Mu Opioids and Their Receptors

Mu Opioids and Their Receptors: Evolution of a Concept | Pharmacol Rev. 2013 Oct | Free Full Text

Opiates are among the oldest medications available to manage a number of medical problems.Although pain is the current focus, early use initially focused upon the treatment of dysentery.

The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain.  

Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years.

Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes—primarily through the synthesis of novel agents.

These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.

I. Historical Overview

Opium has been used for thousands of years, and its clinical value cannot be overstated. Pain transcends the boundaries of all medical specialties and impacts almost everyone at some stage of their life. There are many classes of drugs used to relieve pain. Mild to moderate pain is typically treated with acetaminophen or aspirin or other nonsteroidal anti-inflammatory drugs (NSAID), but the mainstay of pain management for severe pain remains the opiates

Their effects on pain are quite intriguing. Unlike local anesthetics that relieve pain by blocking all sensory transmission, opiates selectively modulate the perception of pain without interfering with basic sensations, such as light touch, temperature, position sense, and discrimination of sharp and dull.

The opioids target the subjective component of pain, an integrated sensation. It is not uncommon for a patient to remark after taking an opiate that “the pain is still there, but it does not hurt.”

The early preparations of opium were oral and were used primarily for relief of diarrhea associated with dysentery, a common problem. Indeed, oral opium preparations to treat diarrhea, such as laudanum (tincture of opium), are still available. As the use of opium and opiates spread and increased, their euphoric and addictive properties became more apparent, along with significant abuse (Macht, 1915; Terry and Pellens, 1928).

This had become prominent in the United States in the mid-1800s, around the time of the Civil War when the development of the hypodermic syringe permitted morphine to be administered parenterally, which greatly enhanced its euphoric activity. Opioid abuse became so problematic in the early 1900s that international treaties limiting its trafficking were instituted.

The importance of opioids in the treatment of pain has never been contested. However, the desire to develop analgesics dissociating pain and abuse potential drove massive synthetic efforts over the years that generated hundreds, if not thousands, of analogs and eventually provided clinicians with dozens of opiate drugs

Although the vast majority of these agents did not separate analgesia from abuse potential and/or many of problematic side effects seen with traditional opiates, the clinical use of these synthesized drugs has given many insights into opiate action.

Indeed, opiates are in the rare position where their clinical pharmacology preceded the development of corresponding animal models and molecular mechanisms of action. Thus, the clinical pharmacology of opiates has driven much of the basic preclinical research into their mechanism of action.

The initial pharmacologic studies of opiates focused on the general effects of morphine in humans (reviewed by Martin, 1963, 1967; Reisine and Pasternak, 1996). Analgesia is very difficult to study, primarily because of its extreme subjectivity. Painful stimuli, their thresholds, and neuronal pathways have been well characterized both neurophysiologically and neuroanatomically.

However, the clinical perception of pain cannot be defined as concretely. It is very dependent on the emotional makeup of the individual, as well as the emotional state and expectations and desires of the individual at the time. In his classic study comparing wounded soldiers to civilians with postoperative pain, Beecher (1946) found that 80% of the civilians asked for pain relief, whereas only 25% of the soldiers made the same request.

Clearly, the stress of combat altered the perception of the nociceptive stimuli. Clinically, opiates act upon the subjective aspects of pain (Beecher, 1946, 1960; Lasagna, 1964). Patients receiving narcotics are able to discern noxious stimuli but report no pain. Thus, the study of analgesia in humans is extremely difficult, especially its quantification.

The subtle nuances and the importance of context further illustrate the complexity of pain measurements and must be taken into consideration when comparing experimental and clinical pain models. These factors also demonstrate the inadequacies and limitations of preclinical studies of analgesics.

Despite their limitations, animal models were needed to evaluate new compounds and explore basic questions in mechanism. The mouse hot-plate test (Woolfe and MacDonald, 1943) and the tail flick (D’Amour and Smith, 1941) were the first two widely used models. Both are reproducible and applicable over wide dose ranges (Janssen and Jageneau, 1957) and highly predictive of analgesic activity in people.

