Dynorphin

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” This 32-amino acid molecule consists of both dynorphin A and dynorphin B. Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” This 32-amino acid molecule consists of both dynorphin A and dynorphin B. Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively). Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord. Dynorphins are stored in large (80-120 nm diameter) dense-core vesicles that are considerably larger than vesicles storing neurotransmitters. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft. Dense-core vesicle storage is characteristic of opioid peptides storage. The first clues to the functionality of dynorphins came from Goldstein et al. in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al. applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency. Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor. Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B. Dynorphin is produced in many different parts of the brain, including the hypothalamus, the striatum, the hippocampus and the spinal cord. Gene expression patterns from the Allen Brain Atlases in mouse, macaque and humans can be seen here. Dynorphin has many different physiological actions, depending upon its site of production. Dynorphin has been shown to be a modulator of pain response. Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency. Analgesia was partially eliminated by opioid antagonist naloxone. Han and Xie found dynorphin to be 6-10 times more potent than morphine on a per mole basis. In addition, morphine tolerance did not reduce dynorphin-induced analgesia. Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia. The authors found that combining subanalgesic levels of morphine and dynorphin A1-13, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects. However, when dynorphin A1-13 was injected into the intracerebroventricular (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia. A study by Lai et al. found that dynorphin might actually stimulate pain. The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors. Lai et al. studied the effects of dynorphin A2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.