Endogenous Opioid-Mediated Analgesia Is Dependent on Adaptive T Cell Response in Mice

Abstract

Pain is an inherent component of inflammation often accompanying immune response. A large spectrum of molecules released within the inflamed tissue induces pain by stimulating primary afferent neurons in situ. Activity of primary sensitive fibers can be counteracted by local opioid release by leukocytes. In this study, we investigated the endogenous regulation of CFA-induced inflammatory pain in the context of adaptive T cell immune response. The nociceptive response to mechanical stimuli was studied using von Frey filaments in mice immunized with OVA in CFA. The nociceptive response of nude versus wild-type mice was dramatically increased, demonstrating T cell deficiency associated with increased pain sensitivity. Based on adoptive transfer experiments of OVA-specific CD4+ T lymphocytes into nude mice, we show that Ag-specific activated, but not resting T lymphocytes are responsible for the spontaneous relief of inflammation-induced pain following Ag challenge. The analgesia was dependent on opioid release by Ag-primed CD4+ T lymphocytes at the inflammatory site. Indeed, T cell-mediated analgesia was inhibited by local injection of an opioid receptor antagonist, unable to cross the blood-brain barrier. Notably, we found opioid precursor mRNA to be >7-fold increased in Ag-specific activated CD4+ T lymphocytes, as compared with resting T lymphocytes in vivo. Taken together, our results show that CD4+ T lymphocytes acquire antinociceptive effector properties when specifically primed by Ag and point out analgesia as a property linked to the effector phase of adaptive T cell response.

Endogenous Regulation of Inflammatory Pain by T-cell-derived Opioids

“…Then, it gradually reduces in immune-competent mice, whereas it remains constant in mice lacking T lymphocytes. 36 Pathogens trigger innate immunity and promote inflammatory processes, which initiate adaptive immune response. Inflammatory cytokines and chemokines released within injured tissue mobilize resident immature DCs and drive the recruitment from the blood stream of an additional source of immature DCs, including monocytes and DC precursors.…”

“…However, the reduction of inflammatory pain observed in immune-competent mice does not occur within the first hours but only 6 days after immunization. 36 The 6-day latency period, which separates the immunization from T-cell-induced analgesia, is the time required for priming, clonal expansion, and differentiation of T cells within the draining lymph nodes and their accumulation in sufficient number at the site of inflammation. In this period, inflammatory mediators released within the injured tissue, including proinflammatory cytokines TNFa, IL-6, or IL-1b, upregulate both synthesis and axonal transport of opioid receptors from cell body to terminal endings of sensory neurons.…”

“…During this process, resting naive CD4 + T lymphocytes, not yet producing opioids, acquire the capacity to synthesize them. 36 Depending on the strength of T-cell receptor activation and the cytokine context, CD4 + T lymphocytes differentiate into different effector subsets of CD4 + T-helper lymphocytes characterized by the profile of cytokines they produce and their related effector functions. The ability to produce opioids is however irrespective of the phenotype Th1, Th2, or Th17 of effector CD4 + T cells.…”

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

“…through the arachidonic acid cascade, they also play a role in mediating endogenous peripheral analgesia, as reflected by the increased expression of opioid receptors on the peripheral terminals of sensory neurons and heightened local production of opioid peptides at the site of inflammation (10,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This suggests an integral role of the immune system in mediating analgesia in response to noxious stimuli.…”

“…Deletion of genes coding for proenkephalin (PENK) in the brain and immunocytes results in down-regulation of Met-ENK release, suggesting that ENK is synthesised from the same precursor protein molecule in both nervous and immune systems (137). In addition, the production of peripheral opioid peptides involves both circulatory and resident inflammatory cells such as T-and B-lymphocytes, granulocytes (during early inflammation) and monocytes/macrophages (during late inflammation) (16,18,(138)(139)(140)(141).…”