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Home , Carbon dioxide, Oxide, Pharmacology, Photorespiration

104 South African Journal of Science 103, March/April 2007 Research in Action

between CO2 and N2O in the Nitrous and dioxide: and . their similar and contrasting , like , is produced endogenously biological effects Nitrous oxide is a metabolic product of certain , some of which are † M.A. Gillman*‡ and F.J. Lichtigfeld* commensals in the gut of animals includ- ing man.10 In recent years, moreover, evidence has appeared indicating that

N2O may be produced in mammalian he similar and contrasting biological 4,7 the CO2 involved in . cells as part of their . When properties of CO2 and N2O appear to acquire their either directly we discovered that N2O could be involved Treflect fundamental biological processes from the or through internal recycling in neurotransmission in humans,11–13 we in both very simple and the most complex . of and . The amount of did not realize that we had stumbled on a ammonium recyling in C3 plants is signifi- new biological principle. The generality of our finding was confirmed when nitric Introduction cantly higher than in C4 plants as a result A recent article in this journal1 discussed of photorespiration. As the rate of ammo- oxide (NO), another endogenously pro- duced , was also discovered to have a the similarities and differences between nia production in C3 plants can be 20 times the rate of primary nitrate , role in neurotransmission.14,15 nitrous oxide (N2O) and carbon dioxide the cannot afford to lose this ammo- The evidence that N2O is produced (CO2) from a physico-chemical perspective. 4,7 Here we consider the apparent similarities nia as a volatile gas but must have an endogenously seems to confirm the and differences between these two effective mechanism for its re-assimi- possibility that it is not only the first gas to in a biological context. lation. Three (glutamine synthe- have been shown to have a role in neuro- tase, and glutamate transmission but that it is formed by the It is well known that biologically active 16,17 chemical agents can act directly with ) have been identified in of NO. This once again highlights the similarities of N O and receptors in the brain to produce physio- transforming into amino 2 2 CO , which both appear to be endoge- logical and pharmacological effects. but there is debate as to the role of the 2 These receptors have unique and specific various oxidized nitrogen intermediates nously produced as metabolic products in physico-chemical structures and proper- which are formed.3 It is possible that bacterial and mammalian cells. These ties. Chemical substances that attach to one of these is NO, which may be gases are therefore involved in the physi- ology of cells from the simplest to the these receptors do so by characteristic reduced to N2O as has been shown in physico-chemical mechanisms, which mammalian cells4 and bacteria.5 In sup- most complex forms. This is perhaps not surprising, given that N O and CO then trigger a cascade of events through port of this idea, plants have been shown 2 2 are linked through the nitrogen and the interaction of the particular agent to emit endogenously produced N2O 2 carbon cycles (see above), which are with the specific . It is therefore during nitrate assimilation.6 not surprising that the structural similari- crucial to living organisms. Nitrous oxide does not substitute for O2 ties of the N2O and CO2 translate in either the cytochrome c oxidase or Actions on the into similar biological actions. On the carbon (CO) diogenase reac- In higher animals, N O and CO have other hand, such structural and other tions that produce, respectively, 2 2 related actions on the nervous system. differences as they have may account for and CO and which are both catalysed by 2 Both gases in high concentrations cause their dissimilar biological effects. cytochrome c oxidase.7 Rather, it acts by depression of the , reducing the rate of electron transfer from Nitrogen and carbon cycles leading eventually to , respiratory cytochrome c to the O reaction site.7 It is Photorespiration involves the - 2 depression and finally death.18–20 Despite therefore possible that N O interacts with dependent of CO and uptake 2 these apparent similarities, however, 2 CO in the plant by reducing the flow of in green . During the 2 there are differences in their biological of electrons to both CO and O reaction 19,20 1950s and 1960s, the synthesis of glycolate 2 2 effects. sites. The latter postulate is supported by by leaves in high O concentrations or low 2 the finding that N O inhibits the use of O CO settings was demonstrated and the 2 2 2 by plant .8 enzymic pathways involved were eluci- The effects of N2O on respiratory drive 3 The link between N Oand CO through dated. bisphosphate carboxy- 2 2 are relatively small, with slight depression lase/ (, RuBP) is the the carbon and nitrogen cycles is also seen of the stimulatory response in humans to in the composition of the atmosphere and 19 primary involved, with both CO2 CO2 when 50% N2O in oxygen is breathed. during glacial cycles.9 The end of a and O2 competing for its active site, the The response to hypoxia is also reduced glacial cycle is marked by the position on the enzyme to which the sub- when 50% N2O is breathed. Since N2Oat strate binds. There is a well-established of N2O, a gas, from water. non-anaesthetic concentrations (such as link between photorespiration and the This is described by a nonlinear model 50%) is an multipotent ,21–23 in plants. During the which takes into account the effect of its effect on respiration could of , ammonia is variations in the ocean’s content of fixed be opioid mediated. Nevertheless, it is produced in stoichiometric amounts with nitrogen following enhanced denitrifi- much less marked than some other cation.9 Outgassing to greater levels and particularly those that are selective *South African Brain Research Institute, 6 Campbell St, Waverley, Johannesburg 2090, South Africa. of atmospheric CO2 during interglacial mu-opioid , such as . † 9 Deceased. periods, showing a direct relationship Competitive opioid antagonists such as ‡Author for correspondence. E-mail: [email protected] Research in Action South African Journal of Science 103, March/April 2007 105

