Skip Navigation LinksHome > March 2003 - Volume 98 - Issue 3 > α2 Adrenoceptor–mediated Presynaptic Inhibition of Primary A...
Laboratory Investigations

α2 Adrenoceptor–mediated Presynaptic Inhibition of Primary Afferent Glutamatergic Transmission in Rat Substantia Gelatinosa Neurons

Kawasaki, Yasuhiko M.D.*; Kumamoto, Eiichi Ph.D.†; Furue, Hidemasa Ph.D.‡; Yoshimura, Megumu M.D., Ph.D.§

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box


Background: Although intrathecal administration of norepinephrine is known to produce analgesia, cellular mechanisms for this action have not yet been fully understood.
Methods: The actions of norepinephrine (50 μm) on glutamatergic transmission were examined by using the whole cell patch clamp technique in substantia gelatinosa neurons of an adult rat spinal cord slice with an attached dorsal root.
Results: Norepinephrine inhibited the amplitude of monosynaptically evoked Aδ-fiber and C-fiber excitatory postsynaptic currents in a reversible manner. When compared in magnitude between the Aδ-fiber and C-fiber excitatory postsynaptic currents, the former inhibition (50 ± 4%, n = 20) was significantly larger than the latter one (28 ± 4%, n = 8). Both actions of norepinephrine were mimicked by an α2 adrenoceptor agonist, clonidine (10 μm), and an α2A agonist, oxymetazoline (10 μm), but not by an α1 agonist, phenylephrine (10 μm), and a β agonist, isoproterenol (40 μm). The inhibitory actions were antagonized by an α2 antagonist, yohimbine (1 μm), all of the results of which indicate an involvement of α2 adrenoceptors. Norepinephrine did not affect the amplitude of miniature excitatory postsynaptic current and of a response of substantia gelatinosa neurons to AMPA, indicating that its action on evoked excitatory postsynaptic currents is presynaptic in origin.
Conclusions: Norepinephrine inhibits Aδ-fiber– and C-fiber–mediated sensory transmission to substantia gelatinosa neurons through the activation of the α2 adrenoceptor (possibly α2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in Aδ-fiber than C-fiber transmission. This could contribute to at least a part of inhibitory modulation of pain sensation in the substantia gelatinosa by intrathecally administered norepinephrine.
CATECHOLAMINES, such as epinephrine and phenylephrine, have been used in spinal anesthesia together with local anesthetics with an expectation of a contraction of local vessels by the monoamines resulting in a decrease in the clearance of the anesthetics from the subarachnoid space and thus antinociception, 1,2 while intrathecal administration of norepinephrine itself is known to have an antinociceptive effect when assessed by the tail-flick and hot-plate tests. 3,4 There is much evidence supporting the latter idea. Nociceptive information is transmitted through thinly myelinated Aδ-afferent and unmyelinated C-afferent fibers from the periphery to the spinal cord, especially substantia gelatinosa (SG) neurons, 5,6 where the information is modulated. Among this modulatory system, there is a descending norepinephrine-containing fiber pathway from cell groups designated A5, A6 (nucleus locus ceruleus), and A7 (subceruleus) in the pons, 7–10 electrical stimulation of which results in behavioral analgesia. 11–14 This norepinephrine pathway is known to be also activated by systemically administrated opioids 15,16 or electrical stimulation of the midbrain periaqueductal gray region. 17,18In situ hybridization and immunohistochemical studies have demonstrated the presence of adrenoceptors in dorsal root ganglion and dorsal horn neurons in the rat, 19,20 suggesting a role of norepinephrine at presynaptic and postsynaptic sites in the modulation. Previous studies have reported in SG neurons of the spinal cord and also spinal trigeminal nucleus that norepinephrine hyperpolarizes membrane, 21,22 potentiates inhibitory (γ-aminobutyric acid–mediated and glycinergic) transmission, 23 and inhibits glutamatergic excitatory transmission. 24 The former two actions have been examined in detail, whereas the last one remains to be examined in detail. Although there is known to be a difference between Aδ-fiber and C-fiber excitatory transmission to SG neurons in the action of neuromodulators, such as a γ-aminobutyric acid type B receptor agonist, baclofen, 25 serotonin, 26 nociceptin, 27 and anandamide, 28 and also of capsaicin, 29 this has not yet been revealed for the norepinephrine action because Travagli and Williams 24 examined the action of norepinephrine on excitatory transmission evoked in spinal trigeminal SG neurons by stimulating the trigeminal tract where the stimulation could not be separately given to each of the fibers. It has not yet been unveiled which types of adrenoceptors engage in modulation by norepinephrine of each of the Aδ-fiber and C-fiber transmissions, although the norepinephrine-induced hyperpolarization and presynaptic facilitation of inhibitory transmission are reported to be due to the activation of α2 and α1 adrenoceptors, respectively. 21–23 In the current study, we examined the effect of norepinephrine on monosynaptic Aδ-fiber and C-fiber excitatory postsynaptic currents (EPSCs) and its pharmacological property in the adult rat SG using the whole cell patch clamp technique under the condition of a blockade of the hyperpolarizing action.
Back to Top | Article Outline

