN2 isoforms, we used pepsin antigen-retrieval to unmask these highly cross-linked protein complexes. We found that GluN2B and GluN2D are preferentially localized to the pain-processing superficial regions of the dorsal horn in males, while only GluN2B is predominantly localized to the superficial dorsal horn of female rats. The GluN2A subunit is diffusely localized to neuropil throughout the dorsal horn of both males and females, while GluN2B and GluN2D immunolabelling are found both in the neuropil and on the soma of dorsal horn neurons. Finally, we identified an unexpected enhanced expression of GluN2B in the medial division of the superficial dorsal horn, but in males only. These sex-specific localization patterns of GluN2-NMDAR subunits across dorsal horn laminae have significant implications for the understanding of divergent spinal mechanisms of pain processing.

Parkinson's disease (PD) is characterized by profound microglial driven inflammatory processes and the loss of dopamine neurons of the substantia nigra (SNc). Both microglia and dopamine neurons that are affected in the SNc are particularly vulnerable to environmental toxicants and finding more selective ways of targeting these cell types is of importance. Quantum dots (QDs) might be a useful vehicle for selectively delivering toxicants to microglia and owing to their fluorescent capability, they can be microscopically tracked within the cell. Accordingly, we assessed the impact of QDs alone and QDs conjugated to the ribosomal toxin, saporin, upon SNc microglia and dopamine neurons. We found that intra-SNc infused QDs selectively entered microglia and induced morphological changes consistent with an activated state. QDs conjugated to saporin also caused a significant loss of dopamine neurons and motor coordination (on a rotarod test) deficits, along with an increase in the inflammatory microglial actin regulatory factors, WAVE2. These data suggest that QDs might be a viable route for toxicant delivery and also has an added advantage of being fluorescently visible. Ultimately, we found SNc neurons to be exceptionally vulnerable to QD-saporin and suggest that this could be a novel targeted approach to model PD-like inflammatory pathology.

Background : Multiple sclerosis (MS) is a chronic demyelinating disease which leads to sensory, motor, autonomic, and cognitive symptoms. Cannabis is a common way for persons with MS (pwMS) to seek symptomatic therapy. Given the capacity for both cannabis and MS to cause cognitive impairment, it is important to determine whether there is any negative impact when the two co-occur. The objective of this systematic review was to evaluate the effects of cannabis and medicinal cannabinoid products on cognition in pwMS in order to provide guidance to clinicians and enable them to make evidence-based recommendations regarding cannabis and cannabinoid products. Methods : A systematic review was carried out searching common keyword combinations for cannabis and MS across five databases, producing 840 unique articles, 18 of which were included in a qualitative synthesis. Results : Aggregate data from existing studies to date highlight potential impairments from chronic whole-plant cannabis use in commonly affected cognitive domains in multiple sclerosis, including attention and working memory, and to a lesser extent, visual memory, verbal memory, and executive function. Results also suggest that in the short-term, medicinal cannabinoid preparations do not significantly impair cognition and may even ameliorate cognitive symptoms in the context of obtrusive MS disease. The findings are limited by disparities in detail of cannabis use data reported across whole-plant cannabis publications. Conclusion : Existing literature on co-occurrence of cannabis use and MS lacks high quality evidence to recommend for or against cannabis and cannabinoid therapies for pwMS based on cognitive effects. Existing data suggest that cognition may be differentially impacted in pwMS depending on the type of product, the duration of use, and the indication. Future studies on whole-plant cannabis require comprehensive cannabis use data reporting including frequency, dosing, duration, and type of cannabis product. Future studies on medicinal cannabinoid products should be long-term to assess the effects of chronicity.