Opioid receptor
Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.
[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.
Phylogenetic analysis demonstrates that the family of opioid receptors was already present at the origin of jawed vertebrates over 450 million years ago.
Tetraploidization events often result in the loss of one or more of the duplicated genes, but in this case, nearly all species retain all four opioid receptors, indicating biological significance of these systems.
Stefano traced the co-evolution of OR and the immune system underlying the fact that these receptors helped earlier animals to survive pain and inflammation shock in aggressive environments.
[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.
[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.
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.
Three GPCR extracellular loops provide a compartment where signaling molecules can attach to generate a response.
[45] When an agonistic ligand binds to the opioid receptor, a conformational change occurs, and the GDP molecule is released from the Gα sub-unit.
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.
cAMP acts as a secondary messenger, as it moves from the plasma membrane into the cell and relays the signal.
[48] CREB (cAMP response element binding protein) belongs to a family of transcription factors and is positioned in the nucleus of the neuron.
The CREB protein binds to cAMP response elements CRE, and can either increase or decrease the transcription of certain genes.
[49] It is also significant in the induction and maintenance of long-term potentiation, which is a phenomenon that underlies synaptic plasticity - the ability of synapses to strengthen or weaken over time.
Voltage-gated dependent calcium channel, (VDCCs), are key in the depolarisation of neurons, and play a major role in promoting the release of neurotransmitters.
When agonists bind to opioid receptors, G proteins activate and dissociate into their constituent Gα and Gβγ sub-units.
These neurotransmitters are vital in the transmission of pain, so opioid receptor activation reduces the release of these substances, thus creating a strong analgesic effect.
