Nitrous oxide


Nitrous oxide, commonly known as laughing gas, 'nitrous, or historically as factitious air, among others, is a chemical compound, an oxide of nitrogen with the formula '. At room temperature, it is a colourless non-flammable gas, and has a slightly sweet scent and taste. At elevated temperatures, nitrous oxide is a powerful oxidiser similar to molecular oxygen.
Nitrous oxide has significant medical uses, especially in surgery and dentistry, for its anaesthetic and pain-reducing effects, and it is on the World Health Organization's List of Essential Medicines. Its colloquial name, "laughing gas", coined by Humphry Davy, describes the euphoric effects upon inhaling it, which cause it to be used as a recreational drug inducing a brief "high". When abused chronically, it may cause neurological damage through inactivation of vitamin B12. It is also used as an oxidiser in rocket propellants and motor racing fuels, and as a frothing gas for whipped cream.
Nitrous oxide is also an atmospheric pollutant, with a concentration of 333 parts per billion in 2020, increasing at 1 ppb annually. It is a major scavenger of stratospheric ozone, with an impact comparable to that of CFCs. About 40% of human-caused emissions are from agriculture, as nitrogen fertilisers are digested into nitrous oxide by soil micro-organisms. As the third most important greenhouse gas, nitrous oxide substantially contributes to global warming. Reduction of emissions is an important goal in the politics of climate change.

Discovery and early use

The gas was first synthesised in 1772 by English natural philosopher and chemist Joseph Priestley who called it dephlogisticated nitrous air or inflammable nitrous air. Priestley published his discovery in the book Experiments and Observations on Different Kinds of Air , where he described how to produce the preparation of "nitrous air diminished", by heating iron filings dampened with nitric acid.
The first important use of nitrous oxide was made possible by Thomas Beddoes and James Watt, who worked together to publish the book Considerations on the Medical Use and on the Production of Factitious Airs . This book was important for two reasons. First, James Watt had invented a novel machine to produce "factitious airs" and a novel "breathing apparatus" to inhale the gas. Second, the book also presented the new medical theories by Thomas Beddoes, that tuberculosis and other lung diseases could be treated by inhalation of "Factitious Airs".
The machine to produce "Factitious Airs" had three parts: a furnace to burn the needed material, a vessel with water where the produced gas passed through in a spiral pipe, and finally the gas cylinder with a gasometer where the gas produced, "air", could be tapped into portable air bags. The breathing apparatus consisted of one of the portable air bags connected with a tube to a mouthpiece. With this new equipment being engineered and produced by 1794, the way was paved for clinical trials, which began in 1798 when Thomas Beddoes established the "Pneumatic Institution for Relieving Diseases by Medical Airs" in Hotwells. In the basement of the building, a large-scale machine was producing the gases under the supervision of a young Humphry Davy, who was encouraged to experiment with new gases for patients to inhale. The first important work of Davy was examination of the nitrous oxide, and the publication of his results in the book: Researches, Chemical and Philosophical . In that publication, Davy notes the analgesic effect of nitrous oxide at page 465 and its potential to be used for surgical operations at page 556. Davy coined the name "laughing gas" for nitrous oxide.
Despite Davy's discovery that inhalation of nitrous oxide could relieve a conscious person from pain, another 44 years elapsed before doctors attempted to use it for anaesthesia. The use of nitrous oxide as a recreational drug at "laughing gas parties", primarily arranged for the British upper class, became an immediate success beginning in 1799. While the effects of the gas generally make the user appear stuporous, dreamy and sedated, some people also "get the giggles" in a state of euphoria, and frequently erupt in laughter.
One of the earliest commercial producers in the U.S. was George Poe, cousin of the poet Edgar Allan Poe, who also was the first to liquefy the gas.
The first time nitrous oxide was used as an anaesthetic drug in the treatment of a patient was when dentist Horace Wells, with assistance by Gardner Quincy Colton and John Mankey Riggs, demonstrated insensitivity to pain from a dental extraction on 11 December 1844. In the following weeks, Wells treated the first 12 to 15 patients with nitrous oxide in Hartford, Connecticut, and, according to his own record, only failed in two cases. In spite of these convincing results having been reported by Wells to the medical society in Boston in December 1844, this new method was not immediately adopted by other dentists. The reason for this was most likely that Wells, in January 1845 at his first public demonstration to the medical faculty in Boston, had been partly unsuccessful, leaving his colleagues doubtful regarding its efficacy and safety. The method did not come into general use until 1863, when Gardner Quincy Colton successfully started to use it in all his "Colton Dental Association" clinics, that he had just established in New Haven and New York City. Over the following three years, Colton and his associates successfully administered nitrous oxide to more than 25,000 patients. Today, nitrous oxide is used in dentistry as an anxiolytic, as an adjunct to local anaesthetic.
Nitrous oxide was not found to be a strong enough anaesthetic for use in major surgery in hospital settings. Instead, diethyl ether, being a stronger and more potent anaesthetic, was demonstrated and accepted for use in October 1846, along with chloroform in 1847. When Joseph Thomas Clover invented the "gas-ether inhaler" in 1876, it became a common practice at hospitals to initiate all anaesthetic treatments with a mild flow of nitrous oxide, and then gradually increase the anaesthesia with the stronger ether or chloroform. Clover's gas-ether inhaler was designed to supply the patient with nitrous oxide and ether at the same time, with the exact mixture being controlled by the operator of the device. It remained in use by many hospitals until the 1930s. Although hospitals today use a more advanced anaesthetic machine, these machines still use the same principle launched with Clover's gas-ether inhaler, to initiate the anaesthesia with nitrous oxide, before the administration of a more powerful anaesthetic.
Colton's popularisation of nitrous oxide led to its adoption by a number of less than reputable quacksalvers, who touted it as a cure for consumption, scrofula, catarrh and other diseases of the blood, throat and lungs. Nitrous oxide treatment was administered and licensed as a patent medicine by the likes of C. L. Blood and Jerome Harris in Boston and Charles E. Barney of Chicago.