Materials and Methods

Preparation of Spinal Cord Slices
This study was approved by the institutional Animal Use and Care Committee at Saga Medical School (Saga, Japan). The technique used for obtaining slice preparations from the rat spinal cord was the same as that described elsewhere. 27,30 Briefly, adult male Sprague-Dawley rats (7–8 weeks old) were deeply anesthetized with urethane (1.2 g/kg). The lumbosacral spinal cord (L1–S3) was then removed and placed in preoxygenated (95% O2 and 5% CO2) Krebs solution (117 mm NaCl, 3.6 mm KCl, 2.5 mm CaCl2, 1.2 mm MgCl2, 1.2 mm NaH2PO4, 25 mm NaHCO3, and 11 mm glucose) at 1–3°C; the rats were then immediately sacrificed by exsanguination. After cutting all of ventral and dorsal roots near the root entry zone, except for the L4 or L5 dorsal root on one side, the pia-arachnoid membrane was removed. The spinal cord was mounted on a Vibratome Series 1000® (Technical Products International, O'Fallon, MO), and then a 600- to 650-μm-thick transverse slice was cut with an attached dorsal root having a length of 6–14 mm. The slice was placed on a nylon mesh in the recording chamber and then perfused at a rate of 15–20 ml/min with Krebs solution maintained at 36 ± 1°C. Before the start of the experiment, the slice was preincubated for at least 1 h with Krebs solution.
Back to Top | Article Outline
Whole Cell Recordings from Substantia Gelatinosa Neurons and Stimulation of the Dorsal Root
Substantia gelatinosa neurons were identified by their location under a binocular microscope with light transmitted from below as reported previously 25,27,31; the SG was discernible as a relatively translucent band. Blind whole cell voltage clamp recordings were made from neurons that are located at the center of SG, with a patch pipette that was made up of a thin-walled fiberglass (1.5-mm OD) using a single-stage horizontal puller (P-97; Sutter Instrument, Novato, CA). The patch pipettes had a tip resistance of 5–10 MΩ when filled with a solution having the following composition: 110 mm Cs2SO4, 0.5 mm CaCl2, 2 mm MgCl2, 5 mm EGTA, 5 mm HEPES, 5 mm Mg-ATP, 5 mm tetraethylammonium, and 1 mm guanosine 5′-O-(2-thiodiphosphate), where guanosine 5′-O-(2-thiodiphosphate) and K+-channel blockers (Cs+ and tetraethylammonium) were added to inhibit a hyperpolarizing effect of norepinephrine through the action of G proteins and to block an activation of K+ channels, respectively. After making a rigid seal (resistances: 5–20 GΩ) in the cell-attached mode by a gentle suction given into the patch pipette, the membrane patch was ruptured by a brief period of more powerful suction, resulting in the whole cell configuration. Signals were amplified with a patch clamp amplifier (Axopatch 200B; Axon Instruments, Foster City, CA) in the voltage clamp mode. Data were low-pass filtered at 5 kHz, digitized at 333 kHz with an A/D converter, and stored and analyzed with a personal computer using the pCLAMP data acquisition program (version 6.0; Axon Instruments). The program used for analyzing miniature EPSCs (mEPSCs) detects spontaneous events if the difference between the baseline and a following current value exceeds a given threshold of 6 pA and separating valleys are less than 50% of adjacent peaks; the validity of the method was confirmed by measuring visually individual mEPSCs on a fast time scale in several cases. 30
Orthodromic stimulation of the dorsal root to elicit EPSCs was performed with a suction electrode at 0.2 Hz unless otherwise mentioned. The strength of stimuli used was 1.2 times the threshold to elicit EPSCs, fearing a conduction block of action potentials in the dorsal root. The holding potential (VH) used was −70 mV, at which glycine and γ-aminobutyric acid type A receptor–mediated synaptic currents were invisible. The duration of stimuli used was 0.1 ms throughout the experiments, and conduction velocities were calculated from the latency of monosynaptic EPSC and the length of dorsal root. Aδ-fiber and C-fiber evoked EPSCs were distinguished from each other on the basis of the conduction velocity of afferent fibers and stimulus threshold; they were considered as monosynaptic in origin when the latency remained constant and there was no failure during stimulation at 20 Hz for 1 s or when failures did not occur during repetitive stimulation at 1 Hz for 20 s, respectively, as reported previously. 25,26,32,33 During these stimulations, a conduction block of action potentials did not occur when examined by using rat dorsal root ganglion neurons. 25,33 Although in some neurons monosynaptic Aδ-fiber or C-fiber EPSCs were accompanied by polysynaptic Aδ-fiber or C-fiber EPSCs, such neurons were not used for analysis if the peak of the monosynaptic EPSCs was contaminated by the polysynaptic EPSCs.
Back to Top | Article Outline
Application of Drugs
Drugs were dissolved in Krebs solution and then applied to the SG by an exchange of superfusing solution via a three-way stopcock with one containing them at known concentrations without a change in superfusion rate and thus in temperature. Solutions in the recording chamber completely altered within 20 s. The drugs used in this work were (±)-norepinephrine (Aldrich Chemical Co., Milwaukee, WI), yohimbine hydrochloride, (−)-phenylephrine (Wako, Osaka, Japan), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), (−)-isoproterenol hydrochloride, clonidine hydrochloride, oxymetazoline hydrochloride, guanosine 5′-O-(2-thiodiphosphate) (Sigma, St Louis, MO), and 6-cyano-7-nitroquinoxaline-2,3-dione (Tocris Cookson, St. Louis, MO).
Back to Top | Article Outline
Statistical Analysis
Data are presented as mean ± SEM. Statistical significance was determined as P < 0.05 using either the paired or unpaired Student t test unless otherwise mentioned. The Kolmogorov-Smirnov test was also used to compare mEPSCs in the absence and presence of norepinephrine in the distributions of their amplitudes and interevent intervals. In all cases, n refers to the number of neurons studied.
Back to Top | Article Outline


