A Promising New Treatment Target for Chemotherapy-Induced Neuropathic Pain
Timothy Doyle, Kali Janes, Wen Hua Xiao, Grant Kolar, Hans F. Luecke, et al.
(see article e1268242024)
Alleviating neuropathic pain following chemotherapy necessitates finding safe, effective treatments. Chemotherapy-induced neuropathic pain may be driven by dysfunctional mitochondria, which research suggests underlies sensory nerve fiber loss in the skin and contributes to abnormal skin nerve activity. Doyle et al. explored whether targeting mitochondrial receptors during chemotherapy reverses these symptoms in rats. After discovering that the A3 adenosine receptor (A3AR) is expressed on rat mitochondria, the authors administered an agonist to activate it during chemotherapy. The drug prevented neuropathic pain from occurring and impeded the loss of skin nerve fibers and abnormal skin nerve activity typically observed with chemotherapy-induced neuropathic pain. Administering the A3AR agonist ex vivo following chemotherapy-induced neuropathic pain provided more evidence of the drug reversing mitochondria dysfunction from chemotherapy in sensory nerves. The findings of this study suggest that mitochondrial A3AR could be an effective treatment target for reducing neuropathic pain from chemotherapy and are thus informative for more advanced animal model studies and clinical work.
Expression of A3AR (green) in the cell membrane and within mitochondria (red) of cultured mouse microglia. See Doyle et al. for more information.
How Neuromodulators Influence the Stress Axis
Emmet M. Power, Dharshini Ganeshan, Jamieson Paul, Hiroyuki Igarashi, Wataru Inoue, and Karl John Iremonger
(see article e1092242024)
Corticotropin-releasing hormone (CRH) neurons in the hypothalamus control the hypothalamic–pituitary–adrenal (HPA) axis or stress axis. Noradrenaline and corticosterone modulate CRH neurons at the cell soma, but researchers do not know how these neuromodulators act on CRH neuron terminals. Power and colleagues used in vitro calcium imaging and measurements of neurotransmitter release at CRH neuron terminals to explore whether noradrenaline and corticosterone act directly on the terminals. The authors were surprised to discover that noradrenaline suppressed CRH secretion and inhibited stimulation-induced CRH neuron terminal activity, which was meant to mimic their activation during stress responses. This effect depended on alpha-2 adrenergic receptor activation by noradrenaline. Corticosterone administration only diminished CRH secretion from the terminals, an effect that depended on glucocorticoid receptors. This study provides new insight into how noradrenaline and corticosterone modulate stress-induced CRH release directly at CRH neuron terminals to impact HPA axis activity.
Footnotes
This Week in The Journal was written by Paige McKeon