Bridging the Gap between Preclinical and Clinical Spinal Cord Injury Research
Karen M. Fisher, Joseph P. Garner, and Corinna Darian-Smith
(see article e0877232023)
Quality of life is significantly diminished following spinal cord injury (SCI), yet treatment options remain limited. Most preclinical research focuses on treating SCI soon after it occurs, but little is understood about the clinically stable state following SCI and the long-term neurological adaptations that occur by chronic stages of recovery. Investigating later recovery stages is critical for the development of improved treatment strategies. In this issue, Fisher et al. bridged the gap between preclinical and clinical research by investigating chronic stages of recovery in a nonhuman primate model of SCI that alters hand function. They found that while somatosensory corticospinal axons initially sprouted following injury, extraneous axonal growth was pruned back to pre-SCI levels by 1 year. In contrast, affected primary afferents sprouted locally in the early months and then remained stable into later stages of recovery. The authors also observed active microglia during the early post-SCI months and sustained high numbers of microglia at 1 year, suggesting that the pruning process is mediated at least partially by inflammation. While sex differences remain unexplored, these data reveal that neuroplasticity still occurs at chronic stages of SCI recovery. This ultimately means that treatment may be possible during these stages, which is a breakthrough in our understanding of SCI.
Representative confocal images taken from the dorsal horn of the spinal cord in a nonhuman primate. Microglia (green) are more present on the injured side (left) as compared with the uninjured side (right) 4–5 months following SCI, and this is maintained for a year.
Context-Dependent Neuron Adaptations from Chronic Morphine
Elizabeth R. Jaeckel, Yoani N. Herrera, Stefan Schulz, and William T. Birdsong
(see article e0293232023)
Morphine is an opioid that effectively relieves pain. However, repeated use results in increased tolerance to its therapeutic effects, thus the same level of pain relief eventually requires higher doses. This is not true of its undesirable effects, such as conditioned reward and locomotor stimulation, which are enhanced with higher doses. Gaps in knowledge remain about the cellular adaptations underlying these oppositional behavioral effects. Jaeckel and colleagues used a mouse model of chronic morphine exposure to explore this. Morphine acts through the mu opioid receptor (MOR), which is widely expressed throughout the brain. Because medial thalamus (MThal) neurons targeting the dorsomedial striatum (DMS) are involved in morphine use-related behaviors and express high levels of MOR in cell bodies as well as axons, the authors used this system to study morphine's mechanism of action with whole-cell patch-clamp electrophysiology. While acute morphine exposure typically decreases neuron excitability, they found that at MThal cell bodies, chronic morphine diminished this decrease in excitability for both males and females, which would contribute to tolerance. The authors also found that chronic morphine treatment strengthened, rather than diminished, morphine's inhibition of MThal→DMS synapses in males only. In a genetic line of mice with MOR that cannot be phosphorylated, this synaptic adaptation did not occur. This study provides new insights into the context dependence of the synaptic effects of opioid use in a behaviorally relevant circuit and is informative for future work on how to mitigate the adverse effects of repeated opioid use.
Footnotes
This Week in The Journal was written by Paige McKeon
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