Whole cell patch clamp recordings were made from a total of 158 SG neurons. Stable recordings could be obtained from neurons in spinal cord slices maintained in vitro for more than 12 h, and recordings were made from single neurons for up to 4 h. All experiments were performed at least 10 min later, enough time for guanosine 5′-O-(2-thiodiphosphate) and K+-channel blockers in patch pipette solutions to diffuse into SG neurons, after the establishment of whole cell configuration; norepinephrine (50 μm) did not change holding currents at −70 mV. In all SG neurons tested, mEPSCs were downward at −70 mV and were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (10 μm; n = 2), as reported previously, 27,30 indicating the activation of AMPA receptors.
Back to Top | Article Outline
More Inhibition by Norepinephrine of Monosynaptic Aδ-fiber Than C-fiber EPSCs Elicited in Substantia Gelatinosa Neurons
Fig. 1
Fig. 1
Image Tools
When stimulating the dorsal root with a strength of less than 200 μA, 82% (n = 75; this percentage was almost comparable to a value [79%] obtained previously 27) of 92 neurons examined could elicit monosynaptic EPSCs that had no failure and no change in latency when elicited at 20 Hz (fig. 1A, left). Conduction velocity values (3.8–15 m/s), estimated from the latency of EPSC and the length of dorsal root, were almost within a range of those of Aδ-fibers obtained from the experiment in dorsal root ganglion neurons, as reported previously. 25,32 Monosynaptic Aδ-afferent EPSCs evoked at 0.2 Hz had a mean amplitude of 279 ± 23 pA (range, 59–884 pA; VH = −70 mV;fig. 1A, right). On the other hand, when stimulated with a strength of more than 200 μA, 83% (n = 53; this percentage was also similar to a value [80%] obtained previously 27) of 64 neurons tested exhibited monosynaptic EPSCs that had no failures in response to stimuli at 1 Hz (fig. 1B, left), albeit a variability in EPSC latency was observed in some neurons. 25 The EPSCs originated from afferent fibers whose conduction velocities were 0.3–0.8 m/s, a range of those of C fibers. 25,32 The amplitude of monosynaptic C-afferent EPSCs evoked at 0.2 Hz averaged to be 253 ± 26 pA (range, 96–714 pA; VH = −70 mV;fig. 1B, right). Thirty-one percent (n = 20) of the neurons tested exhibited both of the monosynaptic Aδ-fiber and C-fiber EPSCs, as seen in figure 1C. These EPSCs were completely inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (10 μm; n = 2), indicative of an involvement of AMPA receptors, as reported previously. 27,32
Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools
Effects of norepinephrine (50 μm) on the monosynaptic Aδ-fiber and/or C-fiber EPSCs were examined in a total of 24 SG neurons. As seen from figures 2A–C, each of the EPSCs was inhibited in amplitude by norepinephrine in a reversible manner. These effects on Aδ-fiber and C-fiber EPSCs were, respectively, maximal at approximately 1 and 2 min following the application of norepinephrine (fig. 3A). When examined in many neurons, the inhibitions (measured at approximately 2 min following norepinephrine superfusion) of the peak amplitudes of Aδ-fiber and C-fiber EPSCs were, respectively, 50 ± 4% (n = 20) and 28 ± 4% (n = 8), with the values being significantly different from each other (P < 0.01), as seen in figure 3B. This greater sensitivity of Aδ-fiber EPSC than C-fiber EPSC to norepinephrine was also observed in a neuron in which both of the EPSCs were elicited (n = 5; for example, see fig. 2C).
Back to Top | Article Outline
Involvement of α2 Adrenoceptors in Norepinephrine-induced Inhibition of Monosynaptic Aδ-fiber and C-fiber EPSCs Evoked in Substantia Gelatinosa Neurons
Fig. 4
Fig. 4
Image Tools
Fig. 5
Fig. 5
Image Tools
Fig. 6
Fig. 6
Image Tools
We next examined which subtypes of adrenoceptors are involved in the norepinephrine-induced inhibition of Aδ-fiber and C-fiber EPSCs by use of their agonists and antagonists. When superfused for 2 min, an α2 adrenoceptor agonist, clonidine (10 μm), as well as norepinephrine, inhibited the peak amplitude of monosynaptically evoked Aδ-fiber and C-fiber EPSCs (by 24 ± 2% [n = 13] and 19 ± 3% [n = 11], respectively), as seen in figures 4Aa and Ba. An agonist of α2A adrenoceptor, oxymetazoline (10 μm), 34 exhibited a similar action on Aδ-fiber and C-fiber EPSCs (inhibition: 34 ± 9% [n = 4] and 16 ± 2% [n = 4], respectively; these were not different from each other;P > 0.05;figs. 4Ab and Bb). On the other hand, an α1 adrenoceptor agonist, phenylephrine (10 μm), and a β adrenoceptor agonist, isoproterenol (40 μm), were without the inhibition on Aδ-fiber and C-fiber EPSCs, as seen in figures 4Ac, Bc, Ad, and Bd. Figure 5 summarizes the effects of the adrenoceptor agonists on Aδ-fiber and C-fiber EPSCs. With respect to antagonists, an α2 adrenoceptor antagonist, yohimbine (1 μm), superfused for 5 min prior to the application of norepinephrine (50 μm), greatly depressed its inhibitory effect on Aδ-fiber or C-fiber EPSCs (peak amplitude: 95 ± 3% [n = 12] and 97 ± 6% [n = 4] of control, respectively, in the presence of the antagonist), as seen in figures 6A and B. Altogether, these results indicate that the suppressive actions of norepinephrine on Aδ-fiber and C-fiber EPSCs are mediated by α2 adrenoceptors.
Back to Top | Article Outline
Lack of the Effect of Norepinephrine on AMPA Responses in Substantia Gelatinosa Neurons
Fig. 7
Fig. 7
Image Tools
Figures 7A and B demonstrate the effect of norepinephrine (50 μm) superfused for 2 min on mEPSCs recorded from SG neurons. Both mEPSC amplitude and frequency were unaffected by norepinephrine; they were 98 ± 7% (P > 0.05; n = 10) and 102 ± 1% (P > 0.05; n = 10) of control (17 ± 3 pA and 9 ± 2 Hz), respectively, as reported by Baba et al.23 When examined for cumulative distributions of the amplitude and interevent interval of mEPSC, they were also unaffected by norepinephrine, as seen from figure 7C. To determine any effect of norepinephrine on the sensitivity of SG neurons to l-glutamate, we examined whether an AMPA (10 μm) response is affected by norepinephrine (50 μm). As seen in figure 7D, norepinephrine did not affect the peak amplitude of the AMPA response (88 ± 5% of control, n = 12;P > 0.05).
Back to Top | Article Outline