The tail-flick assay is dependent upon a spinal reflex, with descending supraspinal influences (Irwin et al., 1951), whereas the hot plate relies upon a more integrated escape response. However, in most paradigms, the nociceptive input in these thermal assays is sufficiently severe that only potent analgesics show activity, with partial agonists or mixed opioid agonist/antagonist drugs and most nonopioids, such as the NSAIDs, often having little effect.

Over time, a wide range of additional assays have been developed and used to explore different types of pain (Le Bars et al., 2001), including mechanical stimuli, inflammation, and neuropathic pain associated with nerve injury to name a few. The activity, or “efficacy,” of a drug commonly varies among the different pain models.

A full discussion of pain models is beyond the scope of this review, and the reader is referred to another review from this journal (Le Bars et al., 2001).

Morphine (Fig. 1A) was isolated from opium in 1805 (Serturner, 1805; Macht, 1915) and first sold by Merck in 1827, with its popularity increasing with the development of the hypodermic needle in 1857. Its synthesis was delayed by its complex ring structure until 1956 (Gates and Tschudi, 1956). However, modifications of its structure were made much earlier. Indeed, diacetylmorphine (heroin) (Fig. 1A) was synthesized in 1874 and marketed as a nonaddictive cough suppressant by Bayer in the late 1800s—a claim we now find amazing and clearly wrong.

The modern era of opioid research came with the demonstration of opioid receptors in 1973

The concept of opioid receptors has a long history, with selective recognition sites being proposed much earlier based upon the rigid structural requirements for activity

This was followed by extensive studies on opioid receptor binding, leading to the cloning and expression of the family of opioid receptors. This review will focus upon the mu drugs, their receptors, and their actions.

II. Opioids

A. Alkaloids

The original opiates, morphine and codeine (Fig. 1A), were isolated from opium. Their structures provided the scaffolds upon which many of the current mu opiates are based. Thebaine, another major component of opium, is a valuable precursor in the synthesis of many of these derivatives.

Most opiates fall under six chemical classes: 4,5α-epoxymorphinans, morphinans, benzomorphans, phenylpiperidines, acylic analgesics, and oripavine. These chemical classes conceptually can be visualized by a systematic dismantling of the morphine structure.

B. Opioid Peptides

  1. Endogenous Opioids.

Soon after the discovery of the opioid receptors, investigators identified materials within the brain with opioid-like activity and affinity for the receptors (Table 1). Kosterlitz and Hughes were the first to sequence the pentapeptide enkephalins (Hughes et al., 1975), which soon expanded into the following three families of peptides, each with its own precursor peptide: preproenkephalin, preprodynorphin, and β-lipotropin (Berezniuk and Fricker, 2011)

Kosterlitz named the two pentapeptides the enkephalins, referring to their presence within the brain, whereas Avram Goldstein coined the term dynorphin for the 17mer he isolated based upon its very high potency. The enkephalins have been associated with the delta receptors, dynorphin A with the kappa1 receptors, and β-endorphin with mu receptors, although it also retains a similar high affinity for delta receptors.

Together, all three families of opioid peptides are referred to as the endorphins at the suggestion of Eric Simon, reflecting a contraction of “endogenous morphine.”

The first public disclosure of the endogenous opioids came at a meeting of the Neuroscience Research Program in Boston in 1974 sponsored by Massachusetts Institute of Technology (Snyder and Matthysse, 1975). A small conference of less than 50 scientists, it included most of the major investigators in the opioid field (Fig. 7). The disclosures were quite dramatic

The isolation and structural determination of the enkephalins was quickly followed by the identification of dynorphin A and β-endorphin

The opioid peptides have been extensively studied and reviewed (Hook et al., 2008; Berezniuk and Fricker, 2011). The enkephalins are the endogenous ligands for the delta-opioid receptor (DOR-1), whereas dynorphin A is the endogenous ligand for the kappa1-opioid receptor (KOR-1). β-Endorphin has high affinity for both mu and delta sites, and some investigators have suggested that it is an endogenous mu peptide. However, this classification may be an oversimplification

Another set of endogenous opioid peptides have been reported, the endomorphins, endomorphin 1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2) (Zadina et al., 1997).

