Neuroimmune Interactions in Chronic Pain: Focus on Mononuclear Phagocytes

Chronic painPain represents a significant unmet therapeutic need, particularly for those chronic painPain states with a neuropathic component (i.e., a lesion or disease of the somatosensory nervous system). Opioids, tricyclic antidepressants and gabapentinoids are used as a means of directly dampening hyperexcitable nociceptive neurons and circuits that result in the sensory experience of painPain. However, interactions between the nervous system and the innate immune system, particularly mononuclear phagocytesPhagocyte (monocytesMonocyte and tissue macrophagesMacrophage, including micorglia) are increasingly recognized as powerful determinants of painPain sensitivity. MacrophagesMacrophage are known to mediate painPain hypersensitivity and resolution of inflammation in most tissues where painPain is generated or experienced, including the skinSkin, muscle and joints, viscera, peripheral nerves, and sensory ganglia. The presence of these cells in the meninges surrounding the brain and spinal cord hints at another key site of action where painPain perception can be influenced, along with phenotypic modification of microgliaMicroglia that sculpt and influence the central nervous systemCentral nervous system circuitry and generate one of the major substrates of chronic painPain. In this chapter, we will describe the ability of resident and monocyteMonocyte-derived macrophagesMacrophage to release proinflammatory, painPain-promoting cytokines and neurotransmittersNeurotransmitter that initiate and maintain painPain. We will also describe their ability to secrete anti-inflammatory cytokines, inhibitory neurotransmittersNeurotransmitter, and other pro-resolving mediators that promote healing following tissue damage. These factors can engage receptor signaling on sensory neurons, which can in turn release neuropeptides that modify mononuclear phagocytePhagocyte function. Ultimately, the pervasive and highly plastic nature of mononuclear phagocytesPhagocyte links them inextricably to neuronal function in health and disease, making them compelling analgesic targets.