Neuropeptides: Opioids and Oxytocin
Thomas F. Murray
Creighton University, Omaha, NE, USA
Endogenous neuropeptide signaling systems have been shown to have a role in a wide array of behavioral functions ranging from promoting social attachment behavior between mating partners in certain species, to regulation of vigilance and modulation of pain perception, to name a few. Neuropeptides have major roles in regulating the activity of neuronal signaling between brain regions, and expression of neuropeptides and their receptors has served as an important genetic substrate on which evolutionary forces have optimized behaviors (McGrath 2017).
Endogenous Opioid Peptides
Opiates are drugs derived from opium and include morphine, codeine (both alkaloids), and a variety of semisynthetic analogs derived from them or from thebaine, which is another component of opium (Pasternak and Pan 2013). Opium preparations extracted from poppy seeds have been used for thousands of years to treat pain, cough, diarrhea, and to produce euphoria. The term opioid is more general and is used to describe all drugs, irrespective of structure, with a morphine‐like activity, including endogenous peptides.
The existence of specific receptors for opiates in mammalian tissues had been suspected since the 1950s based on strict structure–activity requirements, including sterospecificity, for opiate drugs. In the early 1970s, methods developed for the direct biochemical detection of receptors were applied to the search for specific opiate receptors in brain tissue. Using a radioligand binding method, Snyder and colleagues identified an opiate receptor in brain and intestinal tissue in 1973 (Snyder 2004). The identified receptor was pharmacologically relevant in that an extensive series of opiate drugs bound with affinities closely matching their analgesic potencies. These opiate receptors were found to be enriched in areas of animal brain known to be involved in the processing of sensory and pain signals such as the periaqueductal gray, medial thalamus and the substantia gelatinosa of the spinal cord and brainstem. A very high density of opiate receptors was also found in the locus coeruleus where opioids exert a regulatory influence on noradrenergic pathways (Snyder 2004). The discovery of these specific receptors for opiates immediately suggested the presence of endogenous opiate‐like substances that normally target these receptors. The first description of such endogenous substances was in 1975 with the characterization of substances from porcine brain that had opiate agonist properties (Hughes et al. 1975). These substances consisted of two enkephalin pentapeptides: [Met]enkephalin (Tyr‐Gly‐Gly‐Phe‐Met) and [Leu]enkephalin (Tyr‐Gly‐Gly‐Phe‐Leu). Subsequent to the identification of these two enkephalin pentapeptides, other investigators characterized several additional endorphins (endogenous opioids) from porcine hypothalamus‐neurohypophysis. The endorphins all contain the N‐terminal Tyr‐Gly‐Gly‐Phe (Met or Leu) sequence followed by varied C‐terminal extensions yielding peptides from 5 to 31 amino acids in length (Akil et al. 1998). Two important members of the endorphin family are β‐endorphin, an extremely potent endogenous opioid and dynorphin A, a 17‐amino acid peptide with a distinctive neuroanatomical distribution and physiology. In mammals, the endogenous opioid peptides are derived from four precursors: pro‐opiomelanocortin (POMC), pro‐enkephalin, pro‐dynorphin, and pro‐nociceptin/orphanin FQ. The characterization of the POMC gene revealed that it codes for the stress hormone ACTH and the opioid peptide β‐endorphin. The endogenous opioid peptides and their respective precursors are listed in Table 5.1.
Table 5.1 Mammalian endogenous opioids.
|Precursor||Endogenous opioid||Amino acid sequence|
Dynorphin A (1–8)
The Pro‐enkephalin precursor encodes for multiple copies of [Met]enkephalin as well as one copy of [Leu]enkephalin. Similarly, Pro‐dynorphin encodes for three opioid peptides of distinct lengths including dynorphin A, dynorphin B, and the neoendorphins.
The POMC‐derived peptides have a limited distribution in the central nervous system (CNS) with high levels found in the arcuate nucleus and pituitary. The pro‐dynorphin and pro‐enkephalin peptides have a wider distribution in the CNS and are frequently found in the same pathways. The pro‐enkephalin peptides are present in areas of the CNS that are involved with the perception of pain such as laminae I and II of the spinal cord, the spinal trigeminal nucleus, and the periaqueductal gray. These peptides are also found in limbic structures regulating affective behavior and reward, such as the amygdala, the nucleus accumbens, the hippocampus, the locus ceruleus, and the cerebral cortex. Although there are a few long axon enkephalinergic tracts in the brain, these peptides are typically expressed in interneurons. One group of long axon pro‐dynorphin and pro‐enkephalin gene product‐containing pathways comprise part of the output neurons of the striatum and accumbens (Akil et al. 1998). In the dorsal striatum, the striatonigial neurons contain pro‐dynorphin products, substance P and GABA; whereas the striatopallidal neurons contain enkephalin and GABA. As a result of the limited distribution of β‐endorphin in the brain, the enkephalins and dynorphins are considered to be the predominant central opioid peptide neurotransmitters.
It is now well established that these endogenous opioids interact with an opioid receptor family composed of three subtypes. Pharmacological studies using opioid peptides, alkaloids, and synthetic derivatives of opiates indicated multiple subtypes of opioid receptors. This classification of multiple opioid receptors was originally based on the production of distinct syndromes in dogs by derivatives of morphine (Martin et al. 1976). The three drugs used in these early studies were morphine as the prototype for the mu (μ) opioid receptor, ketocyclazocine for the kappa (κ) opioid receptor and SKF‐10,047 (N‐allylnormetazocine) for a sigma receptor. The morphine syndrome (mu μ) in the dog was characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses, and indifference to environmental stimuli. Ketocyclazocine (kappa κ) constricted pupils, depressed the flexor reflex, and produced sedation but did not markedly alter pulse rate or the skin twitch reflex. SKF‐10047 (sigma σ), in contrast to morphine and ketocyclazocine, caused mydriasis, tachypnea, tachycardia, and mania (Martin et al. 1976). The sigma site was subsequently demonstrated not to represent an opioid receptor inasmuch as the actions of SKF‐10047 were not blocked by prototypic opioid antagonists such as naloxone and naltrexone. Investigations with both nonpeptide and peptide derivatives led to the demonstration of the delta (δ) opioid receptor as the third subtype. In fact, the first opioid receptor to be cloned was the delta receptor (Kieffer et al. 1992) and this was soon followed by successful isolation of cDNA clones for the mu and kappa receptors. The cloning and sequencing of all three opioid receptors from a variety of species verified that these receptors belonged to the G‐protein coupled family of receptors.
Opioids modulate neuronal activity and the three opioid receptor subtypes mediate this neuromodulation by activating multiple signaling pathways. Signaling through the cognate mu opioid receptor and the Gi protein, for example, reduces neuronal excitability through physical interactions with the potassium and calcium channels. Opioid‐induced decreases in Ca2+