Chemical properties and reactions

Nitrous oxide is a colourless gas with a faint, sweet odour.
Nitrous oxide supports combustion by releasing the dipolar bonded oxygen radical, and can thus relight a glowing splint.
is inert at room temperature and has few reactions. At elevated temperatures, its reactivity increases. For example, nitrous oxide reacts with at to give :
This reaction is the route adopted by the commercial chemical industry to produce azide salts, which are used as detonators.

Mechanism of action

The pharmacological mechanism of action of inhaled is not fully known. However, it has been shown to directly modulate a broad range of ligand-gated ion channels, which likely plays a major role. It moderately blocks NMDAR and β-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABA and 5-HT receptors, and slightly potentiates GABA and glycine receptors. It also has been shown to activate two-pore-domain channels. While affects several ion channels, its anaesthetic, hallucinogenic and euphoriant effects are likely caused mainly via inhibition of NMDA receptor-mediated currents. In addition to its effects on ion channels, may act similarly to nitric oxide in the central nervous system. Nitrous oxide is 30 to 40 times more soluble than nitrogen.
The effects of inhaling sub-anaesthetic doses of nitrous oxide may vary unpredictably with settings and individual differences; however, Jay suggests that it reliably induces the following states and sensations:
A minority of users also experience uncontrolled vocalisations and muscular spasms. These effects generally disappear minutes after removal of the nitrous oxide source.

Anxiolytic effect

In behavioural tests of anxiety, a low dose of is an effective anxiolytic. This anti-anxiety effect is associated with enhanced activity of GABA receptors, as it is partially reversed by benzodiazepine receptor antagonists. Mirroring this, animals that have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerant to. Indeed, in humans given 30%, benzodiazepine receptor antagonists reduced the subjective reports of feeling "high", but did not alter psychomotor performance.

Analgesic effect

The analgesic effects of are linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically, they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of. Administration of antibodies that bind and block the activity of some endogenous opioids also block the antinociceptive effects of. Drugs that inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of. Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of, but these drugs have no effect when injected into the spinal cord.
Apart from an indirect action, nitrous oxide, like morphine also interacts directly with the endogenous opioid system by binding at opioid receptor binding sites.
Conversely, α-adrenoceptor antagonists block the pain-reducing effects of when given directly to the spinal cord, but not when applied directly to the brain. Indeed, α-adrenoceptor knockout mice or animals depleted in norepinephrine are nearly completely resistant to the antinociceptive effects of. Apparently -induced release of endogenous opioids causes disinhibition of brainstem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signalling. Exactly how causes the release of endogenous opioid peptides remains uncertain.