Pain is a component of virtually all clinical pathologies, and management of pain is a primary clinical imperative. Opioids are a mainstay of pain treatment, but depending upon the pain state, therapy may involve NSAIDs, anticonvulsants, or antidepressants.
The term opiate refers to compounds structurally related to products found in opium derived from the resin of the opium poppy, Papaver somniferum. Opiates include the natural plant alkaloids, such as morphine, codeine, thebaine, and many semisynthetic derivatives. An opioid is any agent that has the functional and pharmacological properties of an opiate. Endogenous opioids are naturally occurring ligands for opioid receptors found in animals. The term endorphin is used synonymously with endogenous opioid peptides but also refers to a specific endogenous opioid, β-endorphin. Although the term narcotic originally referred to any drug that induced narcosis or sleep, the word has become associated with opioids and is often used in a legal context to refer to substances with abuse or addictive potential.
ENDOGENOUS OPIOID PEPTIDES
Several distinct families of endogenous opioids peptides have been identified: principally the enkephalins, endorphins, and dynorphins (Table 18-1). These families have several common properties:
Table 18–1Endogenous Opioid Peptides |Favorite Table|Download (.pdf) Table 18–1 Endogenous Opioid Peptides
|OPIOID LIGANDS ||RECEPTOR TYPES |
| ||μ ||δ ||κ |
|Met-enkephalin (Tyr-Gly-Gly-Phe-Met) ||++ ||+++ || |
|Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) ||++ ||+++ || |
|β-Endorphin (Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu) ||+++ ||+++ || |
|Dynorphin A (Tyr-Gly-Gly-Phe-Leu-Arg-Arg-IIe-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln) ||++ || ||+++ |
|Dynorphin B (Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr) ||+ ||+ ||+++ |
|α-Neoendorphin (Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys) ||+ ||+ ||+++ |
|Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) ||+++ || || |
|Nociceptin (orphanin FQ) (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) ||– ||– ||– |
Each derives from a distinct precursor protein, pre-pro-opiomelanocortin (pre-POMC), preproenkephalin, and preprodynorphin, respectively, encoded by a corresponding gene.
Each precursor is subject to complex cleavages by distinct trypsin-like enzymes, and to a variety of posttranslational modifications resulting in the synthesis of multiple peptides, some of which are active.
Most opioid peptides with activity at a receptor share the common amino-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu) followed by various C-terminal extensions yielding peptides of 5-31 residues; the endomorphins, with different terminal sequences, are exceptions.
The opioid peptide precursors are a protean family (Figure 18-1). The major opioid peptide derived from POMC is the potent opioid agonist, β-endorphin. The POMC sequence also is processed into a variety of nonopioid peptides including adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (α-MSH), and β-lipotropin (β-LPH). Although β-endorphin contains the sequence for met-enkephalin at its amino terminus, it is not converted to this peptide. Proenkephalin contains multiple copies of met-enkephalin, as well as a single copy of leu-enkephalin. Prodynorphin contains 3 peptides of differing lengths ...