MacDonald J. Christie1, Michael M. Morgan2 1Brain & Mind Research Institute M02G, The University of Sydney, Sydney, NSW, Australia

2Department of Psychology, Washington State University Vancouver, Vancouver, WA, USA




The term opiate refers to drugs extracted from opium, i.e., morphine and codeine, whereas an ► opioid is any drug or endogenous agent that acts as an ► agonist or ► antagonist on one of the three major (classical) opioid receptors.

Pharmacological Properties

Opium that contains the principal ► opiate, morphine, has been used for its powerful pain relieving (analgesics), somnorific, and euphoric properties since antiquity (Brownstein 1993). Since the discovery of opioid receptors in 1972 and the first ► endogenous opioid peptides in 1975 much has been learned about the anatomy and function of opioid actions. However, much remains to be discovered about the function of endogenous opioids and opioid drugs in specific populations of neurons and neural systems. In addition to therapeutically valuable actions on the sensory and affective components of pain, opioids also produce profound effects on neural systems involved in respiration, reward and learning, and many other behavioral and physiological processes. Current knowledge of these systems is summarized in the following sections.

Endogenous Opioid Peptides

The general distribution of opioid peptides was reported soon after the discovery of ► enkephalins in 1975 (Khatchaturian et al. 1983). Genes encoding four endogenous opioids and opioid-related peptide precursors have since been identified in the mammalian genome, and the products of all but one act as agonists on the classical opioid receptors: ► mu (m- or MOR, aka OP3, MOP), delta (8- or DOR, aka OP1, DOP), and ► kappa (k- or KOR, aka OP2, KOP) ► receptors. As with other peptide hormones and neurotransmitters, the final active pep-tides are cleaved at dibasic amino acid sites from large polypeptide precursors by processing enzymes. The precursors such as pro-opiomelanocortin (POMC), preproenkephalin, and prodynorphin express the sequences for P-^ endorphin, enkephalins, and ► dynor-phins, respectively. POMC contains a single copy of P-endorphin (which can be lyzed to shorter, potentially active endorphin fragments) along with other biologically important hormones/neurotransmitters including the major ► stress hormone, adrenocorticotrophic hormone (ACTH). Preproenkephalin encodes multiple copies of two enkephalin pentapeptides, leucine-enkephalin and me-thionine enkephalin (longer active peptides can be found in some tissues). Prodynorphin contains the sequences of a-neoendorphin, dynorphin-A and dynorphin-B, as well as "big dynorphin,'' which is the uncleaved sequence of dynorphin-A and dynorphin-B (the dynorphin A and B peptides are separated by one pair of basic amino acids in prodynorphin).

All the endogenous opioid peptide families described above contain a canonical N-terminal amino acid sequence, N-Tyr-gly-gly-phe, followed by one to 26 other amino acids. The extended amino sequences, which vary in length in different cells, confer differential selectivity among the three major opioid receptors as well as potentially modifying susceptibility to degradation by peptidase enzymes such as "► enkephalinase'' (EC It should be noted that deletion (des-tyr) or chemical modification of the N-terminal tyr (N-acetylation occurs for a substantial proportion of the P-endorphin from the pituitary) renders all opioid peptides inactive at opioid receptors. These peptides subserve endocrine (e.g., P-endorphin from the pituitary; pro-enkephalin from the adrenal medulla) and paracrine (opioid peptides are expressed in the immune system;) functions in addition to their well known effects on the nervous system.

The most recently discovered opioid-related peptide family, orphanin-FQ or nociceptin (usually denoted N/OFQ), is distantly related to prodynorphin but contains an N-terminal Phe rather than Tyr. It is the endogenous ligand of the orphan opioid receptor Opioid-receptor-like-1 (ORL1, aka NOP, NOR). It has high affinity and selectivity for ORL1 but interacts very weakly with the KOR (see below). The N/OFQ-ORL1 system is not widely considered to represent an "opioid-system'' because classical opioid drugs and endogenous opioids do not interact significantly with ORL1. It is therefore not considered in detail here.

Two additional endogenous opioids (endomorphin 1 and endomorphin 2) have been purified from mammalian tissue. Although these tetrapeptides are very selective for MOR and can be visualized in neurons immuno-histochemically (which is not proof of presence), no genomic sequences encoding endomorphin 1 and endomorphin 2 have been identified; so their physiological relevance will remain uncertain until a biological synthetic mechanism is identified.

