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in vivo

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Reading peer reviewed material is often confusing and sometimes frustrating. For me, much of the confusion derives from the incredible amount of terms that I'm often unfamiliar with. In an attempt to help other researchers, this thread will be dedicated to providing a glossary of some of these terms.

 

Wikipedia can't be taken for gospel, but it's often a good place to begin research. I'm using that and Webster for most of this glossary:

 

 

An agonist is a chemical that binds to some receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist.

 

Alloseric:  a change in the shape and activity of a protein (receptor) that results from combination with another substance at a point other than the chemically active site

 

Allosteric modulator: An exogenous or endogenous molecule that binds to a distinct and nonoverlapping site to influence binding or signaling at another, usually orthosteric, site.

 

Analgesic: a drug that relieves pain

 

Anorectic: weight loss

 

An antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses.[1] In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active (orthosteric = right place) site or to allosteric (= other place) sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.[2]

 

Antibacterial: slows bacteria growth

 

Anti-diabetic: reduces blood sugar levels

 

Antidepressant: used or tending to relieve or prevent psychic depression

 

Anti-emetic: reduces vomiting and naseau

 

Anti-epileptic: reduces seizures and convulsions

 

Antifungal: treats fungal infection

 

Anti-inflammatory: reduces inflammation

 

Anti-insomnia: aids sleep

 

Anti-ischemic: reduces risk of artery blockage

 

Antioxidant: inhibits oxidation or reactions promoted by oxygen, peroxides, or free radicals

 

Anti-proliferative: inhibits cancer cell growth

 

Antipsioratic: treats psoriasis

 

Antipsychotic: tranquilizing

 

Antispasmodic: suppresses muscle spams

 

Anxiolitic: relieves anxiety

 

Appetite stimulant: stimulates appetite

 

Bone stimulant: promotes bone growth

 

Bronchodilatory: relaxes bronchial muscle resulting in expansion of the bronchial air passages

 

Cannabinoids are a class of diverse chemical compounds that activate cannabinoid receptors on cells that repress neurotransmitter release in the brain. These receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals),[1] the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (produced chemically by humans).

 

 

Cannabinoid receptor type 1 (CB1), is a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous system. It is activated by the endocannabinoid neurotransmitters anandamide and 2-arachidonoyl glyceride (2-AG); by plant cannabinoids, such as the compound THC, an active ingredient of the psychoactive drug cannabis; and by synthetic analogues of THC, such as dronabinol.

 

 

Cannabinoid receptor type 2 (CB2) is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene.[1][2] It is closely related to the cannabinoid receptor type 1, which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol, the active agent in marijuana, and other phytocannabinoids.[1][3] The principal endogenous ligand for the CB2 receptor is 2-arachidonoylglycerol (2-AG).[2]

 

The central nervous system (CNS) is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the body.

 

There are many central nervous system diseases, including infections of the central nervous system such as encephalitis and poliomyelitis, early-onset neurological disorders including ADHD and autism, late-onset neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and essential tremor, autoimmune and inflammatory diseases such as multiple sclerosis and acute disseminated encephalomyelitis, genetic disorders such as Krabbe's disease and Huntington's disease, as well as amyotrophic lateral sclerosis and adrenoleukodystrophy. Lastly, cancers of the central nervous system can cause severe illness and, when malignant, can have very high mortality rates.

 

Cyclooxygenase-1 (COX-1) is inhibited by nonsteroidal anti-inflammatory drugs such as aspirin. Research has shown that the inhibition of COX-1 is sufficient to explain why aspirin is effective at reducing cardiac events.

COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.[9][7]

 

Cyclooxygenase-2 (COX-2) is unexpressed under normal conditions in most cells, but elevated levels are found during inflammation.

