Neuroimmune-Driven Neuropathic Pain Establishment: A Focus on Gender Differences

Abstract

The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been shown to be key players in the induction of tactile allodynia, as they release proinflammatory molecules that, in turn, sensitize nociceptive neurons within the spinal cord. However, the role of peripheral immune cells such as macrophages, infiltrating monocytes, mast cells, and T-cells has been highlighted in the last few studies, even though the data are still conflicting and need to be clarified. Intriguingly, the central (microglia) and peripheral (T-cell)-adaptive immune cells that orchestrate maladaptive process-driven neuropathic pain seem to be involved in a gender-dependent manner. In this review, we highlight the role of the microglia and peripheral immune cells in chronic degenerative disease associated with neuro-immune-inflammatory processes.

Keywords: T-cell; allodynia; microglia; neuropathic pain.

Figure 1

Schematic representation of immune system-related sex differences in injured spinal synapses. The upper panel shows resting microglia (red) and astroglial (blue) cells surrounding glutammatergic synapses under physiological conditions (non-injured). Following nerve injury (neuropathic pain i.e.,), allodynia and neuronal excitability appear at the dorsal horn of spinal cord. These events are mediated by abnormal glutamate, substance P, and ATP release in the synaptic cleft accompanied by microglia activation (red body) with consequent upregulation of P2X₄R in males (lower-left panel) but not in females. Indeed, in female subjects (lower-right panel), allodynia is mainly associated with T-cell infiltration (green body) at the spinal cord level.