Opioid Receptors

MOR, DOR, and KOR opioid receptor types were first identified using pharmacological approaches. ct (sigma)-Opioid receptors also were proposed, but structural and pharmacological studies indicate that ► CT-receptors are not part of the opioid family. Three independent genes encoding MOR, DOR, and KOR have been identified, firmly establishing that these are the three principal opi-oid receptors. Soon after the isolation of these genes a fourth opioid-receptor like (ORL1) sequence was identified by homology screening of cDNA libraries for sequences resembling the other receptors. The biochemistry and regulation of opioid receptors are extensively reviewed elsewhere (e.g., Waldhoer et al. 2004). Briefly, the amino acid sequences of all opioid receptors (and ORL1) are about 60% identical with each other. They belong to a small subfamily of G-protein coupled receptors (► GPCR) that includes the ► somatostatin receptors. Multiple RNA ► splice variants have been identified, in particular MOR1A, B, and C (the biological relevance of other putative splice variants is uncertain). The B and C variants differ in the amino acid composition at the C-terminus and affect receptor regulatory events such as receptor distribution, ► internalization, and recycling rates but have little or no influence on drug selectivity. Opioid receptor subtypes, such as p1 and p2 receptors, also have been proposed, but they remain tentative. Splice variants of DOR or KOR may explain differential pharmacology of proposed receptor subtypes (e.g., putative 81 and 82 receptors), but these have not yet been established. Formation of ► hetero-oligomers between different opi-oid receptor types could also explain experimental results claiming existence of opioid receptor subtypes. As for other GPCRs, oligomer formation of opioid receptors appears to be obligatory for membrane expression and function (Milligan and Bouvier 2005). While homo-oligomers are probably the most commonly formed and appear to explain most opioid pharmacology in vivo, there is growing biochemical and pharmacological evidence that different subtypes of opioid receptors can form hetero-oligomers in isolated experimental systems and perhaps in vivo.

Interaction of Opioids with Opioid Receptors

Some authors have attempted to ascribe three distinct signaling systems to the three different opioid peptide families matching them respectively with the three receptor types. This is incorrect because each opioid pep-tide family can interact with more than one receptor type, as summarized in Fig. 1. Among the three peptide groups and receptors, the dynorphin-KOR pair is the best candidate to be defined as a distinct signaling system because dynorphin is the only endogenous opioid that interacts significantly with KOR. However, dynorphins are also potent MOR agonists and can potentially be metabolized to shorter and less selective dynorphin fragments (including leucine-enkephalin), which interact potently with both MOR and DOR. It should also be noted that early studies suggesting that enkephalins are the endogenous ligands for DOR were premature because they were subsequently shown to be nearly equi-effective agonists at both MOR and DOR.

A large number of small, organic molecule agonists for opioid receptors have been developed since the first isolation of morphine from opium in 1806 and synthesis of heroin in 1898 (Brownstein 1993). Nearly all of the small molecule agonists in clinical use are selective for MOR although experimental opioid agonists selective for DOR and KOR have been developed. A more limited

Opioids. Fig. 1. Selectivity profiles of the major endogenous opioids for the different opioid receptors are shown with thickness of the arrows indicating relative selectivities or potencies for MOR (blue), DOR (green), KOR (yellow) and ORL1 (orange). All endogenous opioids except nociceptin/OFQ (which is not generally considered an opioid) can act as agonists at more than one opioid receptor type. All opioid receptors couple to Gi proteins to modulate the major signaling mechanisms shown.

range of small molecule antagonists exists, although some of these commercially available antagonists display high receptor type selectivity. Most commercially available small molecule opioids have the advantage that they readily penetrate the central nervous system following systemic injection. However, some have been specifically developed to avoid crossing the ► blood-brain barrier (e.g., methylnaloxone). The optimal selection of an opioid for a given experimental purpose depends on a number of considerations, so recommendation of particular drugs for an opioid receptor type is beyond the current scope. The major pharmacological societies provide and regularly update comprehensive guides to the most appropriate selective agonists and antagonists for each receptor. These include The International Union of Basic and Clinical Pharmacology (IUPHAR) (http://www.iuphar-db.org/ index.jsp) and the British Pharmacological Society (http: //www3.interscience.wiley.com/journal/122206250/ issue).

