Acute stress exacerbates spontaneous pain in a sex-dependent manner in mice with nerve injury or bone metastasis

Jun-Ming Zhang

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Acute stress exacerbates spontaneous pain in a sex-dependent manner in mice with nerve injury or bone metastasis Open Access Deposited

Date Uploaded: 10/21/2026
Date Modified: 10/21/2026

Spontaneous pain, characterized by unpredictable, episodic shooting or stabbing sensations, is linked to vasomotion-evoked cluster firing in injured dorsal root ganglion (DRG) sensory neurons. Since acute stress triggers a sympathetic "fight-or-flight" response involving vasoconstriction, we investigated whether stress-induced cardiovascular changes exacerbate neuropathic pain. Spontaneous pain-related behaviors (shaking, flinching, and licking) were recorded in male and female mice with spared nerve injury (SNI). While a 10-min acute restraint stress exposure significantly increased pain scores (flinches/shakes) in male SNI mice, no significant increase was observed in females, who displayed higher baseline spontaneous pain scores. Increased licking was observed in both sexes and in naive mice, suggesting it represents a general stress response rather than pain. Importantly, both the α-adrenoceptor antagonist phentolamine and the β-blocker propranolol prevented stress-induced pain exacerbation. Similar results were observed in a mouse bone cancer pain model, and the vasoconstrictor phenylephrine induced robust c-Fos activation in the ipsilateral spinal dorsal horn in both models. These findings demonstrate that, contrary to typical stress-induced analgesia, acute stress in animals with peripheral neuropathy can exacerbate spontaneous pain through a sex-dependent, sympathetically mediated neurovascular mechanism.

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