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Evidence for the Involvement of Spinal Cord 1 Adrenoceptors in Nitrous

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Evidence for the Involvement of Spinal Cord 1 Adrenoceptors in Nitrous Anesthesiology 2002; 97:1458–65 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Evidence for the Involvement of Spinal Cord ␣ 1 Adrenoceptors in Nitrous Oxide–induced Antinociceptive Effects in Fischer Rats Ryo Orii, M.D., D.M.Sc.,* Yoko Ohashi, M.D.,* Tianzhi Guo, M.D.,† Laura E. Nelson, B.A.,‡ Toshikazu Hashimoto, M.D.,* Mervyn Maze, M.B., Ch.B.,§ Masahiko Fujinaga, M.D.ʈ Background: In a previous study, the authors found that ni- opioid peptide release in the brain stem, leading to the trous oxide (N O) exposure induces c-Fos (an immunohisto- 2 activation of the descending noradrenergic inhibitory chemical marker of neuronal activation) in spinal cord ␥-ami- nobutyric acid–mediated (GABAergic) neurons in Fischer rats. neurons, which results in modulation of the pain–noci- 1 In this study, the authors sought evidence for the involvement ceptive processing in the spinal cord. Available evi- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/6/1458/337059/0000542-200212000-00018.pdf by guest on 01 October 2021 ␣ of 1 adrenoceptors in the antinociceptive effect of N2O and in dence suggests that at the level of the spinal cord, there activation of GABAergic neurons in the spinal cord. appear to be at least two neuronal systems that are Methods: Adult male Fischer rats were injected intraperitone- involved (fig. 1). In one of the pathways, activation of ally with ␣ adrenoceptor antagonist, ␣ adrenoceptor antago- 1 2 ␣ nist, opioid receptor antagonist, or serotonin receptor antago- the 2 adrenoceptors produces either direct presynaptic nist and, 15 min later, were exposed to either air (control) or inhibition of neurotransmitter release from primary af- 75% N2O. In some animals, nociception was investigated with ferent neurons or postsynaptic inhibition of the second- the plantar test after 30 min of exposure, while in other animals, order neurons.1 In a second hypothetical pathway, we gas exposure was continued for 90 min and the spinal cord was ␥ examined for c-Fos immunostaining. In a separate experiment, propose that inhibitory -aminobutyric acid–mediated ␣ animals were exposed to the above gases alone, after which the (GABAergic) interneurons are activated via 1 adreno- spinal cords were examined immunohistochemically for c-Fos ceptors, resulting in either presynaptic inhibition of the ␣ and 1 adrenoceptor by double-staining methods. nociceptive primary afferent neurons or postsynaptic Results: The antinociceptive effect of N2O was attenuated by 2 ␣ ␣ inhibition of second-order neurons. In this study, we prazosin (an 1 adrenoceptor antagonist), yohimbine (an 2 adrenoceptor antagonist), and naloxone (an opioid receptor sought evidence to link the participation of GABAergic antagonist) but not by methysergide and tropisetron (serotonin neurons in the antinociceptive effect of N2O to their receptor antagonists). N O exposure induced c-Fos expression ␣ 2 activation by 1 adrenoceptors. in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colo- ␣ calized with 1 adrenoceptor immunoreactivity in laminae III–IV. Conclusions: These findings support the hypothesis that N2O ␣ Materials and Methods activates GABAergic interneurons through 1 adrenoceptors to produce its antinociceptive effect. Animals Adult male Fischer rats (11–12 weeks old) were used WE have sought to characterize the molecular mecha- throughout the study (B&K Universal, Grimston Ald- nism and neural substrates involved in the antinocicep- brough, Hull, United Kingdom). All animal procedures tive action of nitrous oxide (N2O). In brief, N2O induces were carried out in accordance with the United King- dom (Scientific Procedures) Act of 1986, and the study protocol was approved by the Home Office of the United Additional material related to this article can be found on the Kingdom (London, United Kingdom). All efforts were ANESTHESIOLOGY Web site. Go to the following address, click on made to minimize animal suffering and reduce the num- Enhancements Index, and then scroll down to find the appro- ber of animals used. priate article and link. http://www.anesthesiology.org Drug Treatment * Postdoctoral Fellow, † Research Fellow, ‡ Ph.D. Student, § Professor, ʈ Se- Animals were injected intraperitoneally with the fol- nior Lecturer. lowing drugs 15 min before gas exposure: prazosin, an Received from the Department of Anaesthetics and Intensive Care, Imperial ␣ College of Science, Technology and Medicine, University of London, London, 1 adrenoceptor antagonist (Cat. No. 0623; Tocris Cook- United Kingdom, and the Magill Department of Anaesthesia, Intensive Care and ␣ son, Ballwin, MO); yohimbine, an 2 adrenoceptor an- Pain Management, Chelsea and Westminster Hospital, Chelsea and Westminster Healthcare NHS Trust, London, United Kingdom. Submitted for publication tagonist (Cat. No. Y-3125; Sigma Chemical Co., St Louis, March 13, 2002. Accepted for publication June 12, 2002. Supported by the MO); naloxone, an opioid