These are quite distinct from the other opioid peptides in that they are highly selective for mu receptors

  1. Synthetic Mu Peptides.

Early studies with the endogenous opioids were complicated by their rapid enzymatic degradation

a vast array of opioid peptides have been synthesized with striking differences in their receptor binding selectivity and pharmacology

C. Mu Antagonists

A major step forward in opioid pharmacology came with the synthesis of naloxone, the first pure antagonist

The importance of this compound cannot be overstated. Naloxone is one of the most widely used opioids and is the primary treatment of overdose and opioid-induced respiratory depression. It also has been instrumental in assessing and defining opioid actions in preclinical studies.

D. Endogenous Mu Alkaloids

There is strong evidence for the presence of endogenous morphine and codeine within the brain.

The question arose whether the endogenous morphine is synthesized in the brain or whether it is absorbed from foodstuffs, particularly with its isolation from milk and plants other than the poppy

Although ingestion remains one potential mechanism for accumulation of endogenous morphine, there is evidence it can be synthesized de novo by mammals

In addition to morphine, other metabolites have been isolated from brain, including morphine-6β-glucuronide and morphine-6-sulfate

These two analogs are notable because of their far greater analgesic potency than morphine

With the availability of an array of morphine-like (i.e., mu) opiates, clinicians made a number of important observations.

First, it was not uncommon for patients to respond differently to each opiate. This was not a simple matter of sensitivity to opioids in general. Some patients would respond well to one mu opiate and not another, whereas the reverse might be seen in a different patient.

Second, physicians found that although the equianalgesic dosing tables were helpful in naive patients, the relative potencies of the drugs in tolerant patients differed markedly

This is best illustrated when switching a morphine-tolerant patient from morphine to methadone, when the equianalgesic methadone dose determined from the tables needs to be reduced by 50–75%

It is clear that incomplete cross-tolerance among mu opiates can be quite profound and has major clinical implications, including being the basis for opioid rotation.

Third, the side effect profile of different opiates within a single patient can differ. It is not unusual for a patient incapable of tolerating morphine because of nausea and/or vomiting to take methadone without a problem. Together, these observations raised major questions regarding the receptor mechanism(s) of action of these drugs. They also illustrate the value of clinical insights and experience in focusing preclinical opiate research.

C. Analgesia

The actions of morphine have been well studied, and analgesia remains the major focus of mu opioid action. Studies of morphine analgesia even go back to Darwin, who tried to assess whether morphine was active in plants “but with no certain result”

It is extraordinary how much was known before the “modern era.”

Early investigators also emphasized differences in responses among species and even among strains of mice—supporting a physiologic basis of the clinical observations.

Several factors must be considered whenever analyzing opioid analgesia. The first is the intensity of the nociceptive stimulus. Clinically, lower doses of drug are required to relieve mild pain than severe pain. Drugs with ceiling effects may be effective for mild pain and not for more severe pain. The second is more difficult to assess and involves the quality/type/nature of the pain.

Pain encompasses many different sensations.

Three major types of pain have been proposed:

  1. somatic,
  2. visceral, and
  3. neuropathic.

However, they rarely exist alone, and most clinical situations are combinations of them. The various types of pain differ in their sensitivities to therapeutic drugs and are described by terms such as sharp, dull, aching, burning, throbbing, shooting, and cramping.

Finally, in the clinical situation, the meaning of the pain is crucial. The perception of pain does not always correlate with nociceptive intensity. Context is important.

The brain “filters” pain depending upon its context. In addition to its minimization in stressful situations or with distraction, the perception of pain may be enhanced in other situations.

The importance of context led many investigators to believe that experimental pain models in humans, or in animals, are not accurate models of the clinical situation



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