The expression of COX-2 is upregulated in many cancers. The overexpression of COX-2 along with increased angiogenesis and GLUT-1 expression is significantly associated with gallbladder carcinomas.[21] Furthermore the product of COX-2, PGH2 is converted by prostaglandin E2 synthase into PGE2, which in turn can stimulate cancer progression. Consequently inhibiting COX-2 may have benefit in the prevention and treatment of these types of cancer.[22][23]

 

The endocannabinoid system is a group of neuromodulatory lipids and their receptors that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis and, broadly speaking, includes:

 

Endogenous: produced or synthesized within the organism or system <an endogenous hormone>

 

Exogenous : introduced from or produced outside the organism or system; specifically :  not synthesized within the organism or system

 

Functional selectivity: Selective activation of a subset of the signaling pathways available to a receptor by a ligand.

 

G protein coupled receptors (GPCRs) constitute a large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. They are called transmembrane receptors because they pass through the cell membrane, and they are called seven-transmembrane receptors because they pass through the cell membrane seven times.

 

G protein-coupled receptors are involved in many diseases, and are also the target of approximately 40% of all modern medicinal drugs.[3][4]

 

There are two principal signal transduction pathways involving the G protein-coupled receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.[6] When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G-protein by exchanging its bound GDP for a GTP. The G-protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).[7]:1160

 

G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.[1]

GPR55, along with GPR119 and GPR18, have been implicated as novel cannabinoid receptors.[2][3]

 

Heteromeric receptor: A signaling unit composed of two or more GPCR protomers that by themselves are nonfunctional.

 

Immunosuppressive: reduces funtion in the immune system
 

In vivo: in the living body of a plant or animal

 

In vitro: outside the living body and in an artificial environment

 

Intenstinal anti-prokinetic: reduces small intestine contractions

 

A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing receptor. Many studies include CB1 deficient (CB1 -/-) and CB2 deficient (CB2 -/-) mice.

 

Knockout mice are important animal models for studying the role of receptors whose functions have not been determined (like cannabinoid receptors). By causing a specific receptor to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.

 

A ligand is a substance (usually a small molecule), that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.

 

Negative allosteric modulator: Reduces binding or activity.

 

Neuroinflammation, which is a fundamental reaction to brain injury, is characterized by the activation of resident microglia and astrocytes and local expression of a wide range of inflammatory mediators. COX-2 pathways are implicated in neuroinflammatory processes that are caused by low-LET radiation. COX-2 up-regulation in irradiated microglia cells leads to prostaglandin E2 production, which appears to be responsible for radiation-induced gliosis (overproliferation of astrocytes in damaged areas of the CNS).[50][51][52]

 

Neuropathic pain is pain caused by damage or disease that affects the somatosensory system.[1] It may be associated with abnormal sensations called dysesthesia, and pain produced by normally non-painful stimuli (allodynia). Neuropathic pain may have continuous and/or episodic (paroxysmal) components. The latter are likened to an electric shock. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching. Nociceptive pain, by contrast, is more commonly described as aching.

3 Treatments

 

Neuroprotection refers to the relative preservation of neuronal structure and/or function.[1] In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation.[1] It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, and spinal cord injury. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons.[2] Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms include increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation.[2][3][4] Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own.[5] Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection.

 

Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being "thermal" (heat or cold), "mechanical" (crushing, tearing, etc.) and "chemical" (iodine in a cut, chili powder in the eyes).

 

Nociceptive pain may also be divided into "visceral", "deep somatic" and "superficial somatic" pain. Visceral structures are highly sensitive to stretch, ischemia and inflammation, but relatively insensitive to other stimuli that normally evoke pain in other structures, such as burning and cutting. Visceral pain is diffuse, difficult to locate and often referred to a distant, usually superficial, structure. It may be accompanied by nausea and vomiting and may be described as sickening, deep, squeezing, and dull.[16]Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or other superficial tissue, and is sharp, well-defined and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first degree) burns.[14]

 

When nociceptors are stimulated they transmit signals through sensory neurons in the spinal cord. These neurons release the excitatory neurotransmitter glutamate at their synapses.

 

If the signals are sent to the reticular formation and thalamus, the sensation of pain enters consciousness in a dull poorly localized manner. From the thalamus, the signal can travel to the somatosensory cortex in the cerebrum, when the pain is experienced as localized and having more specific qualities.

