Neuropathic pain and cytokines: current perspectives

Abstract

Neuropathic pain represents a major problem in clinical medicine because it causes debilitating suffering and is largely resistant to currently available analgesics. A characteristic of neuropathic pain is abnormal response to somatic sensory stimulation. Thus, patients suffering peripheral neuropathies may experience pain caused by stimuli which are normally nonpainful, such as simple touching of the skin or by changes in temperature, as well as exaggerated responses to noxious stimuli. Convincing evidence suggests that this hypersensitivity is the result of pain remaining centralized. In particular, at the first pain synapse in the dorsal horn of the spinal cord, the gain of neurons is increased and neurons begin to be activated by innocuous inputs. In recent years, it has become appreciated that a remote damage in the peripheral nervous system results in neuronal plasticity and changes in microglial and astrocyte activity, as well as infiltration of macrophages and T cells, which all contribute to central sensitization. Specifically, the release of pronociceptive factors such as cytokines and chemokines from neurons and non-neuronal cells can sensitize neurons of the first pain synapse. In this article we review the current evidence for the role of cytokines in mediating spinal neuron-non-neuronal cell communication in neuropathic pain mechanisms following peripheral nerve injury. Specific and selective control of cytokine-mediated neuronal-glia interactions results in attenuation of the hypersensitivity to both noxious and innocuous stimuli observed in neuropathic pain models, and may represent an avenue for future therapeutic intervention.

Keywords: anti-inflammatory cytokines; astrocytes; first pain synapse; microglia; proinflammatory cytokines.

Figure 1

Schematic representation of morphological glial cell changes and immune cell infiltration in the lumbar spinal cord following peripheral nerve injury. Notes: The altered activity states of spinal glial cells induced by peripheral nerve injury are most commonly identified by changes in cell morphology. Microglia transition from a surveillant state to an “enhance-response” state,, which is evident by retraction of their fine processes and enlargement of cell bodies. Astrocytes transition from an active state to reactive state., Infiltration of macrophages and T lymphocytes is also evident within the dorsal horn.,–

Figure 2

CX3CR1 is expressed only by microglial cells in the spinal cord. Notes: Immunohistochemical analysis conducted in our laboratory using a mouse in which the CX3CR1 receptor is tagged with GFP reveals this protein is expressed exclusively by microglia in the dorsal horn of the spinal cord. Colocalization of CX3CR1 is with a microglial cell marker (Iba1), but not an astrocytic (GFAP) or neuronal (NeuN) marker. Scale bars are equal to 100 μm and 30 μm in high magnification inserts. Abbreviations: CX3CR1, CX3C chemokine receptor 1; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; Iba1, ionized calcium-binding adapter molecule 1; NeuN, neuronal nuclei.

Figure 3

Schematic representation of spinal cytokine/chemokine signaling mechanisms which contribute to enhanced nociceptive transmission following peripheral nerve injury. Notes: Primary afferent fibers (Aβ [blue], Aδ [green] and C [red]) transmit signals from the periphery, through the DRG to the dorsal horn of the spinal cord. Following damage to a peripheral nerve, a number of cytokine/chemokine signaling systems exhibit plastic changes at the first synapse in the pain pathway. Abbreviations: Aβ, A beta fiber; Aδ, A delta fiber; DRG, dorsal root ganglia; JAK/STAT, Janus kinase/signal transducer and activator of transcription; IL, interleukin; NMDA, N-methyl-D-aspartate; CCL2, chemokine ligand 2; TNF, tumor necrosis factor; NFκB, nuclear factor kappa B; TNFR, tumor necrosis factor receptor; CX3CR1, CX3C chemokine receptor 1; CX3CL1, CX3C chemokine ligand 1; CatS, cathepsin S; CCR2, chemokine receptor type 2; R, receptor; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; p38, p38 mitogen-activated protein kinase.