The current study demonstrated that norepinephrine inhibits glutamatergic excitatory transmission to SG neurons in the spinal dorsal horn from the periphery. It was revealed here for the first time that both of Aδ and C primary afferent transmission are depressed by norepinephrine, although Travagli and Williams 24 had not examined the action of norepinephrine on each of their transmissions to SG neurons of the spinal trigeminal nucleus. Both actions of norepinephrine were due to the activation of α2 adrenoceptors, as reported for evoked EPSCs in spinal trigeminal SG neurons. 24 This result may be consistent with the observations that an antinociceptive effect of either intrathecally administrated norepinephrine or electrical stimulation of sites near the A7 cell group and also of the periaqueductal gray is due to the activation of α2 adrenoceptors. 4,14,16,17 Although the α2 adrenoceptors are subdivided into α2A, α2B, and α2C receptors, 34 the α2 action in the current study appears to be due to the activation of the α2A type because an α2A adrenoceptor agonist, oxymetazoline, 34 reduced the Aδ and C afferent transmission. This idea is supported by a report of Stone et al.35 which demonstrated that a mouse expressing a point mutation in the α2A receptor was without α2 agonist–mediated spinal analgesia in the tail-flick test. Although the activation of β adrenoceptors is known to enhance neurotransmitter release in many types of neurons, including sympathetic ganglion neurons, 36 this was not the case in SG neurons because isoproterenol did not affect the transmission.
Since norepinephrine did not affect mEPSC amplitude and the sensitivity of SG neurons to AMPA, its actions on evoked EPSCs were presynaptic in origin. Since these actions were examined for monosynaptic transmission, the norepinephrine actions are suggested to be due to the activation of α2, possibly α2A, adrenoceptors existing in primary afferent central terminals. Consistent with this idea, an inhibition by norepinephrine of the release of l-glutamate from rat spinal cord synaptosomes is mediated by α2 adrenoceptors, 37 and the α2A adrenoceptor is expressed in primary afferent terminals in the rat. 20 The action on C-fiber transmission in the current study may be consistent with the observation that capsaicin-induced release of l-glutamate from spinal cord synaptosomes is reduced by the activation of the α2A adrenoceptor 38 because capsaicin is known to excite C fibers. Although a cellular mechanism for the norepinephrine action was not examined here, this would be due to an inhibition of voltage-gated Ca2+ channels existing in nerve terminals because norepinephrine reduces Ca2+-channel currents in many types of neurons, including dorsal root ganglion neurons. 39 There was a dissociation between the actions of norepinephrine on evoked EPSC and mEPSC in that the former was presynaptically depressed, while mEPSC frequency was unaffected, an observation different from that in spinal trigeminal SG neurons. 24 One explanation for this discrepancy may be that norepinephrine acts differentially on evoked and spontaneous transmitter release mechanisms in the spinal dorsal horn, resulting in a distinct action on their EPSCs, because each of the releases in the SG is suggested to be mediated by different types of Ca2+ channels. 40 Alternatively, mEPSCs in spinal cord SG neurons may be produced by inputs not only from primary afferent fiber axon but also from interneuron axon, the former terminals having more α2 adrenoceptors than the latter ones, where mEPSCs mainly originate from interneuron terminals. This idea may be consistent with the observation that many α2A adrenoceptors are colocalized in the spinal dorsal horn with neuropeptides, which are contained in primary afferent fibers. 20 A similar discrepancy between spontaneous and evoked transmission has been seen in the actions of a μ-opioid receptor agonist 31 and anandamide 28 in spinal cord SG neurons. Although Pan et al.41 have very recently reported a clonidine-induced decrease in mEPSC frequency in SG neurons, a discrepancy between this and the current study may be due to the fact that different SG neurons were tested because they examined neurons in the outer layer of SG, while we investigated neurons located at the center of SG. The possibility cannot be ruled out that SG neurons exhibiting no effect of norepinephrine on mEPSCs in the current study (where the blind patch clamp technique was used) had located in the inner layer of SG because visually identified neurons in the inner layer of SG appeared to be without actions of clonidine on mEPSCs. 41
The current study revealed for the first time that norepinephrine inhibits Aδ-fiber transmission more effectively than C-fiber transmission. There are two possible explanations for this result. One is that α2 adrenoceptors are more densely expressed in Aδ-fiber than C-fiber terminals in the spinal dorsal horn. The other is that there is a different type of α2 adrenoceptors in each of the Aδ-fiber and C-fiber terminals, although oxymetazoline could not discriminate between them in the extent of inhibition. This remains to be examined by using other agents regarding subtypes of α2 adrenoceptors. The action of norepinephrine was the same as that of anandamide 28 but different from those of baclofen 25 and nociceptin 27 in that Aδ-fiber transmission was more sensitive than C-fiber transmission. It is suggested that norepinephrine as well as anandamide may inhibit fast-conducting transmission more potently than slow-conducting pain transmission.
In conclusion, the current study provides a cellular basis for the antinociceptive action of norepinephrine through a mechanism in primary afferent terminals at the spinal cord level. Although norepinephrine may contribute to a prolongation of analgesia through its vasoconstrictive action in spinal anesthesia, the current finding of the inhibition of excitatory transmission supports its role as an important negative modulator of pain transmission to SG neurons together with a norepinephrine-induced hyperpolarization 21,22 and enhancement of inhibitory transmission. 23
The authors thank Tadahide Totoki, M.D., Ph.D. (Professor of Anesthesiology, Saga Medical School, Saga, Japan), for his encouragement during this study.
Back to Top | Article Outline


