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IMPACT OF AHA1 ON MORPHINE ACTIVITY IN POST-OPERATIVE PAIN MODEL

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posted on 2025-06-24, 17:16 authored by Ishrat JahanIshrat Jahan

Enhancing the therapeutic index of opioids remains a critical goal in improving pain management. Our previous work has demonstrated that spinal inhibition of heat shock protein 90 (Hsp90) potentiates morphine analgesia without exacerbating its side effects, primarily through activation of ERK-RSK signaling. However, systemic Hsp90 inhibition is associated with off-target toxicities, including hepatotoxicity, underscoring the need for more selective strategies. In this study, we explore a targeted approach by inhibiting the Hsp90 co-chaperone, activator of Hsp90 ATPase (Aha1), using KU-177. Our prior findings in the tail-flick assay indicated that spinal inhibition of Aha1 enhances morphine-induced antinociception. Here, we extend our investigation to evaluate the systemic effects of KU-177 on morphine analgesia in a mouse model of post-operative pain. We report that intraperitoneal administration of KU-177 significantly augments morphine’s analgesic efficacy without altering withdrawal responses or affecting liver weight. We are investigating the molecular mechanisms by analyses of protein expression and activation in the spinal cord, brainstem, and periaqueductal gray (PAG). In summary, these findings suggest that Aha1 inhibition via KU-177 represents a promising strategy to enhance opioid analgesia while minimizing adverse effects, although the molecular mechanism remains unclear.

History

Degree Type

  • Master of Science

Department

  • Biological Sciences

Campus location

  • Fort Wayne

Advisor/Supervisor/Committee Chair

Ahmed Mustafa

Additional Committee Member 2

Wei Lei

Additional Committee Member 3

Chakkunny Jose Thekkiniath

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