Physiology & behavior · 2026
Microglial involvement in inflammatory pain hypersensitivity in adult rats after adolescent morphine exposure.
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Jalali Fatemeh, Alami Kawsar, Hashemizadeh Shiva, Shahabi Rana, Semnanian Saeed, Azizi Hossein
Аннотация
BACKGROUND AND AIM: Adolescent morphine exposure (AME) is increasingly recognized as a risk factor for long-term alterations in pain processing, predisposing individuals to persistent pain in adulthood. Microglia are key regulators of neuroimmune signaling and central sensitization, yet their contribution to inflammatory pain hypersensitivity following adolescent opioid exposure remains unclear. This study examined whether inhibiting microglial activation during adolescence prevents the development of inflammatory pain hypersensitivity induced by chronic morphine exposure.
METHODS: Male Wistar rats received escalating doses of morphine (2.5-25 mg/kg, s.c., twice daily) during adolescence (postnatal days [PND] 28-37), with or without the microglial inhibitor minocycline. After a one-month drug-free washout period, inflammatory pain sensitivity was assessed in adulthood using the formalin test. Nociceptive scores, paw licking, and flinching behaviors were quantified across test phases. Multivariate behavioral patterns were analyzed using principal component analysis (PCA). Lumbar spinal cord expression of inflammatory and neurotrophic genes was measured by RT-qPCR two hours after formalin injection.
RESULTS: Adolescent morphine exposure produced persistent inflammatory pain hypersensitivity in adulthood, characterized by enhanced nociceptive scores, licking, and flinching behaviors, particularly during the late inflammatory phase of the formalin test. Cotreatment with minocycline during adolescence significantly attenuated morphine-induced hyperalgesia and partially normalized nociceptive behavioral profiles in PCA. At the molecular level, adolescent morphine exposure paradoxically reduced spinal Tlr4, Il-12, and Bdnf expression in adulthood despite heightened pain behaviors, and minocycline did not prevent morphine effects.
CONCLUSIONS: These findings demonstrate that microglial activity during adolescence plays a potential role in the long-term enhancement of inflammatory pain sensitivity after morphine exposure, yet the behavioral hypersensitivity occurs independently of classical inflammatory transcriptional upregulation in the spinal cord. Microglia remain a potential therapeutic target, but the relevant functional state is not captured by the classical markers assessed.
METHODS: Male Wistar rats received escalating doses of morphine (2.5-25 mg/kg, s.c., twice daily) during adolescence (postnatal days [PND] 28-37), with or without the microglial inhibitor minocycline. After a one-month drug-free washout period, inflammatory pain sensitivity was assessed in adulthood using the formalin test. Nociceptive scores, paw licking, and flinching behaviors were quantified across test phases. Multivariate behavioral patterns were analyzed using principal component analysis (PCA). Lumbar spinal cord expression of inflammatory and neurotrophic genes was measured by RT-qPCR two hours after formalin injection.
RESULTS: Adolescent morphine exposure produced persistent inflammatory pain hypersensitivity in adulthood, characterized by enhanced nociceptive scores, licking, and flinching behaviors, particularly during the late inflammatory phase of the formalin test. Cotreatment with minocycline during adolescence significantly attenuated morphine-induced hyperalgesia and partially normalized nociceptive behavioral profiles in PCA. At the molecular level, adolescent morphine exposure paradoxically reduced spinal Tlr4, Il-12, and Bdnf expression in adulthood despite heightened pain behaviors, and minocycline did not prevent morphine effects.
CONCLUSIONS: These findings demonstrate that microglial activity during adolescence plays a potential role in the long-term enhancement of inflammatory pain sensitivity after morphine exposure, yet the behavioral hypersensitivity occurs independently of classical inflammatory transcriptional upregulation in the spinal cord. Microglia remain a potential therapeutic target, but the relevant functional state is not captured by the classical markers assessed.