Limits...
Biotransformation of beta-endorphin and possible therapeutic implications.

Asvadi NH, Morgan M, Hewavitharana AK, Shaw PN, Cabot PJ - Front Pharmacol (2014)

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, The University of Queensland Brisbane, Queensland, Australia.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Their activity is not only attributable to action the three main opioid receptors, mu (MOR), delta (DOR), and kappa (KOR) opioid receptors but their impacts appear to extend to activities at sodium channels, cytokine receptors (Finley et al., ), calcium channels and non-specific and partially undefined pharmacological effects inconsistent with G-protein coupled opioid receptor activity... Of the family of opioid peptides beta-endorphin (BE 1-31) is one of the most prominent and is the prototypical endogenous peptide for the MOR class of opioid receptors and is found within the CNS and the immune system (Cabot et al., )... In addition, BE 1-31 is a non-selective endogenous peptide with the highest affinities for MOR and DOR (Binder et al., ), suggesting that the endogenous system is not modulated by specific and selective opioid agonists in isolation... This could seemingly point to a multitude of combinations of drugs of both G-protein receptor targeting ligands or extend to those targeting other receptor classes including sodium channels (Su et al., ), potassium channels (Welch and Dunlow, ) and calcium channels (Smart et al., )... 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... These acidic pH values have been shown to be concordant with those found within inflamed tissue (Dray, )... Many studies have investigated the pharmacological changes observed following opioid peptide modification and truncation... Deakin et al. showed that the removal of one, two, or four amino acids from the C-terminal of BE 1–31 reduced the analgesic effect of fragments and that the removal of eight amino acids from the N-terminal of BE 1–31 resulted in an absence of analgesic activity (Deakin et al., )... Many other studies have provided evidence for the structural necessity of a tyrosine residue at position 1 in BE 1–31 for the retention of analgesic activity... In agreement with this notion, N-acetyl derivatives of BE 1–31 naturally found in the pituitary do not produce opioid activity (Deakin et al., )... These compounds are not only ineffective as analgesics but BE 1–27 intra-cerebroventricularly injected into mice has been shown to block the analgesia produced by BE 1–31, with a potency four times greater than that of naloxone - the non-selective opioid antagonist (Hammonds et al., )... However, further truncation to BE 1-26 decreased the antagonist effect whilst further reduction of the peptide chain resulted in the complete loss of inhibition of analgesic activity (Nicolas and Choh Hao, )... The analgesic potency of further abbreviated forms remains from peptide sequences of BE 1–31 right down to BE 1–4, the overwhelming consequence of the truncation to smaller N-terminal conserved sequences is decreased affinity for MOR, but increased activity at DOR and KOR (Jaba et al., )... There is also a substantial body of evidence for opioids interacting with Toll-like receptors within the immune system (Franchi et al., ), with stereo selectivity for the plus isomers of common opioids such as morphine-3-glucuronide (Lewis et al., ), naloxone and naltrexone (Hutchinson et al., )... These effects have been correlated with modulation of cytokine expression or release, and result in changes that may effect cell proliferation and chemotaxis.

No MeSH data available.


Biotransformation of beta-endorphin 1–31 within inflamed tissue and fragment actions. Immune cells containing beta-endorphin migrate to inflamed tissue in a site directed manner. Beta-endorphin is released within the inflammatory mileu and biotransformed rapidly producing fragments with various pharmacological actions. Adapted with permission from Kapitzke et al. (2005).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3928545&req=5

Figure 1: Biotransformation of beta-endorphin 1–31 within inflamed tissue and fragment actions. Immune cells containing beta-endorphin migrate to inflamed tissue in a site directed manner. Beta-endorphin is released within the inflammatory mileu and biotransformed rapidly producing fragments with various pharmacological actions. Adapted with permission from Kapitzke et al. (2005).

Mentions: This concept touches on a new theme evolving in novel therapeutic strategies in the pain field, i.e. the targeting of multiple channels with either one non-selective ligand or a combination of selective ligands to produce effects that are either synergistic or, at a minimum, differential in terms of side effects. This could seemingly point to a multitude of combinations of drugs of both G-protein receptor targeting ligands or extend to those targeting other receptor classes including sodium channels (Su et al., 2002), potassium channels (Welch and Dunlow, 1993) and calcium channels (Smart et al., 1995). The scope of the possible therapeutic targets is immense and, potentially of even greater complexity, is the dose determination for such combinations. Perhaps the answer in part lies in the endogenous opioid system, which is, in essence, the system designed to mediate noxious stimuli as well as interact with the immune system in disease (Figure 1).