nalorphine and naloxone can reverse consequences are almost certainly recep- Other workers have shown that both 24,25 16,17,21,22,28,31–33 these effects on respiration. Such antag- tor mediated and could also be N2O and hyperventilation have similar onistic outcomes on respiratory depression responsible for its actions on the respira- inhibitory effects on lamina V of the spinal are extremely rapid as would be expected tory centres. cord, where there is convergence of visceral because they are mediated by direct effects and high threshold cutaneous pain.40 on opioid receptors. Moreover, endoge- Sympathetic activity These laminae are rich in opioid termi- nous and exogenous opioids, including Sympathetic activity, which prepares nals.41

N2O, inhibit the responses of the brain- the body for the fright/flight response, is These findings seem to indicate that stem respiratory centre to increased CO increased by both N O34,35 and CO .20 2 2 2 CO2 , like N2O, acts directly on mu-opioid 19 levels. Thus, the control of respira- Nitrous oxide seems to act directly at receptors, especially in their effects on tory ‘may be directly related to opioid receptors as well as via the alpha2- pain perception and possibly also in their 36 competition for opioid receptor sites by system. Carbon dioxide actions on respiration as suggested previ- these various gases as well as endogenous potently activates the central adrenergic ously (see above) on the basis of radio- 22 20 opioid agents.’ It is therefore significant system and there is some preliminary receptor assays.22 that the depressant effect of morphine on evidence that it acts directly on mu-opioid 28 respiration can be as rapidly reversed by receptors, further underlining the simi- Other pharmacological actions of CO 26 2 inhalation of 5% CO2 in oxygen, indicat- larity between the biological actions of and N2O on the central nervous system ing the possibility that this effect is also these two gases. The descending adre- Pharmacological, rather than physio- receptor mediated. nergic and nor-adrenergic cell groups logical, concentrations of CO2 produce 42,43 That this influence of CO2 is likely to form most of the lateral medullary stress reactions such as anxiety and fear. involve receptors is supported by the fact reticular formation and are linked to This outcome is probably mediated by that stimulation of ventilation in man various vital centres in the medulla stimulation of the sympathetic system20 begins within seconds of inhaling low oblongata of the brainstem, which includes and blockade of opioid receptors.26 In 37 concentrations of the gas, with a maximum the respiratory centres. contrast, although also heightening sym- response occurring within less than 5 Apart from the influence of these gases 19,20 20 pathetic stimulation, non-anaesthetic minutes. These stimulatory consequences on the adrenergic system, they also have doses of N O have anti-stress effects44–47 of CO inhalation disappear rapidly after 2 2 local effects. One which they share is the where the agonistic influence of N Oon its withdrawal.20 Indeed, the CO effect on direct local influence on systemic blood 2 2 the opioid receptors seems to outweigh its medullary and peripheral 20,38,39 vessels, resulting in vasodilatation. sympathetic activity.45 Indeed, low doses arterial chemoreceptors are clearly recep- The results of central sympathetic activa- 46 of N O reduce cortisol release. tor mediated.20 In these circumstances, it tion are usually opposite to the local effects 2 Both CO and N O have is likely that the effects of CO on the of CO , whereas the local influence 2 2 2 2 effects.48–50 Interestingly, found that ventilatory neurons in the medullary– on blood vessels seems to be more impor- such effects of CO were magnified if pontine region are also mediated by re- tant than are the adrenergically medi- 2 preceded by a short administration of ceptors. A further clue that this is an ated vasoconstrictor effects.20 Nitrous anaesthetic concentrations of N Ofor8or opioid interaction is that, in barbiturate oxide35,36,38 shares these properties. 