Within BE 1–31 the amino acids identified as the most susceptible for hydrolytic degradation were (Tyr 1–Gly 2), (Lys 9-Ser 10), (Leu 17-Phe 18-Lys 19-Asn 20), (Lys 24-Asn 25), (Lys 28-Lys 29-Gly 30-Gln 31).
The rate of metabolism of BE 1–31 at pH 5.5 was also higher than the rate of metabolism of BE 1–31 at pH 7.4. This study demonstrated that the hydrolytic metabolism of BE 1–31 in homogenised inflamed tissue was faster than in serum and trypsin incubation. A recent study in our laboratory has identified biotransformed fragments of BE 1–31 in rat serum, rat inflamed tissue, and following tyrosine hydrolysis in media. The metabolism of BE 1–31 has previously been examined in rat brain –, cultured aortic endothelial cells, human T cells, thymoma cell line, , human plasma, and human pituitary. There is variability in the reported literature in regards to clearance, distribution and half-life of BE 1–31, , which can be attributed substantially to the species studied, anatomical location and tissue source being examined. Therefore, the role of opioid peptide metabolites in peripheral analgesia is of paramount consideration in understanding peripheral opioid action. During inflammation, the production of BE is increased in leukocytes and it is subsequently released in inflamed tissue after which it undergoes rapid biotransformation –. BE 1–31 is derived from its precursor pro-opiomelanocortin by an enzymatic process. BE 1–31 is primarily produced in the pituitary gland and the brain but can also be synthesised and released by leukocytes. 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.īeta-endorphin (BE 1–31) is an endogenous opioid peptide that has been shown to have important roles in pain, immune system function, , reward, and stress –. There was limited effect for BE 1–31 and the biotransformed peptides at KOR. 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. The majority of the N-terminal fragment of BE 1–31 had similar efficacy to BE 1–31 at MOR. Opioid receptor potency was investigated by examining the modulation of forskolin induced cAMP accumulation. 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). 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.
Within these harsh conditions BE 1–31 is even more susceptible to increased enzymatic degradation over that of plasma or other non-injured tissue. The inflammatory milieu is characterised by increased acidity, temperature and metabolic activity. 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.
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