Canales Cloro Acoplados GABA

7/30/2019 Canales Cloro Acoplados GABA

1/6

Involvement of chloride channel coupled GABAC receptors in the peripheral

antinociceptive effect induced by GABAC receptor agonist

cis-4-aminocrotonic acid

Glucia Maria Lopes Reis, Igor Dimitri Gama Duarte

Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antnio Carlos, 6627, 31270-100, Belo Horizonte, Brazil

Received 5 September 2006; accepted 12 December 2006

Abstract

We investigated the effect of chloride and potassium channel blockers on the antinociception induced by GABAC receptor agonist CACA (cis-4-

aminocrotonic acid) using the paw pressure test, in which pain sensitivity was increased by an intraplantar injection (2 g) of prostaglandin E2(PGE2). CACA administered locally into the right hindpaw (25, 50 and 100 g/paw) elicited a dose-dependent antinociceptive effect which was

demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. The GABAC receptor antagonist (1,2,5,6

tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA; 5, 10 and 20 g/paw) antagonized, in a dose-dependent manner, the peripheral

antinociception induced by CACA (100 g), suggesting a specific effect. This effect was reversed by the chloride channel coupled receptor blocker

picrotoxin (0.8 g/paw). Glibenclamide (160 g) and tolbutamide (320 g), blockers of ATP-sensitive potassium channels, charybdotoxin (2 g), a

large-conductance potassium channel blocker, dequalinium (50 g), a small-conductance potassium channel blocker, and cesium (500 g), a non-

specific potassium channel blocker did not modify the peripheral antinociception induced by CACA. This study provides evidence that activation of

GABAC receptors in the periphery induces antinociception, that this effect results from the activation of chloride channel coupled GABAC receptors

and that potassium channels appear not to be involved. 2007 Elsevier Inc. All rights reserved.

Keywords: cis-4-aminocrotonic acid; CACA; K+ channel; Cl channel; Peripheral antinociception; Picrotoxin; TPMPA

Introduction

In the vertebrate central nervous system, -aminobutyric

acid (GABA) is the major inhibitory neurotransmitter. GABA

receptors can be classified as GABAA and GABAC receptors,

which are ionotropic receptors, or as GABAB receptors, whichare metabotropic receptors coupled to the GTP-binding protein

(Bormann, 2000; Bowery and Enna, 2000). GABAA receptors

have several subunits (6, 4, 3, 1, 1, 1, and 3), which

form a pentameric chloride channel (Barnard et al., 1998).

GABAC receptors are pentameric Cl channels composed of the

subunits ( 13). The GABAA and GABAB receptors show

sensitivities to bicuculline and baclofen, respectively. GABACreceptors do not respond to either drug. GABA analogue cis-4-

aminocrotonic acid (CACA) selectively activates GABACreceptors while TPMPA has been identified as a potent and

highly selective antagonist for GABAC receptors (Bowery et al.,

1981; Bormann, 2000; Bowery and Enna, 2000).The function of GABA in the modulation of nociception is

crucial and complex. Several reports have demonstrated the

participation of GABAergic system in modulation of pain at the

supraspinal (Millan, 2002) and spinal level (Malcangio and

Bowery, 1996; Hammond, 2001). In addition, studies have

demonstrated a peripheral GABAergic antinociceptive action

(Carlton and Zhou, 1998; Motta et al., 2004). Most of these

studies examined the effects of activation of GABAA and

GABAB receptors in nociception. In contrast, less is known

about the involvement of the GABAC receptor in pain. The

function of the GABAC receptor has been extensively studied in

Life Sciences 80 (2007) 12681273

www.elsevier.com/locate/lifescie

Corresponding author. Departamento de Farmacologia, ICB-UFMG, Av.

Antnio Carlos, 6627, Campus da Pampulha, Belo Horizonte, MG, Brasil, CEP:

31.270-100, Brazil.

E-mail address: [email protected](I.D.G. Duarte).

0024-3205/$ - see front matter 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.lfs.2006.12.015
mailto:[email protected]://dx.doi.org/10.1016/j.lfs.2006.12.015http://dx.doi.org/10.1016/j.lfs.2006.12.015mailto:[email protected]


2/6

the retina where the receptor is strongly expressed in bipolar cell

axon terminals (Enz et al., 1996; Koulen et al., 1997; Fletcher

et al., 1998; Lukasiewicz, 1996). However, Zheng et al. (2003)

localized the 1 subunits of the GABAC receptor on lamina I

and II of the dorsal horn and dorsal root ganglia (DRG), crucial

sites for pain transmission.

In this context, the aim of the present study was to verify thepossibility of the peripheral antinociceptive effect of the

GABAC agonist CACA using the rat paw pressure test. The

specificity of CACA in GABAC receptors was also tested

through intraplantar administration of GABAC receptor antag-

onist TPMPA. Furthermore, the possible antinociceptive action

mechanism was evaluated using picrotoxin, a chloride channel

blocker, and specific potassium channel specific blockers.

