The importance of a neuroinflammatory response to the development and maintenance of inflammatory and neuropathic pain have been highlighted in recent years. Inflammatory cells contributing to this response include circulating immune cells such as monocytes, T and B lymphocytes, and neutrophils, as well as microglia in the central nervous system. Pain signals are transmitted via sensory neurons in the peripheral nervous system, which express various receptors and channels that respond to mediators secreted from these inflammatory cells. Chronobiological rhythms, which include the 24-hr circadian cycle, have recently been shown to regulate both nervous and immune cell activity and function. This review examines the current literature on chronobiological control of neuroinflammatory processes, with a focus on inflammatory and neuropathic pain states. While the majority of this work has stemmed from observational studies in humans, recent advances in using animal models have highlighted distinct mechanisms underlying these interactions. Better understanding interactions between the circadian and neuroimmune systems can help guide the development of new treatments and provide improved care for patients suffering from acute and chronic pain.

Circulating immune cells, which are recruited to the site of injury/disease, secrete various inflammatory mediators that are critical to nociception and pain. The role of tissue-resident immune cells, however, remains poorly characterized. One of the first cells to be activated in peripheral tissues following injury are γδT cells, which serve important roles in infection, disease, and wound healing. Using a mouse line lacking these cells, we sought to identify their contribution to inflammatory pain. Three distinct models of peripheral inflammatory pain were used: intraplantar injection of formalin (spontaneous inflammatory pain), incisional wound (acute inflammatory pain), and intraplantar injection of complete Freund's adjuvant (chronic inflammatory pain). Our results show that absence of γδT cells does not alter baseline sensitivity, nor does it result in changes to mechanical or thermal hypersensitivity after tissue injury. Myeloid cell recruitment did show differential changes between models of acute and chronic inflammatory pain. These results were consistent in both male and female mice, suggesting that there are no sex differences in these outcomes. This comprehensive characterization suggests that γδT cells do not contribute to basal sensitivity or the development and maintenance of inflammatory pain.

Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6Clow myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.

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Stimuli of the environment, like objects, systematically activate the actions they are associated to. These activations occur extremely fast. Nevertheless, behavioral data reveal that, in most cases, these activations are then automatically inhibited, around 100 ms after the occurrence of the stimulus. We thus tested whether this early inhibition could be indexed by a central component of the N1 event-related brain potential (ERP). To achieve that goal, we looked at whether this ERP component is larger in tasks that could increase the inhibition and in trials where reaction times (RTs) happen to be long. The illumination of a real space bar of a keyboard out of the dark was used as a stimulus. To maximize the modulation of the inhibition, the task participants had to perform was manipulated across blocks. A look-only task and a count task were used to increase inhibition and an immediate press task was used to decrease it. ERPs of the two block-conditions where presses had to be prevented and where the largest central N1s were predicted were compared to those elicited in the press task, differentiating the ERPs to the third of the trials where presses were the slowest from the ERPs to the third of the trials with the fastest presses. Despite larger negativities due to lateralized readiness potentials (LRPs) and despite greater attention likely in immediate press-trials, central N1s were found to be minimal for the fastest presses, intermediate for the slowest ones and maximal for the two no-press conditions. These results thus provide a strong support for the idea that the central N1 indexes an early and short lasting automatic inhibition of the actions systematically activated by objects. They also confirm that the strength of this automatic inhibition spontaneously fluctuates across trials and tasks. On the other hand, just before N1s, parietal P1s were found larger for fastest presses. They might thus index the initial activation of these actions. Finally, consistent with the idea that N300s index late inhibition processes, that occur preferentially when the task requires them, these ERPs were quasi absent for fast presses trials and much larger in the three other conditions.