receptor antagonist (Cat. No. Medical Research Council of the United Kingdom, London, United Kingdom, and Chelsea and Westminster Health Care National Health Service Trust, London, N-7758; Sigma Chemical Co.); methysergide, a nonselec- United Kingdom. Presented in part at the annual meeting of American Society of tive 5-HT receptor antagonist (Cat. No. 1064; Tocris Anesthesiologists, New Orleans, Louisiana, October 15, 2001. Cookson); and tropisetron, a selective 5-HT3 receptor Address reprint requests to Dr. Fujinaga: Academic Anaesthesia, Chelsea and Westminster Hospital, Imperial College School of Medicine, 369 Fulham antagonist (Cat. No. T-104; Sigma Chemical Co.). Dos- Road, London, SW10 9NH, United Kingdom. Address electronic mail to: ages of each drug examined were derived from the [email protected]. Individual article reprints may be purchased through the 3–6 Journal Web site, www.anesthesiology.org. literature. All drugs were dissolved in saline except Anesthesiology, V 97, No 6, Dec 2002 1458 ␣ 1 ADRENOCEPTOR MEDIATES N2O-INDUCED ANALGESIA 1459 Fig. 1. Putative neuronal pathways in the spinal cord involved in the antinocicep- tive effects of N2O. Closed triangles indi- cate excitatory synapses, and open trian- gles indicate inhibitory synapses. Small closed circles indicate the nucleus of cells activated by N2O exposure, and a small open circle indicates the nucleus of a cell inactivated by N2O exposure. There are at least two neuronal systems that may be involved: (1) direct presynaptic inhibi- tion of the nociceptive primary afferent neurons and/or postsynaptic inhibition Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/97/6/1458/337059/0000542-200212000-00018.pdf by guest on 01 October 2021 of the second-order neurons through acti- ␣ vation of the 2 adrenoceptors, and (2) in- direct presynaptic inhibition of the noci- ceptive primary afferent neurons and/or postsynaptic inhibition of the second-or- der neurons by the activation of GABAergic ␣ inhibitory interneurons through 1 adre- ␣ ؍ ␣ noceptors. 2 AR 2 adrenoceptor; Ex ؍ excitatory neurotransmitters; Ex-R ؍ NT receptors for excitatory neurotransmitters; ؍ aminobutyric acid; GBA-R-␥ ؍ GABA ؍ GABAA receptor; NE norepinephrine. for prazosin, which was dissolved in heated distilled the PWL, the percentage of maximal possible effect water. The injection volume was standardized as 1 ml. (%MPE) was calculated as follows: %MPE ϭ ͕͑PWL with treatment Gas Exposure Ϫ Ϫ Gas exposure was performed in an acryl plastic expo- Baseline PWL)/(Cutoff time Baseline PWL)} sure chamber (18 in long, 9 in wide, and 8 in high). ϫ 100 Either a mixture of 75% N2O and 25% O2 or air at a flow rate of 4 l/min was continuously delivered into the ex- Spinal Cord Preparation and Cryosection posure chamber via an inflow port and exhausted via an In another set of experiments, animals were not sub- outflow port. Gas concentrations, including those for jected to nociceptive testing but were killed by an over- N2O, O2, and CO2, in the chamber were measured con- dose of sodium pentobarbital (100 mg/kg), intraperito- tinuously by infrared gas spectrometry (Ohmeda 5250 neal, following 90 min of gas exposure, which is the RGM; Ohmeda, Hatfield, Hertz, United Kingdom). Ani- time to the peak effect of c-Fos induction in the spinal mals were placed into the chamber through the side 2 cord after N2O exposure. During the terminal anes- door after the desired gas concentrations were achieved thetic, the animals were perfused with 0.1 M phosphate- and stabilized. buffered saline (PBS) followed by 4% paraformaldehyde in 0.1 M phosphate buffer via a 16-gauge cannula in- Plantar Test serted through the left ventricle into the ascending aorta. One hour before the experiment (baseline) and 30 min Following decapitation, the spinal cord was expelled by after the initiation of gas exposure (which coincides rapid injection of PBS at the sacral vertebral level and 7 with the peak antinociceptive effect of N2O), thermal stored in 30% sucrose in 0.1 M phosphate buffer for at nociceptive testing was performed using a plantar test least 24 h at 4°C. A 5-mm portion of the spinal cord at device (Plantar test 7370; Ugo Basile, Comerio, Italy). the lumbar enlargement was cut by a razor blade and Radiant heat was applied on the plantar surface of hind was freeze-mounted in embedding matrix, and 30-␮m paws through the floor of the exposure chamber, and transverse sections were cut at Ϫ15°C; every third sec- the paw withdrawal latency (PWL), defined as the time tion was collected in PBS (approximately 40–50 sections between the activation of the heat source and hind-paw per sample). withdrawal, was automatically recorded. Heat intensity was adjusted such that the baseline PWL was approxi- Immunohistochemistry: Diaminobenzidine Staining mately 4 s. To avoid tissue damage, a predetermined of c-Fos cutoff time of 10 s was imposed. Each PWL data set Approximately 15–20 undamaged free-floating spinal consisted of a mean of three trials for each animal. From cord sections were selected and were first incubated at Anesthesiology, V 97, No 6, Dec 2002 1460 ORII ET AL.
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