British journal of pharmacology · 2026
The contribution of dorsal horn cyclin-dependent kinase 5 (CDK5) to the initiation and maintenance of chronic pain is defined by the nature of injury.
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Pinto-Pardo Nicolas, Herault Karine, Dallel Radhouane, Artola Alain
Аннотация
BACKGROUND AND PURPOSE: Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, involved in neuronal development and neurodegenerative diseases, regulates pain. Whereas its contribution to pain processing within nociceptors is well established, but within dorsal horn neurons remains poorly understood.
EXPERIMENTAL APPROACH: We used behaviour, electrophysiology, western blot and immunohistochemistry in the trigeminal ganglion (TG) and medullary dorsal horn (MDH) of male and female rats.
KEY RESULTS: In naïve animals, intracisternal roscovitine (seliciclib), a CDK5 inhibitor, suppresses selectively noxious-evoked responses of MDH wide dynamic range (WDR) neurons and leaves the windup phenomenon unchanged, suggesting that CDK5 signalling within TG, but not MDH, regulates nociceptive pain. Under inflammatory conditions, roscovitine prevents the facial spontaneous pain-like behaviour, and static and dynamic secondary mechanical hypersensitivities in both sexes and the sensitization of MDH WDR neurons. But it cannot reverse them. Conversely, roscovitine reduces the neuropathic mechanical hypersensitivities. Therefore, CDK5 signalling within MDH is differently involved in chronic pain, contributing to the maintenance of neuropathic pain but only the initiation of inflammatory pain, in both sexes. Interestingly, whereas p35, p25 and pERK1/2 MDH expressions increase under inflammatory and neuropathic conditions, CDK5 expression only enhances under neuropathic ones. Finally, p35 MDH expression strongly increases following inflammatory pain, occurring in ~70-80% of neurons and also in astrocytes and microglia.
CONCLUSION AND IMPLICATIONS: MDH CDK5-p35 specifically regulates, though differently, inflammatory and neuropathic pain, making it an attractive target for the development of long-lasting analgesics in both sexes. The therapeutic indication of CDK5 inhibitors needs to consider the nature of injury.
EXPERIMENTAL APPROACH: We used behaviour, electrophysiology, western blot and immunohistochemistry in the trigeminal ganglion (TG) and medullary dorsal horn (MDH) of male and female rats.
KEY RESULTS: In naïve animals, intracisternal roscovitine (seliciclib), a CDK5 inhibitor, suppresses selectively noxious-evoked responses of MDH wide dynamic range (WDR) neurons and leaves the windup phenomenon unchanged, suggesting that CDK5 signalling within TG, but not MDH, regulates nociceptive pain. Under inflammatory conditions, roscovitine prevents the facial spontaneous pain-like behaviour, and static and dynamic secondary mechanical hypersensitivities in both sexes and the sensitization of MDH WDR neurons. But it cannot reverse them. Conversely, roscovitine reduces the neuropathic mechanical hypersensitivities. Therefore, CDK5 signalling within MDH is differently involved in chronic pain, contributing to the maintenance of neuropathic pain but only the initiation of inflammatory pain, in both sexes. Interestingly, whereas p35, p25 and pERK1/2 MDH expressions increase under inflammatory and neuropathic conditions, CDK5 expression only enhances under neuropathic ones. Finally, p35 MDH expression strongly increases following inflammatory pain, occurring in ~70-80% of neurons and also in astrocytes and microglia.
CONCLUSION AND IMPLICATIONS: MDH CDK5-p35 specifically regulates, though differently, inflammatory and neuropathic pain, making it an attractive target for the development of long-lasting analgesics in both sexes. The therapeutic indication of CDK5 inhibitors needs to consider the nature of injury.