1. Concepcion M, Maddi R, Francis D, Rocco AG, Murray E, Convino BG: Vasoconstrictors in spinal anesthesia with tetracaine: A comparison of epinephrine and phenylephrine. Anesth Analg 1984; 63: 134–8

2. Vaida GT, Moss P, Capan LM, Turndorf H: Prolongation of lidocaine spinal anesthesia with phenylephrine. Anesth Analg 1986; 65: 781–5

3. Reddy SVR, Maderdrut JL, Yaksh TL: Spinal cord pharmacology of adrenergic agonist-mediated antinociception. J Pharm Exp Ther 1980; 213: 525–33

4. Howe JR, Wang J-Y, Yaksh TL: Selective antagonism of the antinociceptive effect of intrathecally applied alpha adrenergic agonists by intrathecal prazosin and intrathecal yohimbine. J Pharm Exp Ther 1983; 224: 552–8

5. Kumazawa T, Perl ER: Excitation of marginal and substantia gelatinosa neurons in the primate spinal cord: Indications of their place in dorsal horn functional organization. J Comp Neurol 1978; 177: 417–34

6. Willis Jr WD, Coggeshall RE: Sensory Mechanisms of the Spinal Cord, 2nd edition. Edited by Willis WD Jr, Coggeshall RE. New York, Plenum Press, 1991, pp 94–115

7. Satoh K, Kashiba A, Kimura H, Maeda T: Noradrenergic axon terminals in the substantia gelatinosa of the rat spinal cord: An electron-microscopic study using glyoxylic acid-potassium permanganate fixation. Cell Tissue Res 1982; 222: 359–78

8. Westlund KN, Bowker RM, Ziegler MG, Coulter JD: Noradrenergic projections to the spinal cord of the rat. Brain Res 1983; 263: 15–31

9. Hagihira S, Senba E, Yoshida S, Tohyama M, Yoshiya I: Fine structure of noradrenergic terminals and their synapses in the rat spinal dorsal horn: An immunohistochemical study. Brain Res 1990; 526: 73–80

10. Rajaofetra N, Ridet J-L, Poulat P, Marlier L, Sandillon F, Geffard M, Privat A: Immunocytochemical mapping of noradrenergic projections to the rat spinal cord with an antiserum against noradrenaline. J Neurocytol 1992; 21: 481–94

11. Jones SL, Gebhart GF: Quantitative characterization of ceruleospinal inhibition of nociceptive transmission in the rat. J Neurophysiol 1986; 56: 1397–410

12. Proudfit HK: Pharmacologic evidence for the modulation of nociception by noradrenergic neurons. Prog Brain Res 1988; 77: 357–70

13. Jones SL: Descending noradrenergic influences on pain. Prog Brain Res 1991; 88: 381–94

14. Yeomans DC, Clark FM, Paice JA, Proudfit HK: Antinociception induced by electrical stimulation of spinally projecting noradrenergic neurons in the A7 catecholamine cell group of the rat. Pain 1992; 48: 449–61

15. Wilson PR, Yaksh TL: Pharmacology of pain and analgesia. Anaesth Intensive Care 1980; 8: 248–56

16. Yaksh TL: Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav 1985; 22: 845–58

17. Aimone LD, Jones SL, Gebhart GF: Stimulation-produced descending inhibition from the periaqueductal gray and nucleus raphe magnus in the rat: Mediation by spinal monoamines but not opioids. Pain 1987; 31: 123–36

18. Bajic D, Proudfit HK: Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception. J Comp Neurol 1999; 405: 359–79

19. Nicholas AP, Pieribone V, Hökfelt T: Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: An in situ hybridization study. J Comp Neurol 1993; 328: 575–94

20. Stone LS, Broberger C, Vulchanova L, Wilcox GL, Hökfelt T, Riedl MS, Elde R: Differential distribution of α2A and α2C adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 1998; 18: 5928–37

21. North RA, Yoshimura M: The actions of noradrenaline on neurones of the rat substantia gelatinosa in vitro. J Physiol 1984; 349: 43–55

22. Grudt TJ, Williams JT, Travagli RA: Inhibition by 5-hydroxytryptamine and noradrenaline in substantia gelatinosa of guinea-pig spinal trigeminal nucleus. J Physiol 1995; 485: 113–20

23. Baba H, Shimoji K, Yoshimura M: Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord: I. Effects on axon terminals of GABAergic and glycinergic neurons. A nesthesiology 2000; 92: 473–84

24. Travagli RA, Williams JT: Endogenous monoamines inhibit glutamate transmission in the spinal trigeminal nucleus of the guinea-pig. J Physiol 1996; 491: 177–85

25. Ataka T, Kumamoto E, Shimoji K, Yoshimura M: Baclofen inhibits more effectively C-afferent than Aδ-afferent glutamatergic transmission in substantia gelatinosa neurons of adult rat spinal cord slices. Pain 2000; 86: 273–82

