Spatial and temporal relationship between monocyte chemoattractant protein‐1 expression and spinal glial activation following peripheral nerve injury

Abstract

Peripheral nerve injury can induce spinal microglial/astrocyte activation. Substances released by activated glial cells excite spinal nociceptive neurons. Pharmacological disruption of glial activation or antagonism of substances released by activated glia prevent or reverse pain hypersensitivity. It is not known, however, what causes spinal cord glia to shift from a resting to an activated state. In an attempt to understand the potential role of monocyte chemoattractant protein-1 (MCP-1) in triggering spinal glial activation and its contribution to the development of neuropathic pain, we investigated the effect of peripheral nerve injury on MCP-1 expression in dorsal root ganglia (DRG) and the spinal cord, and established its temporal relationship with activation of spinal microglia and astrocytes. We observed that MCP-1 was induced by chronic constriction of the sciatic nerve in DRG sensory neurons, spinal cord motor neurons and in the superficial dorsal horn, ipsilateral to the injury. Neuronal MCP-1 induction was followed by surrounding microglial activation. After peaking at day 7 after injury, MCP-1 levels began to decline rapidly and had returned to baseline by day 150. In contrast, microglial activation peaked by day 14 and declined afterwards to reach a lower, yet significantly raised level beyond day 22 and remained increased until the end of the test period. Astrocyte activation became detectable later, progressed more slowly and also remained increased until the end of the test period, in parallel with a decreased nociceptive threshold. Our results suggest that neuronal MCP-1 may serve as a trigger for spinal microglial activation, which participates in the initiation of neuropathic pain. Delayed, sustained astrocyte activation may participate with microglia in the persistent phase of pain hypersensitivity.

The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

“…The cuff is usually 2 mm long, but other lengths have also been used in rats 22 . The polyethylene tubing depends on the species: PE-20 in mice 9 , and PE-60 24,25 or PE-90 7,8,26,27 in rats.…”

“…It was used to study morphological changes in myelinated and unmyelinated fibers 6,29 , and functional changes in sensory neurons, primary afferents and spinal neurons 19,21,22,[30][31][32][33][34][35] . It allowed demonstration that glial activation and a central shift in neuronal anion gradient participate in changes in the activity and in the responses of spinal nociceptive neurons and in neuropathic allodynia 24,[36][37][38] . The influence of glutamate receptors 7,[39][40][41] , of opioid receptors 16,[42][43][44][45] and of nicotinic receptors 46 was also studied in this model.…”

Differential astroglial responses in the spinal cord of rats submitted to a sciatic nerve double crush treated with local injection of cultured Schwann cell suspension or lesioned spinal cord extract: implications on cell therapy for nerve repair

“…Responses of astrocytes and microglia to nerve injury differ temporally. While astroglial activation is characterized by a slight increase in the cell number/size that continues in a moderate and progressive manner, microglial reaction is an acute event 42 . It was mentioned that activated microglia make an important contribution to the initiation of neuropathic pain while activated astrocytes might contribute to its maintenance.…”

Do glial cells control pain?

“…Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is a well known chemoattractant for microglia. Nerve injury increases MCP-1 expression in the DRG (Tanaka et al, 2004;White et al, 2005;Zhang & De Koninck, 2006). Mice lacking CCR2 show an impaired neuropathic pain (Abbadie et al, 2003).…”