 

Orthosteric binding site: The primary binding site of the receptor, usually where the endogenous ligand binds and elicits a signal.

 

The peripheral nervous system (PNS) is the part of the nervous system consisting of the nerves and ganglia outside of the brain and spinal cord.[1] The main function of the PNS is to connect the central nervous system (CNS) to the limbs and organs, essentially serving as a communication relay going back and forth between the brain and the extremities.[2] Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain barrier, leaving it exposed to toxins and mechanical injuries. The peripheral nervous system is divided into the somatic nervous system and the autonomic nervous system; some textbooks also include sensory systems.

 

The main neurotransmitters of the peripheral nervous system are acetylcholine and noradrenaline. However, there are several other neurotransmitters as well, jointly labeled Non-noradrenergic, non-cholinergic (NANC) transmitters. Examples of such transmitters include non-peptides: ATP, GABA, dopamine, NO, and peptides: neuropeptide Y, VIP, GnRH, Substance P and CGRP.[5]

 

Positive allosteric modulator: Enhances binding or activity.

 

A receptor is a molecule usually found on the surface of a cell, that receives chemical signals from outside the cell. When such external substances bind to a receptor, they direct the cell to do something, such as divide, die, or allow specific substances to enter or exit the cell.

 

Receptors are proteins embedded in either the cell's plasma membrane (cell surface receptors), in the cytoplasm, or in the cell's nucleus (nuclear receptors), to which specific signaling molecules may attach. A molecule that binds to a receptor is called a ligand, and can be a peptide (short protein) or another small molecule such as a neurotransmitter, hormone, pharmaceutical drug, or toxin.

 

Numerous receptor types are found in a typical cell. Each type is linked to a specific biochemical pathway, and binds only certain ligand shapes, similarly to how locks require specifically shaped keys to open. When a ligand binds to its corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway.

 

Ligand binding changes the conformation (three-dimensional shape) of the receptor molecule. This alters the shape at a different part of the protein, changing the interaction of the receptor molecule with associated biochemicals, leading in turn to a cellular response mediated by the associated biochemical pathway. However, some ligands called antagonists merely block receptors from binding to other ligands without inducing any response themselves.

 

Receptor heteromers: Two or more molecularly distinct and individually functional GPCRs that combine to form a molecular entity with distinct pharmacology.

 

Receptor homomers: Two or more molecularly equivalent and functional GPCRs that combine to form a molecular entity with distinct pharmacology.

 

TRPV (Transient Receptor Potential Vanilloid) is a family of transient receptor potential (TRP) ion channels.[2][3] These channels are selective for calcium and magnesium over sodium ions.

 

The first member of this family that was isolated, TRPV1, is also sensitive to capsaicin, the pungent ingredient in "hot" chili peppers and accordingly TRPV1 is also sometimes referred to as the capsaicin or vanilloid receptor.[6]

 

The TRPV receptors can also form heteromers that exhibit unique conductance and gating properties, further increasing their functional diversity.[3]

 

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group.[2][3] This protein is a member of the TRPV group of transient receptor potential family of ion channels.[4]

 

The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides sensation of scalding heat and pain (nociception).

 

Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, upon prolonged application, TRPV1 activity would decrease (desensitization), leading to alleviation of pain. Agonists can be applied locally to the painful area as through a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization; it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials.[18] 8% capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30-minute treatment can provide up to 3 months analgesia by causing regression of TRPV1-containing neurons in the skin.[19]

 

The endocannabinoid anandamide has been shown to act on TRPV1 receptors.[20] N-Arachidonoyl dopamine, another endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an EC50 of approximately of 50 nM. The high potency makes it the putative endogenous TRPV1 agonist.[7]

The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors.[22]

 

Signal transduction occurs when an extracellular signaling[1] molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response.[2] There are two stages in this process:

  1. A signaling molecule activates a specific receptor protein on the cell membrane.
  2. A second messenger transmits the signal into the cell, eliciting a physiological response.

In either step, the signal can be amplified. Thus, one signalling molecule can cause many responses.[3] A signal transduction functions much like a switch.[citation needed]

 

 

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