26. Ito A, Kumamoto E, Takeda M, Takeda M, Shibata K, Sagai H, Yoshimura M: Mechanisms for ovariectomy-induced hyperalgesia and its relief by calcitonin: Participation of 5-HT1A-like receptor on C-afferent terminals in substantia gelatinosa of the rat spinal cord. J Neurosci 2000; 20: 6302–8

27. Luo C, Kumamoto E, Furue H, Chen J, Yoshimura M: Nociceptin inhibits excitatory but not inhibitory transmission to substantia gelatinosa neurones of adult rat spinal cord. Neuroscience 2002; 109: 349–58

28. Luo C, Kumamoto E, Furue H, Chen J, Yoshimura M: Anandamide inhibits excitatory transmission to rat substantia gelatinosa neurones in a manner different from that of capsaicin. Neurosci Lett 2002; 321: 17–20

29. Yang K, Kumamoto E, Furue H, Li Y-Q, Yoshimura M: Action of capsaicin on dorsal root-evoked synaptic transmission to substantia gelatinosa neurons in adult rat spinal cord slices. Brain Res 1999; 830: 268–73

30. Lao L-J, Kumamoto E, Luo C, Furue H, Yoshimura M: Adenosine inhibits excitatory transmission to substantia gelatinosa neurons of the adult rat spinal cord through the activation of presynaptic A1 adenosine receptor. Pain 2001; 94: 315–24

31. Kohno T, Kumamoto E, Higashi H, Shimoji K, Yoshimura M: Actions of opioids on excitatory and inhibitory transmission in substantia gelatinosa of adult rat spinal cord. J Physiol 1999; 518: 803–13

32. Nakatsuka T, Park J-S, Kumamoto E, Tamaki T, Yoshimura M: Plastic changes in sensory inputs to rat substantia gelatinosa neurons following peripheral inflammation. Pain 1999; 82: 39–47

33. Nakatsuka T, Ataka T, Kumamoto E, Tamaki T, Yoshimura M: Alteration in synaptic inputs through C-afferent fibers to substantia gelatinosa neurons of the rat spinal dorsal horn during postnatal development. Neuroscience 2000; 99: 549–56

34. Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR, Trendelenburg U: International union of pharmacology nomenclature of adrenoceptors. Pharmacol Rev 1994; 46: 121–36

35. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL: The α2a adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci 1997; 17: 7157–65

36. Kumamoto E, Kuba K: Mechanism of long-term potentiation of transmitter release induced by adrenaline in bullfrog sympathetic ganglia. J Gen Physiol 1986; 87: 775–93

37. Kamisaki Y, Hamada T, Maeda K, Ishimura M, Itoh T: Presynaptic α2 adrenoceptors inhibit glutamate release from rat spinal cord synaptosomes. J Neurochem 1993; 60: 522–6

38. Li X, Eisenach JC: α2A-Adrenoceptor stimulation reduces capsaicin-induced glutamate release from spinal cord synaptosomes. J Pharm Exp Ther 2001; 299: 939–44

39. HolzIV GG, Rane SG, Dunlap K: GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels. Nature 1986; 319: 670–2

40. Bao J, Li JJ, Perl ER: Differences in Ca2+ channels governing generation of miniature and evoked excitatory synaptic currents in spinal laminae I and II. J Neurosci 1998; 18: 8740–50

41. Pan Y-Z, Li D-P, Pan H-L: Inhibition of glutamatergic synaptic input to spinal lamina IIo neurons by presynaptic α2-adrenergic receptors. J Neurophysiol 2002; 87: 1938–47

Cited By:

This article has been cited 50 time(s).

Wang, H; Xie, YF; Chiang, CY; Dostrovsky, JO; Sessle, BJ
Neuroscience, 236(): 244-252.
Journal of Physiology-London
Endogenous activation of presynaptic NMDA receptors enhances glutamate release from the primary afferents in the spinal dorsal horn in a rat model of neuropathic pain
Yan, XS; Jiang, ES; Gao, M; Weng, HR
Journal of Physiology-London, 591(7): 2001-2019.
Brain Research
AM404 enhances the spontaneous release of L-glutamate in a manner sensitive to capsazepine in adult rat substantia gelatinosa neurones
Yue, HY; Fujita, T; Kawasaki, Y; Kumamoto, E
Brain Research, 1018(2): 283-287.
Pharmacological Research
Antinociceptive mechanisms associated with diluted bee venom acupuncture (apipuncture) in the rat formalin test: involvement of descending adrenergic and serotonergic pathways
Kim, HW; Kwon, YB; Han, HJ; Yang, IS; Beitz, AJ; Lee, JH
Pharmacological Research, 51(2): 183-188.
Anesthesia and Analgesia
Intravenous but not perineural clonidine prolongs postoperative analgesia after psoas compartment block with 0.5% levobupivacaine for hip fracture surgery
Mannion, S; Hayes, I; Loughnane, F; Murphy, DB; Shorten, GD
Anesthesia and Analgesia, 100(3): 873-878.
Cell and Tissue Research
Adrenoceptors and signal transduction in neurons
Hein, L
Cell and Tissue Research, 326(2): 541-551.
Developmental enhancement of alpha(2)-adrenoceptor-mediated suppression of inhibitory synaptic transmission onto mouse cerebellar purkinje cells
Hirono, M; Matsunaga, W; Chimura, T; Obata, K
Neuroscience, 156(1): 143-154.
Journal of Urology
Role of alpha(2)-Adrenoceptors and Glutamate Mechanisms in the External Urethral Sphincter Continence Reflex in Rats
Furuta, A; Asano, K; Egawa, S; de Groat, WC; Chancellor, MB; Yoshimura, N
Journal of Urology, 181(3): 1467-1473.
Pharmacology Biochemistry and Behavior
Water soluble fraction (< 10 kDa) from bee venom reduces visceral pain behavior through spinal alpha(2)-adrenergic activity in mice
Kwon, YB; Ham, TW; Kim, HW; Roh, DH; Yoon, SY; Han, HJ; Yang, IS; Kim, KW; Beitz, AJ; Lee, JH
Pharmacology Biochemistry and Behavior, 80(1): 181-187.
Neuroscience Letters
Noradrenaline inhibits substantia gelatinosa neurons in mice trigeminal subnucleus caudalis via alpha(2) and beta adrenoceptors
Han, SK; Park, JR; Park, SA; Chun, SW; Lee, JC; Lee, SY; Ryu, PD; Park, SJ
Neuroscience Letters, 411(2): 92-97.
Collegium Antropologicum
Effects of clonidine preemptive analgesia on acute postoperative pain in abdominal surgery
Persec, J; Persec, Z; Bukovic, D; Husedzinovic, I; Bukovic, N; Pavelic, L
Collegium Antropologicum, 31(4): 1071-1075.