Materials and methods

Animals

The experiments were performed on 160200 g male Wistar

rats (N= 47 per group) from CEBIO-UFMG (The Animal

Centre of the Federal University of Minas Gerais). The animals

were housed in a temperature-controlled room (23 1 C) on an

automatic 12-h light/dark cycle (06:00 to 18:00 h of light

phase). All testing was concluded during the light phase (8:00

15:00). Food and water were freely available until the beginning

of the experiments. Naive animals were used throughout. All

the experiments were approved by the Ethics Committee on

Animal Experimentation (CETEA) of the Federal University of

Minas Gerais.

Measurement of the hyperalgesia

Hyperalgesia was induced by a subcutaneous injection of

prostaglandin E2 (PGE2, 2 g) into the plantar surface of the

rat's hindpaw and measured by the paw pressure test described

by Randall and Selitto (1957). An analgesimeter (Ugo-Basile,

Italy) with a cone-shaped paw-presser with a rounded tip was

used to apply a linearly increasing force to the rat's right

hindpaw. The weight in grams required to elicit nociceptive

response paw flexion or struggle was determined as the

nociceptive threshold. A cut-off value of 300 g was used to

prevent damage to the paws. The nociceptive threshold was

measured in the right paw and determined by the average ofthree consecutive trials recorded before (zero time) and 3 h after

PGE2 injection (peak of effect). The results were calculated by

the difference between these two averages ( of nociceptive

threshold) and expressed as grams (Fig. 1). To reduce stress, the

rats were habituated to the apparatus 1 day before the

experiments.

Drug administration

The drug used as a hyperalgesic agent was PGE2 (Sigma,

USA), and cis-4-aminocrotonic acid (CACA; Tocris, USA) was

used as the GABAC receptor agonist. 1,2,5,6 tetrahydropyridin-

4-yl (TPMPA; Sigma) was used as a GABAC receptor

antagonist. The Cl- channel blocker was picrotoxin (Sigma)

and the K+ channels blockers were glibenclamide (Sigma),

tolbutamide (ICN Biomedicals, USA), charybdotoxin (Sigma),

dequalinium (Calbiochem, USA), tetraethylammonium

(Sigma), 4-aminopyridine (Sigma), and cesium (Mitsuwa's

Pure Chemical, Japan). Prostaglandin E2 (ethanol 8% in saline),

CACA, TPMPA, picrotoxin, TEA, 4-AP, charybdotoxin,

cesium and dequalinium were dissolved in isotonic saline

while the sulphonylureas glibenclamide and tolbutamide were

dissolved in Tween 80 vehicle (2% in saline). All drugs were

dissolved immediately before use and injected in a volume of100 l/paw, with exception of K+ channel blockers, TPMPA

and picrotoxin, which were injected in a volume of 50 l/paw.

Experimental protocol

CACA was administered subcutaneously in the right

hindpaw 2 h and 45 min after the local injection of PGE 2. In

the protocol used to determine whether CACA was acting

outside the injected paw, PGE2 was injected into both hindpaws,

while CACA was administered into the left or right paw. The

nociceptive threshold was always measured in the right

hindpaw. TPMPA was administered subcutaneously in theright paw 5 min before CACA and picrotoxin was injected

40 min before CACA. All the K+ channel blockers were

injected subcutaneously into the right hindpaw 30 min before

CACA. The protocol above was assessed in the literature and

pilot experiments to determine best moment of injection for

each substance.

Statistical analysis

The data were analysed statistically by one-way analysis of

variance (ANOVA) using the Bonferroni test post-hoc for

multiple comparisons. Probabilities less than 5% (Pb0.05)

were considered statistically significant.

Fig. 1. Parameter utilized for calculation of of nociceptive threshold. Left bars

represent the nociceptive threshold express in gram (g) before prostaglandin E 2(PGE2, 2 g) or saline (Sal) administration (0 h). Central bars are the mechanical

threshold measured 3 h after PGE2 or Sal administration (3rd h). Right bars refer to

difference between these measurements ( of nociceptive threshold).

1269G.M.L. Reis, I.D.G. Duarte / Life Sciences 80 (2007) 12681273


3/6

Results

Peripheral antinociceptive effect of CACA

Fig. 2 shows that intraplantar administration of CACA (25,

50 and 100 g) in the right paw antagonized the hyperalgesic

effect of PGE2 (2 g/paw) in a dose-dependent manner. CACAat a dose of 100 g/paw, when injected into left paw, did not

produce an antinociceptive effect in the right paw, whereas

CACA at a dose of 200 g/paw, when injected into the left paw,

induced antinociceptive effect in the contralateral paw (Fig. 3).

Antagonism of CACA-induced antinociception by TPMPA

The intraplantar injection of TPMPA (5, 10, and 20 g)

reduced the peripheral antinociception induced by CACA

(100 g/paw; Fig. 4) in a dose-dependent manner. TPMPA did

not modify the nociceptive threshold in control animals or

induce any overt behavioural effect at the doses used.

