Opioid receptor

Opioid receptors are a group of inhibitory

By the mid-1960s, it had become apparent from pharmacologic studies that opioids were likely to exert their actions at specific receptor sites, and that there were likely to be multiple such sites.^[4] Early studies had indicated that opiates appeared to accumulate in the brain.^[5] The receptors were first identified as specific molecules through the use of binding studies, in which opiates that had been labeled with radioisotopes were found to bind to brain membrane homogenates. The first such study was published in 1971, using ³H-levorphanol.^[6] In 1973, Candace Pert and Solomon H. Snyder published the first detailed binding study of what would turn out to be the μ opioid receptor, using ³H-naloxone.^[7] That study has been widely credited as the first definitive finding of an opioid receptor, although two other studies followed shortly after.^[8][9]

Purification

Purification of the receptor further verified its existence. The first attempt to purify the receptor involved the use of a novel opioid antagonist called chlornaltrexamine that was demonstrated to bind to the opioid receptor.^[10] Caruso later purified the detergent-extracted component of rat brain membrane that eluted with the specifically bound ³H-chlornaltrexamine.^[11]

Major subtypes

There are four major subtypes of opioid receptors.^[12] OGFr was originally discovered and named as a new opioid receptor zeta (ζ). However it was subsequently found that it shares little sequence similarity with the other opioid receptors, and has quite different function.

(I). Name based on order of discovery

Evolution

The opioid receptor (OR) family originated from two duplication events of a single ancestral opioid receptor early in vertebrate evolution.

The receptor families delta, kappa, and mu demonstrate 55–58% identity to one another, and a 48–49% homology to the nociceptin receptor. Taken together, this indicates that the NOP receptor gene, OPRL1, has equal evolutionary origin, but a higher mutation rate, than the other receptor genes.^[17]

Although opioid receptor families share many similarities, their structural differences lead to functional difference. Thus, mu-opioid receptors induce relaxation, trust, satisfaction, and analgesia.^[18][19] This system may also help mediate stable, emotionally committed relationships. Experiments with juvenile guinea pigs showed that social attachment is mediated by the opioid system. The evolutionary role of opioid signaling in these behaviors was confirmed in dogs, chicks, and rats.^[18] Opioid receptors also have a role in mating behaviors.^[20] However, mu-opioid receptors do not just control social behavior because they also make individuals feel relaxed in a wide range of other situations.^{[citation needed]}

Kappa- and delta-opioid receptors may be less associated with relaxation and analgesia because kappa-opioid receptor suppresses mu-opioid receptor activation, and delta-opioid receptor interacts differently with agonists and antagonists. Kappa-opioid receptors are involved in chronic anxiety's perceptual mobilization, whereas delta-opioid receptors induce action initiation, impulsivity, and behavioural mobilization.^[19][21] These differences led some researches to suggest that up- or down-regulations within three opioid receptors families are the basis of different dispositional emotionality seen in psychiatric disorders.^[22][23][24]

Human-specific opioid-modulated cognitive features are not attributable to coding differences for receptors or ligands, which share 99% similarity with primates, but to regulatory changes in expression levels.^[25][26]

Nomenclature

The receptors were named using the first letter of the first

Separate opioid receptor subtypes have been identified in human tissue. Research has so far failed to identify the genetic evidence of the subtypes, and it is thought that they arise from post-translational modification of cloned receptor types.^[29]

An IUPHAR subcommittee^[30][31] has recommended that appropriate terminology for the 3 classical (μ, δ, κ) receptors, and the non-classical (nociceptin) receptor, should be MOP ("Mu OPiate receptor"), DOP, KOP and NOP respectively.

Additional receptors

The existence of further opioid receptors (or receptor subtypes) has also been suggested because of pharmacological evidence of actions produced by endogenous opioid peptides, but shown not to be mediated through any of the four known opioid receptor subtypes. The existence of receptor subtypes or additional receptors other than the classical opioid receptors (μ, δ, κ) has been based on limited evidence, since only three genes for the three main receptors have been identified.^[32][33][34] The only one of these additional receptors to have been definitively identified is the zeta (ζ) opioid receptor, which has been shown to be a cellular growth factor modulator with met-enkephalin being the endogenous ligand. This receptor is now most commonly referred to as the opioid growth factor receptor (OGFr).^[35][36]

Epsilon (ε) opioid receptor

Another postulated opioid receptor is the ε opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide

When an agonistic ligand binds to the opioid receptor, a conformational change occurs, and the GDP molecule is released from the Gα sub-unit. This mechanism is complex, and is a major stage of the signal transduction pathway. When the GDP molecule is attached, the Gα sub-unit is in its inactive state, and the nucleotide-binding pocket is closed off inside the protein complex. However, upon ligand binding, the receptor switches to an active conformation, and this is driven by intermolecular rearrangement between the trans-membrane helices. The receptor activation releases an ‘ionic lock’ which holds together the cytoplasmic sides of transmembrane helices three and six, causing them to rotate. This conformational change exposes the intracellular receptor domains at the cytosolic side, which further leads to the activation of the G protein. When the GDP molecule dissociates from the Gα sub-unit, a GTP molecule binds to the free nucleotide-binding pocket, and the G protein becomes active. A Gα(GTP) complex is formed, which has a weaker affinity for the Gβγ sub-unit than the Gα(GDP) complex, causing the Gα sub-unit to separate from the Gβγ sub-unit, forming two sections of the G protein. The sub-units are now free to interact with effector proteins; however, they are still attached to the plasma membrane by lipid anchors.^[46] After binding, the active G protein sub-units diffuses within the membrane and acts on various intracellular effector pathways. This includes inhibiting neuronal adenylate cyclase activity, as well as increasing membrane hyper-polarisation. When the adenylyl cyclase enzyme complex is stimulated, it results in the formation of Cyclic Adenosine 3', 5'-Monophosphate (cAMP), from Adenosine 5' Triphosphate (ATP). cAMP acts as a secondary messenger, as it moves from the plasma membrane into the cell and relays the signal.^[47]

cAMP binds to, and activates cAMP-dependent

Some forms of mutations in δ-opioid receptors have resulted in constant receptor activation.[52]

Protein–protein interactions

Receptor heteromers

• δ-κ^[53]
• δ-μ
• κ-μ
• μ-ORL1
• δ-
  CB1
• μ-CB1
• κ-CB1
• δ-α2A
• δ-β2
• κ-β2
• μ-α2A
• δ-CXCR4
• δ-SNSR4
• κ-APJ
• μ-CCR5
• μ1D-GRPR
• μ-mGlu5
• μ-5-HT1A
• μ-NK1
• μ-sst2A

See also

• List of opioids
• Opioid antagonist
• Opioidergic

References