Acta Anaesthesiologica Scandinavica
Activity of the descending noradrenergic pathway after surgery in rats
Wang, Y; Feng, C; Wu, Z; Wu, A; Yue, Y
Acta Anaesthesiologica Scandinavica, 52(): 1336-1341.
American Journal of Veterinary Research
Effect of romifidine on the nociceptive withdrawal reflex and temporal summation in conscious horses
Spadavecchia, C; Arendt-Nielsen, L; Andersen, OK; Spadavecchia, L; Schatzmann, U
American Journal of Veterinary Research, 66(): 1992-1998.

Progress in Neurobiology
The synaptic connectivity that underlies the noxious transmission and modulation within the superficial dorsal horn of the spinal cord
Wu, SX; Wang, W; Li, H; Wang, YY; Feng, YP; Li, YQ
Progress in Neurobiology, 91(1): 38-54.
Journal of Physiology-London
Actions of noradrenaline on substantia gelatinosa neurones in the rat spinal cord revealed by in vivo patch recording
Sonohata, M; Furue, H; Katafuchi, T; Yasaka, T; Doi, A; Kumamoto, E; Yoshimura, M
Journal of Physiology-London, 555(2): 515-526.
CNS Drug Reviews
Antinociceptive properties of fadolmidine (MPV-2426), a novel alpha(2)-adrenoceptor agonist
Pertovaara, A
CNS Drug Reviews, 10(2): 117-126.

Journal of Pharmacological Sciences
Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord
Yoshimura, M; Furue, H
Journal of Pharmacological Sciences, 101(2): 107-117.
Biochemical and Biophysical Research Communications
Enhancement of the releases of GABA and glycine during ischemia in rat spinal dorsal horn
Kawasaki, Y; Fujita, T; Kumamoto, E
Biochemical and Biophysical Research Communications, 316(2): 553-558.
Journal of Cerebral Blood Flow and Metabolism
Noradrenergic agonists and antagonists influence migration of cortical spreading depression in rat - a possible mechanism of migraine prophylaxis and prevention of postischemic neuronal damage
Richter, F; Mikulik, O; Ebersberger, A; Schaible, HG
Journal of Cerebral Blood Flow and Metabolism, 25(9): 1225-1235.
Anesthesia and Analgesia
An evaluation of the postoperative antihyperalgesic and analgesic effects of intrathecal clonidine administered during elective cesarean delivery
Lavand'homme, PM; Roelants, F; Waterloos, H; COllet, V; De Kock, MF
Anesthesia and Analgesia, 107(3): 948-955.
Current Medical Research and Opinion
Dihydroergotamine nasal spray for relief of refractory headache: a retrospective chart review
Fisher, M; Gosy, EJ; Heary, B; Shaw, D
Current Medical Research and Opinion, 23(4): 751-755.
Pharmacology & Therapeutics
Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis
Fairbanks, CA; Stone, LS; Wilcox, GL
Pharmacology & Therapeutics, 123(2): 224-238.
Journal of Physiology-London
Selective action of noradrenaline and serotonin on neurones of the spinal superficial dorsal horn in the rat
Lu, Y; Perl, ER
Journal of Physiology-London, 582(1): 127-136.
Direct excitation of spinal GABAergic interneurons by noradrenaline
Gassner, M; Ruscheweyh, R; Sandkuhler, J
Pain, 145(): 204-210.
Neuroscience and Biobehavioral Reviews
Interactions between the cardiovascular and pain regulatory systems: an updated review of mechanisms and possible alterations in chronic pain
Bruehl, S; Chung, OY
Neuroscience and Biobehavioral Reviews, 28(4): 395-414.
Progress in Neurobiology
Noradrenergic pain modulation
Pertovaara, A
Progress in Neurobiology, 80(2): 53-83.
Inhibition of opioid release in the rat spinal cord by alpha(2C) adrenergic receptors
Chen, WL; Song, BB; Marvizon, JC
Neuropharmacology, 54(6): 944-953.
European Journal of Neuroscience
Action of dexmedetomidine on the substantia gelatinosa neurons of the rat spinal cord
Ishii, H; Kohno, T; Yamakura, T; Ikoma, M; Baba, H
European Journal of Neuroscience, 27(): 3182-3190.
European Journal of Neuroscience
Actions of propofol on substantia gelatinosa neurones in rat spinal cord revealed by in vitro and in vivo patch-clamp recordings
Takazawa, T; Furue, H; Nishikawa, K; Uta, D; Takeshima, K; Goto, F; Yoshimura, M
European Journal of Neuroscience, 29(3): 518-528.
Journal of Comparative Neurology
Coexpression of alpha(2A)-Adrenergic and delta-Opioid Receptors in Substance P-Containing Terminals in Rat Dorsal Horn
Riedl, MS; Schnell, SA; Overland, AC; Chabot-Dore, AJ; Taylor, AM; Ribeiro-Da-Silva, A; Elde, RP; Wilcox, GL; Stone, LS
Journal of Comparative Neurology, 513(4): 385-398.
Journal of Neurophysiology
Adenosine inhibits GABAergic and Glycinergic transmission in adult rat substantia gelatinosa neurons
Yang, K; Fujita, T; Kumamoto, E
Journal of Neurophysiology, 92(5): 2867-2877.
Modulation by adenosine of A delta and C primary-afferent glutamatergic transmission in adult rat substantia gelatinosa neurons
Lao, LJ; Kawasaki, Y; Yang, K; Fujita, T; Kumamoto, E
Neuroscience, 125(1): 221-231.
Phospholipase A(2) activation by melittin enhances spontaneous glutamatergic excitatory transmission in rat substantia gelatinosa neurons
Yue, HY; Fujita, T; Kumamoto, E
Neuroscience, 135(2): 485-495.
Experimental Brain Research
The effect of clonidine on cell survival, glutamate, and aspartate release in normo- and hyperglycemic rats after near complete forebrain ischemia
Jellish, WS; Murdoch, J; Kindel, G; Zhang, X; White, FA
Experimental Brain Research, 167(4): 526-534.
Journal of Applied Physiology
Noradrenergic modulation of XII motoneuron inspiratory activity does not involve alpha(2)-receptor inhibition of the I-h current or presynaptic glutamate release
Adachi, T; Robinson, DM; Miles, GB; Funk, GD
Journal of Applied Physiology, 98(4): 1297-1308.
European Journal of Neuroscience
Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn
Papp, I; Szucs, P; Hollo, K; Erdelyi, F; Szabo, G; Antal, M
European Journal of Neuroscience, 24(5): 1341-1352.
Collegium Antropologicum
Analysis of preincisional and postincisional treatment with alpha2-adrenoreceptor agonist clonidine regarding analgesic consumption and hemodynamic stability in surgical patients
Persec, J; Bukovic, D; Majeric-Kogler, V; Sakic, K; Persec, Z; Kasum, M
Collegium Antropologicum, 31(4): 1065-1070.

