Mode of action of astrocytes in pain: From the spinal cord to the brain

Chronic pain is a maladaptive condition affecting 7%- 10% of the population worldwide and can be accompanied by depression, anxiety, and insomnia. In particular, chronic pain is becoming more common due to the increasing incidence of diabetes mellitus, cancer, systemic (body-wide) autoimmune, trauma, and infections that attack nerve tissues with an aging global population. Upon stimuli, pain responses are evoked from nociceptive primary sensory neurons in the peripheral nervous system (PNS). Still, pathological changes leading to central sensitization of the pain circuitry in the central nervous system (CNS) is a key mechanism underlying pain maintenance. In humans, chronic pain can last for years, even after the observable signs and symptoms of the primary inflammation or damage have resolved. It is clear that astrocytes, the most abundant cell type in the CNS, are highly involved in regulating pain signaling under health and disease. Multiple astrocyte subsets and diversified activation states driven by intrinsic and extrinsic cues have recently been identified in the spinal cord and brain, playing complex roles in pain development and resolution. Targeting detrimental astrocyte subtypes and activity is considered a promising pain management strategy. Here, we integrate the latest findings to review differential astrocytes activities in distinct regions of the CNS during pain pathophysiology and discuss the underlying molecular mechanisms that control their mode of action in beneficial or/and harmful aspects of pain. Finally, we provide a translational overview of current progress for pain therapies via modulating astrocytic activity.