T-lymphocyte-derived enkephalins reduce T_h1/T_h17 colitis and associated pain in mice

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_h1/T_h17-associated inflammation, enkephalins released by colitogenic CD4⁺ 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_h1/T_h17-associated colitis.

The anti-inflammatory effects of endogenous opioids were investigated in both T_h1/T_h17-associated (transfer of CD4⁺CD45RB^high T lymphocytes) and T_h2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4⁺ 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⁺CD45RB^high T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred.

Peripheral opioid receptor blockade increases the severity of T_h1/T_h17-induced colitis and attenuates T_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_h2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4⁺CD45RB^high T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury.

Endogenous opioids, including T-cell-derived enkephalins, promote a T_h2-type immune response, which, depending on the context, may either attenuate (T_h1/T_h17-associated) or aggravate (T_h2-associated) intestinal inflammation.