Abstract
A large body of evidence now exists for the immune cell expression, production, and the release of beta-endorphin (BE 1–31) within inflamed tissue. The inflammatory milieu is characterised by increased acidity, temperature and metabolic activity. Within these harsh conditions BE 1–31 is even more susceptible to increased enzymatic degradation over that of plasma or other non-injured tissue. To elucidate the biotransformation pathways of BE 1–31 and provide an insight to the impact of inflamed tissue environments, BE 1–31 and three of its major N-terminal fragments (BE 1–11, BE 1–13 and BE 1–17) were incubated in inflamed tissue homogenates at pH 5.5 for 2 hrs. In addition, the potency of BE 1–31 and five main N – terminal fragments (BE 1–9, BE 1–11, BE 1–13, BE 1–17, BE 1–20) was assessed at mu-opioid receptors (MOR), delta-opioid receptors (DOR), and kappa-opioid receptors (KOR). Opioid receptor potency was investigated by examining the modulation of forskolin induced cAMP accumulation. The majority of the N-terminal fragment of BE 1–31 had similar efficacy to BE 1–31 at MOR. The shortest of the major N-terminal fragments (BE 1–9), had partial agonist activity at MOR but possessed the highest potency of all tested peptides at DOR. There was limited effect for BE 1–31 and the biotransformed peptides at KOR. Major N-terminal fragments produced within inflamed tissue have increased presence within inflamed tissue over that of the parent molecule BE 1–31 and may therefore contribute to BE 1–31 efficacy within disease states that involve inflammation.
Highlights
Beta-endorphin (BE 1–31) is an endogenous opioid peptide that has been shown to have important roles in pain, immune system function [1,2], reward [3], and stress [4,5,6]
BE 1–31 is released from immune cells within inflamed tissue to provide analgesia [7]
The cleavage of BE peptides is proposed to be largely due to aminopeptidases [36], angiotensin-converting enzyme (ACE), serine peptidases [22], insulin degrading enzyme [37], dipeptidyl peptidase III and dipeptidyl peptidase IV
Summary
Beta-endorphin (BE 1–31) is an endogenous opioid peptide that has been shown to have important roles in pain, immune system function [1,2], reward [3], and stress [4,5,6]. BE 1–31 is primarily produced in the pituitary gland and the brain but can be synthesised and released by leukocytes [7,8]. The production of BE is increased in leukocytes and it is subsequently released in inflamed tissue after which it undergoes rapid biotransformation [11,12,13]. The role of opioid peptide metabolites in peripheral analgesia is of paramount consideration in understanding peripheral opioid action. There is variability in the reported literature in regards to clearance, distribution and half-life of BE 1–31 [14,15], which can be attributed substantially to the species studied, anatomical location and tissue source being examined
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