Current Pain and Headache Reports
Spinal inhibitory neurotransmission in neuropathic pain
Taylor, BK
Current Pain and Headache Reports, 13(3): 208-214.
Neuroscience Research
Sensory processing and functional reorganization of sensory transmission under pathological conditions in the spinal dorsal horn
Furue, H; Katafuchi, T; Yoshimura, M
Neuroscience Research, 48(4): 361-368.
Clinical Neurophysiology
Pupil dilation response to noxious stimulation: Effect of varying nitrous oxide concentration
Oka, S; Chapman, CR; Kim, B; Nakajima, I; Shimizu, O; Oi, Y
Clinical Neurophysiology, 118(9): 2016-2024.
Topical clonidine antinociception
Dogrul, A; Uzbay, IT
Pain, 111(3): 385-391.
Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces tactile hypersensitivity after surgery in rats
Obata, H; Conklin, D; Eisenach, JC
Pain, 113(3): 271-276.
Pharmacological Research
Selective serotonin re-uptake inhibition attenuates evoked glutamate release in the dorsal horn of the anaesthetised rat in vivo
Langman, NJ; Smith, CGS; Whitehead, KJ
Pharmacological Research, 53(2): 149-155.
Reviews of Physiology Biochemistry and Pharmacology, Vol 154
Synaptic modulation in pain pathways
Zeilhofer, HU
Reviews of Physiology Biochemistry and Pharmacology, Vol 154, 154(): 73-100.
British Journal of Pharmacology
Dexmedetomidine and ST-91 analgesia in the formalin model is mediated by alpha(2A)-adrenoceptors: a mechanism of action distinct from morphine
Nazarian, A; Christianson, CA; Hua, XY; Yaksh, TL
British Journal of Pharmacology, 155(7): 1117-1126.
Journal of Biomedical Science
DNIC-mediated analgesia produced by a supramaximal electrical or a high-dose formalin conditioning stimulus: roles of opioid and alpha 2-adrenergic receptors
Wen, YR; Wang, CC; Yeh, GC; Hsu, SF; Huang, YJ; Li, YL; Sun, WZ
Journal of Biomedical Science, 17(): -.
Journal of Neurochemistry
2A adrenoceptor-mediated presynaptic inhibition of GABAergic transmission in rat tuberomammillary nucleus neurons
Nakamura, M; Suk, K; Lee, MG; Jang, IS
Journal of Neurochemistry, 125(6): 832-842.
Journal of Neuroscience
Neuropeptides Amplify and Focus the Monoaminergic Inhibition of Nociception in Caenorhabditis elegans
Hapiak, V; Summers, P; Ortega, A; Law, WJ; Stein, A; Komuniecki, R
Journal of Neuroscience, 33(): 14107-14116.
European Journal of Pharmacology
The noradrenergic pain regulation system: A potential target for pain therapy
Pertovaara, A
European Journal of Pharmacology, 716(): 2-7.
Ephedrine Blocks Rat Sciatic Nerve In Vivo and Sodium Channels In Vitro
Hung, Y; Kau, Y; Zizza, AM; Edrich, T; Zurakowski, D; Myers, RR; Wang, GK; Gerner, P
Anesthesiology, 103(6): 1246-1252.

PDF (924)
Back to Top | Article Outline

© 2003 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.

Article Tools