Background & Aims

Knee osteoarthritis (OA) is a leading cause of chronic pain disproportionately affecting women. Standard knee OA interventions remain suboptimal due to steep costs, lack of accessibility, and risks associated with long-term use. Green light has emerged as a potential low-risk, low-cost therapeutic for various chronic pain conditions, with hypoalgesic effects reported in fibromyalgia and chronic migraine patients [1,2] and in animal models of chronic pain [3,4,5,6]. Moreover, one study has reported the anxiolytic effects of green light exposure [7], which is compelling given the prevalence of comorbid anxiety and mood disorders in chronic pain patients. However, the effects of green light emitting diode (GLED) exposure on a chronic inflammatory condition such as knee OA have not been well-studied, especially with consideration of sex as a biological variable.

Methods

Male and female Sprague Dawley rats received a single injection of monoiodoacetate (MIA, 3mg/15µL) into the left knee joint to recapitulate the main features of knee OA. One day post-injection, knee mechanical thresholds were measured using the small animal algometer (smalgo, Bioseb) to assess primary hyperalgesia. Starting 2 days after injection, rats were exposed to either GLED or ambient room light (ARL) 8 hours daily for 24 days. Every three days up to 24 days following injection, knee mechanical thresholds were recorded using smalgo. A final measurement was taken 30 days after injection (5 days after light exposure termination). Resting-state functional MRI scans were performed on the rats under light isoflurane anesthesia (1.5-2%) to assess changes in brain functional connectivity using network analysis [8] following ARL or GLED exposure. fMRI data was acquired 30-31 days after the induction of the osteoarthritis model and 4-5 days after the last GLED or ARL session.

Results

One day post-injection, both GLED- and ARL-exposed rats exhibited a marked decrease in mechanical threshold. However, GLED exposure attenuated mechanical hyperalgesia in both sexes compared to ARL controls, an effect that was maintained 5 days after light exposure termination. Within the treatment-matched groups, GLED-induced hypoalgesia occurred sooner (6 GLED sessions) and with greater magnitude in males than in females. Network Analysis revealed significantly fewer brain regions connected to the Right Angular Thalamic Nucleus, Bilateral Caudate-Putamen, & Left Inferior Cerebellar Peduncle for GLED rats compared to ARL controls. GLED males showed a significantly reduced number of regions connected to each of the following regions: Bilateral Primary Somatosensory Regions & Right Caudate-Putamen compared to GLED females. GLED males showed a higher number of brain regions connected to the periaqueductal gray (PAG) than GLED females and ARL males.

Conclusions

These results show that GLED exposure attenuates mechanical hyperalgesia associated with chronic inflammatory pain in the MIA model. GLED-induced hypoalgesia and changes in brain functional connectivity exhibit sex-dependent differences, which may reflect sex differences in central mechanisms of OA pain maintenance and recovery. The higher number of functional connections to the PAG region for GLED males compared to GLED females and GLED males compared to ARL males suggest that GLED exposure might enhance the endogenous pain inhibitory system.

References

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[4] Martin LF, Moutal A, Cheng K, Washington SM, Calligaro H, Goel V, Kranz T, Largent-Milnes TM, Khanna R, Patwardhan A, Ibrahim MM. Green Light Antinociceptive and Reversal of Thermal and Mechanical Hypersensitivity Effects Rely on Endogenous Opioid System Stimulation. J Pain. 2021 Dec;22(12):1646-1656. doi: 10.1016/j.jpain.2021.05.006. Epub 2021 Jun 19. PMID: 34157406; PMCID: PMC8664962.

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[6] Wu XQ, Tan B, Du Y, Yang L, Hu TT, Ding YL, Qiu XY, Moutal A, Khanna R, Yu J, Chen Z. Glutamatergic and GABAergic neurons in the vLGN mediate the nociceptive effects of green and red light on neuropathic pain. Neurobiol Dis. 2023 Jul;183:106164. doi: 10.1016/j.nbd.2023.106164. Epub 2023 May 20. PMID: 37217103.

[7] Melo-Carrillo A, Rodriguez R, Ashina S, Lipinski B, Hart P, Burstein R. Psychotherapy Treatment of Generalized Anxiety Disorder Improves When Conducted Under Narrow Band Green Light. Psychol Res Behav Manag. 2023 Jan 26;16:241-250. doi: 10.2147/PRBM.S388042. PMID: 36726697; PMCID: PMC9885775.

[8] Gaynor LS, Ravi M, Zequeira S, Hampton AM, Pyon WS, Smith S, Colon-Perez LM, Pompilus M, Bizon JL, Maurer AP, Febo M, Burke SN. Touchscreen-Based Cognitive Training Alters Functional Connectivity Patterns in Aged But Not Young Male Rats. eNeuro. 2023 Feb 24;10(2):ENEURO.0329-22.2023. doi: 10.1523/ENEURO.0329-22.2023. PMID: 36754628; PMCID: PMC9961373.

Presenting Author

Laura Ventura

Poster Authors

Laura Ventura

BSc

University of Maryland Baltimore

Lead Author

E-mail

Topics

  • Pain Imaging