Opioid Receptor Signaling and Regulation

As shown in Fig. 1, all opioid receptors when activated by an agonist transduce intracellular signals via activation of inhibitory G-proteins. The major consequence of opioid receptor activation in neurons is inhibition in both cell bodies and nerve terminals. Downstream signaling includes modulation of many biochemical and gene regulatory cascades - a full description of which is beyond the current scope (see however, Williams et al. 2001; Waldhoer et al. 2004). Briefly, while subtle variations occur among the specific G-proteins activated by different receptor types (and perhaps hetero-oligomers), all opioid receptors activate Gi-proteins, which leads to the release of GTP bound active Gia subunits and Gbg subunits from the receptor. The major immediate consequence (within ~50ms of receptor activation) is inhibition of neuronal excitability via Gbg subunit inhibition of ► voltage-gated calcium channels (VGCCs; particularly CaV2.2-2.3) and activation of ► G-protein coupled inwardly rectifying potassium channels (GIRKs) in the local membrane. Inhibition of VGCCs in nerve terminals can contribute to inhibition of neurotransmitter ► release probability upon invasion of action potentials. Other ionic channels and biochemical effects (e.g., inhibition of ► cAMP formation) also contribute to presynaptic inhibition. Free Gbg subunits may also activate (more slowly) components of protein kinase cascades. Gia-subunits inhibit most isoforms of adenylate cyclase that are expressed in many types of neurons. Other cascades are modulated by the opioid receptor trafficking and internalization that occurs after activation in an agonist dependent manner

(Waldhoer et al. 2004). It should also be noted that many of these mechanisms can contribute to the cellular and

► synaptic plasticity of signaling that are associated with

► tolerance, ► physical dependence, and ► addiction following chronic opioid treatment (Williams et al. 2001).

The complexity produced by multiple opioid receptor types and signaling mechanisms requires that opioid actions and adaptations in different neural systems be determined on a case by case basis. While the direct effects of opioids on cell bodies and synapses are almost invariably inhibitory, activation of neural systems can be the net outcome when the dominant opioid effect is localized to inhibitory interneurons and synapses. For example, MOR activation in the ► ventral tegmental area enhances ► do-pamine release because MOR are located on inhibitory interneurons that synapse on dopaminergic neurons. This type of disinhibition is common to opioids. Thus, localization of opioid receptors to a particular structure provides little information about function without an understanding of the local cellular circuitry.

Opioid Receptor Distribution

Opioid receptors are found throughout the central and peripheral nervous systems. Some of the peripheral tissue locations such as the guinea pig ileum and mouse vas deferens are well known because of their use for many decades as assays for opioid receptor activity. Opioid receptor expression in the gut largely accounts for constipation, a major side effect of MOR agonists. Opioid receptors are also found on primary afferent nociceptors and immune cells (Stein et al. 2003).

MOR, DOR, and KOR can be found from the cerebral cortex to the spinal cord. The distribution of opioid receptors revealed by in situ hybridization, ligand binding, and immunohistochemsitry (Mansour et al. 1995) is so extensive that describing the many brain structures with receptors is more tedious than useful. This point is highlighted by a list of the structures in which opioid receptors have been reported (Table 1). High levels of MOR and KOR are found from the cerebral cortex to the dorsal horn of the spinal cord. DOR distribution also is extensive, but more limited than MOR and KOR. However, recent studies showing that DOR are mobilized by environmental stimuli (Cahill et al. 2007) indicate that DOR have a much broader distribution than previously thought. For example, chronic administration of morphine or prolonged stress stimulates the movement of DOR in the periaqueductal gray (PAG) from intracellular stores to the plasma membrane. Although previous studies did not report DOR in the PAG, functional membrane receptors can be found under these conditions. Thus, the

Opioids. Table 1. Location and density of opioid receptors in the rat CNS.

Opioids. Table 1. (continued)


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  • Lilla
    What are the psychopharmacological properties of opioids?
    7 months ago
  • vilho
    Is an opioid a psychopharmocological medication?
    4 months ago

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