91: Activation of Pain-Related Brain Regions in a Nonhuman Primate Model of Knee Osteoarthritis

Topic: Basic Science

Choose one of the following: Pain category (ICD-11)

Choose one of the following: Chronic primary musculoskeletal pain

Choose one to three of the following: Developing methodology/technology, Animal imaging (includes Ca2+ imaging, fluorescence microscopy), Behavioral studies

Background and Aims: Complete understanding of association between in vivo brain functioning and chronic pain has yet to be fully elucidated. Uncovering the association between brain functioning and pain could lead to utilization of brain functioning as a marker for pain, an individual and subjective experience. Complicating clinical understanding of the association between brain functioning and pain is the use of a preclinical species that is phylogenetically distant from humans. The goal of the current study is to identify brain activation in response to peripheral stimulation in cynomolgus macaques with a unilateral knee osteoarthritis (OA). A secondary goal is to identify potential sex differences in brain activation, as sex differences in responses to chronic pain have been reported.

Methods: Before MMx, Macaca fascicularis were habituated to weight bearing and knee pressure threshold measurement. To assess weight bearing, macaques stood on two scales. Knee pressure threshold (kg) was assessed with a modified algometer. Under general anesthesia, male and female underwent a medial meniscectomy (MMx) of the left knee. Appropriate post-operative care was performed, including antibiotic and analgesic treatments. Under propofol sedation, functional magnetic resonance imaging (fMRI) was performed with a 3 T MRI (GE Healthcare). Non-noxious pressure (1.5 kg) was applied to the left knee joint using a block design. The effects of acute vehicle and morphine (6 mg/kg, i.m.) treatment on behavior and brain activation were also assessed.

Results: Prior to MMx, mean knee pressure threshold was 3 kg (100%) and mean weight bearing was 50% (even weight bearing of the left and right feet). Seven to eight weeks after MMx, mean ipsilateral weight bearing decreased and pressure response threshold decreased compared to the contralateral knee (i.e., pressure hypersensitivity). No behavioral differences were observed between males and females either before or after MMx. Seven weeks after MMx, non-noxious pressure applied to the ipsilateral knee joint activated the contralateral insular cortex/secondary somatosensory cortex (Ins/SII). Between 8-11 weeks after MMx, contralateral thalamus activation was also observed in male macaques but not in female macaques. Between 8-11 weeks after MMx, mean contralateral Ins/SII activation was greater in male macaques compared to female macaques. Morphine increased ipsilateral weight bearing and knee pressure thresholds and suppressed Ins/SII and thalamus activation.

Conclusions: Stimulus evoked brain activation could be utilized as a quantifiable marker of pain in OA patients and could be further utilized to quantitatively assess analgesic efficacy. Furthermore, apparent sex differences in brain activation were observed in the current macaque OA model, despite the lack of noticeable differences in response to stimulation. The significant of a potential functional difference needs further elaboration, but could underlie qualitative differences in pain perception between male and female OA patients.

References: --
This project has been funded in whole or in part with Federal funds from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N95019D00026.

Who is the presenting author?: Aldric Hama

Who is the senior author?: Mark Varney

Is your abstract directly related to the IASP 2026 Global Year theme of Neuropathic Pain?: No
Co-Authors:

• Rintaro Fujii: DVM - CMIC Pharma Science Co., Ltd.
• Mizuho Yano: DVM - CMIC Pharma Science Co., Ltd.
• Kenya Nozawa: NA - CMIC Pharma Science Co., Ltd.
• Yoshitaka Itani: NA - CMIC Pharma Science Co., Ltd.
• Takahiro Natsume: PhD - CMIC Pharma Science Co., Ltd.
• Smriti Iyengar: PhD - National Institute of Neurological Disorders and Stroke, Division of Translational Research
• Sarah Woller: PhD - National Institute of Neurological Disorders and Stroke, Division of Translational Research
• Taleen Hanania: PhD - PyschoGenics Inc.
• Mark Varney: PhD - PsychoGenics Inc.