2 9 inhalations. Nitrous oxide at 100% used poisoning, which is not mediated by 27 as an anaesthetic, also for a few inhala- opioid receptors, the administration of Pain perception tions (less than a minute’s exposure), has CO2 has no positive effect on stimulating Analgesia can be produced by hyper- 49 26 an antidepressant action. Furthermore, respiration. That various gases influence capnia, which triggers the release of inhalation of 80% N O (with 20% O ) for respiration by interacting directly at 2 2 endogenous opioids, presumably from 50 opioid receptors is supported by the find- the spinal dorsal horn,29 a region in the between 1.5 and 5 minutes demon- ing that 100% oxygen altered the in vitro spinal cord involved with pain perception. strated that the gas has antidepressant ef- 3 fects. Low concentrations of N O mixed binding of H-dihydromorphine as well The dorsal horn appears to be implicated 2 3 28 with high concentrations of O titrated to as that of H-ketocyclazocine. Dihydro- because the modification of tail-flick 2 morphine and ketocyclazocine are opioid latency persists after spinalization.29 The a level where the patient is relaxed but receptor , so that evidence that in authors responsible for these results con- fully conscious [so-called psychotropic 17 vitro binding with these agents is inter- cluded that may produce nitrous oxide (PAN)] also have 51 fered with by oxygen indicates that direct excitatory effects on spinal or marked antidepressant properties. 50,51 oxygen itself also binds to opioid recep- bulbo-spinal enkephalinergic (that is, Moreover, this work indicates that tors and therefore has opioid proper- opioid) interneurones. Since this effect endogenous depressions (which are ties. Other studies have confirmed this was also present in animals spinalized at caused by an underlying biological work.31 lower thoracic levels, at least one popula- disturbance) are resistant to the effects of N O, whereas reactive depressions (which Although binding studies with CO2 tion of these neurones must have been in 2 using opioid ligands have not been the lumbo-sacral region.29 Gamble and are related to a stressful life event) are ameliorated by exposure to the gas. performed, as far as we are aware, the Milne draw the analogy with N2O when similarity of the actions of the specific they state that: ‘It is interesting that Carbon dioxide at high concentrations opioid antagonistic, naloxone, on CO2 analgesia induced by the structurally (75% in O2 administered for 30–120 29 and N2O analgesia (see below) may similar compound nitrous oxide can be seconds) is effective for treating addicts indicate that CO2 also binds to opioid partly blocked by relatively high doses of from whom abused substances such as receptors, to exert some of its respiratory naloxone under some circumstances.’ alcohol52,53 and opioids54,55 are suddenly 56 effects. They found that analgesia caused by CO2 withdrawn. PAN has also been used 53,57 The pharmacological effects of N2O are was also blocked with relatively high successfully to treat both acute also rapid in onset and offset19,30 and these doses of naloxone (2 mg/kg).29 and opioid58,59 withdrawal states. 106 South African Journal of Science 103, March/April 2007 Research in Action

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