T lymphocytes releasing enkephalins in the gut : how to modulate chronic inflammatory pain – LYMPHOPIOID

Pain is clearly the number one reason for patients to consult medical doctors, and is the first symptom they want to be relieved by therapy. Opioids are the most efficient drugs to treat pain but their chronic use at pharmacological doses results in major side effects. The observation that analgesia, free of side effects, can be mediated by opioid receptors expressed on peripheral sensory fibers has opened new therapeutic perspectives for pain treatment. Furthermore, a number of studies suggest that a large part of analgesic effects induced by systemic administration of opioids can be dependent on stimulation of opioid receptors expressed on peripheral sensory fibers. Thus, the finding that endogenous opioid peptides produced by immune cells within inflamed tissues relieve pain represents a sufficiently promising therapeutic way to better understand the physiology of this endogenous pain regulatory mechanism. Although the three classes of endogenous opioids enkephalins, endorphins and dynorphins, have been described in immune cells, their relative prevalence in each immune cell subsets involved in innate and adaptive immune responses have not been investigated so far. The mechanisms involved in the synthesis, production and release of opioids by T lymphocytes in the context of an antigen-specific immune response have not been either explored.
In a preliminary study, we have quantified the expression level of mRNA encoding for all three opioid precursors in dendritic cells (DCs), CD4+ and CD8+ T lymphocytes, B lymphocytes and macrophages in mice. We found that although precursors for endorphins and dynorphins may be expressed, the precursor for enkephalins (proenkephalin, PENK) is the main endogenous opioid produced by immune cell subsets. In resting conditions, CD4+ T lymphocytes, macrophages and DCs but not B lymphocytes and CD8+ T lymphocytes express PENK mRNA. Cell activation up-regulates PENK mRNA level only in DCs and CD4+ T lymphocytes. In activated CD4+ T lymphocytes, PENK mRNA level were the highest, reaching more than 50% of that measured in brain. Thus, mature activated CD4+ T lymphocytes could constitute the main sources of opioids (enkephalins) in peripheral tissues. We propose here to establish the contribution of CD4+ T lymphocytes-derived endogenous opioids to inflammatory pain relief. From all peripheral tissues, opioid receptors are the most largely expressed in the gut, where they seem to exert a strong role on inflammatory responses. The objectives of the present study will be 1/ to define the role of effector functions of CD4+ T lymphocyte on their ability to release opioids, 2/ to define the expression and release of endogenous opioids by CD4+ in gut inflammation (inflammatory bowel disease), 3/ to investigate the contribution of CD4+ T lymphocyte-derived opioids to inflammatory pain relief, 4/ to study the control of CD4+-derived opioid synthesis by inflammatory mediators such as proteases and their receptors, and 5/ to determine the opioid receptors activated by CD4+-derived endogenous opioids.
The general objective of the present program is to understand the processes and functions of endogenous opioid release, in the context of adaptive and innate immune response such as inflammatory bowel diseases. Determining the conditions and cell types involved in the activation of endogenous mechanisms for the control of pain, constitute a first necessary step towards the definition of new therapeutic options for the treatment of pain: favoring endogenous control of pain.