Endorphin Release And The Alleviation Of Pain Biology Essay

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Endorphins are a class of polypeptides found in neurons which act as opiates in their ability to induce analgesic affects. In particular, Beta-endorphin is a naturally occurring endogenous opioid produced primarily in the intermediate anterior pituitary (Hartwig, 1991). Beta-endorphin has shown to be vital for the alleviation of pain and anxiety. Beta-endorphin research has lead to pharmaceutical advancements in pain management. In this review, the cellular-molecular mechanisms of Beta-endorphin biosynthesis, regulation, and distribution will be outlined, along with the roles of pharmacologic agents such as fentanyl and naloxone in nociception.

As noted by Hartwig 1991, in 1979 Roberts et al and Nakanishi et al first identified the 31kD glycoprotein, known as pro-opiomelanocortin (POMC) and its respective gene as the precursor for a family of multifunctional neuropeptides. This family of peptides included α-melanocyte stimulating hormone (α-MSH), β-lipotropin (β-LPH), and adrenocorticotropin (ACTH) (Loh, 1992). It was discovered that proteolytic cleavage of POMC is used in the process of synthesizing these peptides (β-LPH and ACTH) (Loh, 1992). Beta-endorphin (β-endorphin 1-31) is synthesized by the cleavage of β-LPH at the 61-91 sequence sites (Loh, 1992). It was also found that inactivated forms of β-endorphin 1-31, such as β -endorphin1-27 and β -endorphin 1-26 are synthesized through peptide N-acetylation (Loh, 1992). The 41 aminoacid enzyme, corticotropin releasing hormone (CRH), has been identified as the protein which commonly facilitates the cleavage of POMC at paired basic residues (other less common enzymes: PCE, PC1, PC2, & CPH) (Hartwig, 1991). CRH is Ca2+ activated and specific towards Lys-Arg cleavage sites on POMC, thereby freeing peptides with extended C-terminals (Loh, 1992). CRH is made in the parvocellular neuroendocrine cells of the hypothalamus, and as noted by Hartwig 1991, is transported to the anterior and interior pituitary through "hypophyseal portal veins". The stimulation of CRH release has been linked to numerous molecules which are characteristically found at higher concentrations during instances of pain. These include neurotransmitters such as acetylcholine and 5-hydroxytryptamine (serotonin) (Hartwig, 1991).

The proteolysis of POMC and subsequent release of Beta-endorphin is tissue specific, and thus processed differently between the brain and the interior and anterior pituitary lobes (Loh, 1992). For example, as indicated above, POMC processing in the intermediate and anterior pituitary produces almost entirely, activated β-endorphin 1-31. In the brain however, particularly the arcuate nucleus of the hypothalamus (Bancroft, 2005), POMC processing primarily produces β-endorphin 1-31, although significant amounts of inactivated opiate, β-endorphin 1-26, are also found (Loh, 1992). POMC cells are also found in the other areas of the brain, such as the midbrain, locus coeruleus (lower brain stem) and the limbic system (Hartwig, 1991). This is noteworthy as all locations to which POMC cells are found play crucial roles in pain reception.

As noted by Loh 1992, in experiments by Gainer at al and Chen et al, where rats were treated with haloperidol (dopamine antagonist), it was demonstrated that Beta-endorphin synthesis is regulated at "post transcriptional and post translational" levels. In these experiments, Haloperidol was administered to stimulate the synthesis and cleavage of POMC cells. It was discovered that haloperidol increased the number of POMC neuropeptides released, including β-endorphin 1-31. This indicated that common "dopaminergic agents" (as indicated by Loh 1992), found at high concentrations during instances of pain, regulate the secretion of POMC peptides (Loh 1992).

