Spinal astrogliosis in pain models: cause and effects

Abstract

Pathological pain has been subjected to intense research to shed light on the underlying mechanisms of key symptoms, such as allodynia and hyperalgesia. The main focus has by and large concerned plasticity of spinal cord neurons and the primary afferent nerves relaying peripheral information to the spinal cord. Animal pain models display an increased presence of reactive astrocytes in the spinal cord, but in contrast to neurons, little is known about how they contribute to abnormal pain sensation. However, astrocytes are now beginning to receive greater attention, and as new information is emerging, it appears that astrocytes undertake critical roles in manifesting pathological pain. Through the secretion of diffusible transmitters, such as interleukins, ATP, and NO, astrocytes may augment primary afferent neuronal signaling or sensitize second order neurons in the spinal cord. In addition, astrocytes might lead to altered pain perception by a direct modulation of synaptic transmission between neurons in the nociceptive pathway or through the creation of astrocytic networks capable of transducing signals for extended distances across and along the spinal cord. Future research in astrocyte activation and signaling may therefore reveal novel drug targets for managing pathological pain.

Fig. 1

Temporal changes in the expression of nociceptor-derived cotransmitters in neuropathic and inflammatory pain models. Altered expression levels of SP and CGRP in both the DRG and the dorsal horn of the spinal cord are commonly observed in animal pain models. In nerve injury models, SP and CGRP expression seems to be increased just following the insult, but later decreased below basal levels. In contrast, inflammatory pain models show an initial increase, which is not followed by a decreased expression state, but rather is found to normalize over time

Fig. 2

Extensive spinal astrogliosis in a murine pain model. Cancer growth in the femoral bone in mice is associated with plantar hypersensitivity as well as increased GFAP expression in all lamina of the spinal cord ipsilateral to the cancer bearing leg (right side). Arrows indicate areas with increased numbers of GFAP positive astrocytes. Scale bar 300 μm

Fig. 3

Projections to and from the spinal cord. Afferent neurons, which are responsible for relaying information, including noxious stimuli, from the periphery to the CNS have their cell bodies located in the DRG. The dorsal roots consist of fibers projecting from the DRG into the dorsal horn, where they synapse onto second order neurons. Efferent neurons have their cell bodies located in the gray matter of the ventral horn and comprise motor neurons and preganglionic neurons of the autonomic nervous system. These fibers constitute the ventral roots, which merge with the dorsal roots near the DRG to make up the spinal nerves. The reason for microglial activation in both the dorsal and the ventral horn in nerve injury pain models may be that both the primary afferent and efferent nerve fibers are damaged

Fig. 4

Calcium wave propagation in astrocytic networks. Astrocytes initially challenged with substances, such as glutamate or ATP or by a physical insult, react by producing the secondary messenger IP₃, which triggers calcium release from internal stores. Astrocytes in a network are connected by gap junctions, which allow the passive diffusion of IP₃ between neighboring cells. The spread of calcium waves also depends on ATP secretion from activated astrocytes. The extracellular ATP stimulates surrounding astrocytes to increase their intracellular calcium concentration, thus letting the wave propagate for an extended range