Biotransformation of beta-endorphin and possible therapeutic implications.

Asvadi NH, Morgan M, Hewavitharana AK, Shaw PN, Cabot PJ - Front Pharmacol (2014)

Biotransformation of beta-endorphin 1–31 within inflamed tissue and fragment actions. Immune cells containing beta-endorphin migrate to inflamed tissue in a site directed manner. Beta-endorphin is released within the inflammatory mileu and biotransformed rapidly producing fragments with various pharmacological actions. Adapted with permission from Kapitzke et al. (2005).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928545&req=5

Figure 1: Biotransformation of beta-endorphin 1–31 within inflamed tissue and fragment actions. Immune cells containing beta-endorphin migrate to inflamed tissue in a site directed manner. Beta-endorphin is released within the inflammatory mileu and biotransformed rapidly producing fragments with various pharmacological actions. Adapted with permission from Kapitzke et al. (2005).
Mentions: This concept touches on a new theme evolving in novel therapeutic strategies in the pain field, i.e. the targeting of multiple channels with either one non-selective ligand or a combination of selective ligands to produce effects that are either synergistic or, at a minimum, differential in terms of side effects. This could seemingly point to a multitude of combinations of drugs of both G-protein receptor targeting ligands or extend to those targeting other receptor classes including sodium channels (Su et al., 2002), potassium channels (Welch and Dunlow, 1993) and calcium channels (Smart et al., 1995). The scope of the possible therapeutic targets is immense and, potentially of even greater complexity, is the dose determination for such combinations. Perhaps the answer in part lies in the endogenous opioid system, which is, in essence, the system designed to mediate noxious stimuli as well as interact with the immune system in disease (Figure 1).

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, The University of Queensland Brisbane, Queensland, Australia.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Their activity is not only attributable to action the three main opioid receptors, mu (MOR), delta (DOR), and kappa (KOR) opioid receptors but their impacts appear to extend to activities at sodium channels, cytokine receptors (Finley et al., ), calcium channels and non-specific and partially undefined pharmacological effects inconsistent with G-protein coupled opioid receptor activity... Of the family of opioid peptides beta-endorphin (BE 1-31) is one of the most prominent and is the prototypical endogenous peptide for the MOR class of opioid receptors and is found within the CNS and the immune system (Cabot et al., )... In addition, BE 1-31 is a non-selective endogenous peptide with the highest affinities for MOR and DOR (Binder et al., ), suggesting that the endogenous system is not modulated by specific and selective opioid agonists in isolation... This could seemingly point to a multitude of combinations of drugs of both G-protein receptor targeting ligands or extend to those targeting other receptor classes including sodium channels (Su et al., ), potassium channels (Welch and Dunlow, ) and calcium channels (Smart et al., )... 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... These acidic pH values have been shown to be concordant with those found within inflamed tissue (Dray, )... Many studies have investigated the pharmacological changes observed following opioid peptide modification and truncation... Deakin et al. showed that the removal of one, two, or four amino acids from the C-terminal of BE 1–31 reduced the analgesic effect of fragments and that the removal of eight amino acids from the N-terminal of BE 1–31 resulted in an absence of analgesic activity (Deakin et al., )... Many other studies have provided evidence for the structural necessity of a tyrosine residue at position 1 in BE 1–31 for the retention of analgesic activity... In agreement with this notion, N-acetyl derivatives of BE 1–31 naturally found in the pituitary do not produce opioid activity (Deakin et al., )... These compounds are not only ineffective as analgesics but BE 1–27 intra-cerebroventricularly injected into mice has been shown to block the analgesia produced by BE 1–31, with a potency four times greater than that of naloxone - the non-selective opioid antagonist (Hammonds et al., )... However, further truncation to BE 1-26 decreased the antagonist effect whilst further reduction of the peptide chain resulted in the complete loss of inhibition of analgesic activity (Nicolas and Choh Hao, )... The analgesic potency of further abbreviated forms remains from peptide sequences of BE 1–31 right down to BE 1–4, the overwhelming consequence of the truncation to smaller N-terminal conserved sequences is decreased affinity for MOR, but increased activity at DOR and KOR (Jaba et al., )... There is also a substantial body of evidence for opioids interacting with Toll-like receptors within the immune system (Franchi et al., ), with stereo selectivity for the plus isomers of common opioids such as morphine-3-glucuronide (Lewis et al., ), naloxone and naltrexone (Hutchinson et al., )... These effects have been correlated with modulation of cytokine expression or release, and result in changes that may effect cell proliferation and chemotaxis.

No MeSH data available.