Antioxidant Therapy Reverses Sound Stress-Induced Opioid Resistance in a Mouse Model of Mechanical Allodynia.

PURPOSE: Mechanical allodynia is associated with psychological stress, and environmental stimuli may exacerbate it in individuals with pain; however, the effects of analgesics on stress-induced mechanical allodynia remain unclear. Therefore, the present study aimed to determine whether oxidative stress contributes to opioid resistance development under stress-induced allodynia and to evaluate whether antioxidant therapy can restore opioid efficacy.

METHODS

Sound stress was induced using the distress vocalizations of a mouse whose tail was pinched with an artery clip. Mice were subjected to a 4 h sound stress protocol and subsequently tested for mechanical allodynia using the von Frey test under control, sound-stress, inflammatory (CFA), and corresponding drug-treatment conditions (n = 6 per group). The effects of morphine (1 and 3 mg/kg; an opioid agonist), celecoxib (10 and 20 mg/kg; a selective COX-2 inhibitor), and N-tert-butyl-α-phenylnitrone (PBN; 75 and 150 mg/kg; a reactive oxygen species scavenger) were evaluated.

RESULTS

Sound stress induced mechanical allodynia (P < 0.01) but did not affect plasma prostaglandin E2 or corticosterone levels 24 h post-exposure. However, it increased the expression of oxidative stress-related genes in the brain (P < 0.05). Celecoxib and PBN each reduced mechanical allodynia (P < 0.05), whereas morphine did not. In mice with CFA-induced mechanical allodynia, sound stress reduced the analgesic efficacy of both morphine and celecoxib, but not PBN (P < 0.01). Morphine and PBN combined produced stronger analgesia than morphine alone at the same dose.

CONCLUSION

These findings suggest that sound stress-induced hyperalgesia is mediated by oxidative stress and that antioxidants such as PBN are effective both as stand-alone treatments and adjuvants that restore or enhance the analgesic effect of morphine. The study highlights the role of physiological stress in pain modulation and underscores the therapeutic potential of antioxidant analgesics in stress-related mechanical allodynia.