Once Beta-endorphin is synthesized from POMC, it is released into the bloodstream. Subsequently, hypothalamic neurons will transport Beta-endorphin into the brain and spinal cord (Dalayeun et al, 1993). Beta-endorphins will then bind to specific opiate receptors such as the µ1 receptor located in the periaqueductal gray region of the midbrain and dorsal horn of the spinal cord (Hartwig, 1991). It is noteworthy to highlight that in the brain stem, the network of periaqueductal gray matter projects into the spinal cord where Beta-endorphin acts as an inhibitor for spinal neurons stimulated by pain stimuli (Dalayeun et al, 1993). All opiate receptors are G-protein coupled, thereby making the opioid (in this case Beta-endorphin) the ligand (Hartwig, 1991). A conformational change is seen when binding occurs, and dependant upon the location, other secondary receptors will couple to form a "receptor complex" (Hartwig, 1991). This results in the analgesic affects characteristic of Beta-endorphin. It is crucial to note that all opioid receptors, when bound to its opiate, are natural inhibitors of neurotransmitters such as GABA, which inhibits (GABA) analgesic chemicals such as dopamine (Loh, 1992). As such, opioid-receptor interactions unblock dopamine pathways by inhibiting GABA. The µ1 receptor is also characteristic of promoting calcium uptake and activating protein kinase A via increasing cyclic AMP levels (Hartwig, 1991).

When examining pharmacologic agonists and antagonists in nociception, interesting revelations are made based on the cellular-molecular mechanisms of Beta-endorphins. First naloxone, an endogenous μ-opioid receptor antagonist, is often used in the event of morphine overdose (Loh, 1992). Naloxone acts by competing for μ-opioid receptor binding sites, thereby reducing the effects of Beta-endorphin (Hartwig, 1991). Experiments where patients were administered this drug showed high levels of pain and high blood Beta-endorphin levels (Hartwig, 1991). Fentanyl, on the other hand, acts as an opioid agonist. Patients administrated this drug during surgery for example, showed low levels of pain coupled with low blood levels of Beta-endorphin (Hartwig, 1991). In Hartwig 1991, it is noted that Hargreaves et al explains that these results are indicative of a negative feedback loop with the "hypothalamo-pituitary-adrenal axis". This model serves great future potential as a basis for the development of drugs in pain modulation for diseases such as neuralgia and rheumatoid arthritis.

In this review, the cellular-molecular mechanisms of Beta-endorphin biosynthesis, regulation, and distribution were elucidated on the basis of outlining how the modulation of pain is intricate, complex, yet entirely natural. Numerous reports continue to show that beta-endorphine is 30 times more potent than morphine (Hartwig, 1991), and as such, aid in emphasizing the importance research built upon the intricacies of the human body.

Word count: 990

Annotated References:

Hartwig, A.C. (1991). Peripheral Beta Endorphin and Pain Modulation. Anesth Prog. 38 (1), 75-78.

This review article examines the synthesis, storage and distribution of Beta Endorphin for the modulation of pain.

Nakanishi S, Inoue A, Kita T, Nakamura M, Chang ACY, Choen S.N, Numa S. (1979). Nucleotide sequence of cloned cDNA for bovine corticotropin-f3-lipotropin precursor. Nature. 278(1), 423-427.

This review article explains the discovery of the gene for POMC peptide and its relative neuropeptides

Loh, Y.P. (1992). Molecular Mechanisms of Beta Endorphin Synthesis. Biochemical Pharmacology. 44 (5), 843-849.

This review article explains in depth, the molecular mechanisms involved in the biosynthesis of beta-endorphin and its mediation through translational and post translational means.

Bancroft. (2005). The endocrinology of sexual arousal. Journal of Endocrinology. 186 (5), 411-427.

This review explains the entirety of sexual arousal enzymology, including the roles of testosterone and estrogen.

Gainer H, Russell JT, Loh YP. (1984). An aminopeptidase activity in bovine pituitary secretory vesicles that cleaves the N-terminal arginine from @lipotropin,. FEBS. 175 (1), 135-139.

This article explains how its experiment demonstrated that Beta-endorphin synthesis is regulated at "post transcriptional and post translational" levels

Dalayeun JF, Nores JM, Bergal S. (1993). Physiology of /3-endorphins. A close-up view and a review of the literature. Biomed & Pharmacother. 47 (1), 311-320.

This article explains how hypothalamic neurons will transport Beta-endorphin into the brain and spinal cord

Hargreaves KM, Dionne RA, Mueller GP, Goldstein DS, Dubner R. (1986) Naloxone, fentanyl, and diazepam modify plasma beta-endorphin levels during surgery. Clin Pharmacol Ther 40(1), 165-171.

This article explains that the results of high beta-endorphin levels after Naloxone administration are indicative of a negative feedback loop with the "hypothalamo-pituitary-adrenal axis"