T-lymphocyte-derived enkephalins reduce T.sub.h1/T.sub.h17 colitis and associated pain in mice

Background Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal T.sub.h1/T.sub.h17-associated inflammation, enkephalins released by colitogenic CD4.sup.+ T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in T.sub.h1/T.sub.h17-associated colitis. Methods The anti-inflammatory effects of endogenous opioids were investigated in both T.sub.h1/T.sub.h17-associated (transfer of CD4.sup.+CD45RB.sup.high T lymphocytes) and T.sub.h2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4.sup.+ T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4.sup.+CD45RB.sup.high T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred. Results Peripheral opioid receptor blockade increases the severity of T.sub.h1/T.sub.h17-induced colitis and attenuates T.sub.h2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a T.sub.h2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4.sup.+CD45RB.sup.high T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury. Conclusions Endogenous opioids, including T-cell-derived enkephalins, promote a T.sub.h2-type immune response, which, depending on the context, may either attenuate (T.sub.h1/T.sub.h17-associated) or aggravate (T.sub.h2-associated) intestinal inflammation.