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BDKRB2 upregulation by dystrophic microglia drives pain hypersensitivity in aged mice
An Liu1, Ming-Jun Zhang2, Jin-Rong Guo3
1Department of Anatomy, Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
Abstract:
Although pain sensitization is among the most common conditions affecting the elderly, its underlying neural mechanisms remain unclear. Here, we found that mechanical hypersensitivity arises from enhanced glutamatergic excitability in primary somatosensory cortex due to bradykinin receptor B2 (BDKRB2) upregulation by dystrophic microglia during aging. Specifically, in vivo fiber photometry in aged mice revealed hyperactivity of glutamatergic neurons in primary somatosensory cortex of hindlimb (S1HLGlu), while chemogenetic inhibition of these neurons reverses pain hypersensitivity in aged mice. BDKRB2 expression on S1HLGlu neurons is significantly increased in aged mice, whereas its conditional knockdown restores pain sensitization, and its overexpression leads to nociceptive hypersensitivity in young mice. Moreover, chemogenetic or pharmacological inhibition of dystrophic microglia in aged mice reduces BDKRB2 levels, alleviating pain hypersensitivity. The present study thus demonstrates that microglia-mediated S1HLGlu hyperactivity drives development of aging-related pain via BDKRB2 signaling, suggesting several potentially effective therapeutic targets for treating geriatric pain.
Insights
Aging causes pain hypersensitivity through increased brain excitation. Dystrophic microglia upregulate bradykinin receptor B2 (BDKRB2) in the somatosensory cortex, driving this age-related pain.
Area of Science:
- Neuroscience
- Gerontology
- Immunology
Background:
- Pain sensitization is common in the elderly, but its neural basis is poorly understood.
- Aging is associated with neuroinflammation and altered neuronal function.
- Microglia play a crucial role in brain aging and immune responses.
Purpose of the Study:
- To elucidate the neural mechanisms underlying age-related pain hypersensitivity.
- To investigate the role of microglia and specific receptors in geriatric pain.
- To identify potential therapeutic targets for age-related pain.
Main Methods:
- In vivo fiber photometry in aged mice to measure neuronal activity.
- Chemogenetic manipulation of specific neuronal populations and microglia.
- Conditional knockdown and overexpression of BDKRB2 in neurons.
- Pharmacological inhibition of microglia.
Main Results:
- Aged mice exhibit mechanical hypersensitivity linked to hyperactivity of glutamatergic neurons in the primary somatosensory cortex (S1HLGlu).
- Bradykinin receptor B2 (BDKRB2) is upregulated on S1HLGlu neurons in aged mice, and its modulation affects pain sensitivity.
- Inhibition of dystrophic microglia reduces BDKRB2 levels and alleviates pain hypersensitivity in aged mice.
Conclusions:
- Microglia-mediated hyperactivity of S1HLGlu neurons, driven by BDKRB2 signaling, is a key mechanism in aging-related pain.
- Targeting microglia and BDKRB2 signaling offers potential therapeutic strategies for geriatric pain.