Antagonism of CACA-induced antinociception by picrotoxin

Picrotoxin (0.8 g/paw) significantly reduced the CACA-

induced peripheral antinociception (100 g/paw; Fig. 5). This

drug did not modify the nociceptive threshold in control animals

or induce any overt behavioural effect at the doses used.

Effect of K+ channel blockers on CACA-induced

antinociception

As shown in Fig. 6, the K+ channel blockers tetraethylam-

monium (30 g), 4-aminopyridine (10 g), glibenclamide

(160 g), tolbutamide (320 g), charybdotoxin (2 g),

dequalinium (50 g) and cesium (500 g), injected into the

paw, did not modify the antinociception induced by CACA

Fig. 2. Effect of GABAC receptor agonist CACA on the nociceptive threshold in

rats with PGE2-induced hyperalgesia. CACA (g/paw) was administered 2 h

and 45 min after local administration of 100 l of PGE2 (2 g). The

antinociceptive response was measured in the paw pressure test as described in

Methods. Each column represents the meanS.E.M. for 45 rats per group.

Indicates a significant difference from the PGE2

+ saline (Sal) injected control(Pb0.05, ANOVA+Bonferroni test).

Fig. 3. Exclusion of outside paw antinociceptive effect of CACA (100 g).

CACA was administered into the right (R) or left (L) paw 2 h and 45 min after

PGE2 (2 g) administration into both hind paws. The antinociceptive response

of the right (R) hindpaw was measured in the paw pressure test as described in

Methods. Each column represents the mean S.E.M. for 5 rats per group.Indicates a significant difference from the PGE2+ Sal injected control (Pb0.05,

ANOVA+Bonferroni test).

Fig. 4. Antagonism induced by intraplantar administration of GABAC receptor

antagonist TPMPA of the peripheral antinociception produced by CACA in

hyperalgesic paws (PGE2, 2 g). TPMPA (g) was administered 05 min before

CACA (100 g/paw). Each column represents the mean S.E.M. for 45 rats per

group. , # Indicate significant differences compared to PGE2+Sal+Sal- and

PGE2

+ CACA+ Sal-injected groups, respectively (Pb

0.05, ANOVA + Bonferronitest). Veh= vehicle.

1270 G.M.L. Reis, I.D.G. Duarte / Life Sciences 80 (2007) 12681273


4/6

(100 g/paw). These drugs did not induce hyperalgesia or

antinociception by themselves (data not shown).

Discussion

The function of GABAC receptors in the visual system hasbeen extensively demonstrated (Quian and Dowling, 1993; Enz

and Cutting, 1999; Koulen et al., 1997; Fletcher et al., 1998;

Lukasiewicz, 1996). In contrast, the involvement of the GABACreceptors in pain has been less studied. In the present study,

CACA, an agonist of GABAC receptors, induced a dose-

dependent and peripheral antinociceptive effect on PGE2-

induced hyperalgesia. This is consistent with data from the

literature reporting the participation of the GABAergic system

in the modulation of pain. For example, Fields et al. (1991)

reported the involvement of the GABAA receptor in the

modulation of central nociception through the descending

inhibitory system. Also, the GABAB receptor agonist baclofen,has been reported to produce central antinociception (Shafiza-

deh et al., 1997; Sabetkasai et al., 1999; Sawynok, 1987; Aran

and Hammond, 1991). In addition, Carlton et al. (1999)

demonstrated that muscimol, a GABAA receptor agonist,

induced peripheral antinociception in the formalin test.

GABAC receptors are formed by a specific subunit (Bormann,

2000). The presence of subunit or mRNA can be used as a

marker for GABAC receptors (Schlicker et al., 2004). The 1subunits have been localized on lamina I and II of the dorsal

horn and DRG; crucial sites for pain transmission (Zheng et al.,

2003). This study also demonstrated that the mechanical pain

threshold with the von Frey filament test was decreased in

rho1/ mice compared with control mice.

The possibility that CACA at a dose of 100 g/paw produced

antinociception by acting at sites outside the paw was excluded,

since its administration into the left paw did not alter hyperalgesia

in the contralateral paw. In these experiments, PGE2 was ad-

ministered in the left paw, so that this site of administration would

be similar to that in the right paw, with an equal possibility that

these agents would reach receptors outside the injected paw.A source of endogenous GABA for this peripheral receptor

might be glutamate-containing primary afferent fibres. This

amino acid is present in more than 90% of primary afferent

fibers (Battaglia and Rustioni, 1988) and is converted by

glutamic acid decarboxylase (GAD) into GABA (Malcangio

and Bowery, 1996). In addition, was demonstrated the presence

of GABA in primary afferent neurons of feline sensory ganglia:

trigeminal ganglia and DRG. The localization of GABA in

primary afferent neurons, which are considered to be nocicep-

tors, suggests that the amino acid may function as a pain

transmitter or modulator (Stoyanova, 2004).

Unlike GABAA receptors, GABAC receptors are not inhibitedby GABAA receptor antagonist bicuculline and, unlike GABABreceptors, they are not activated by GABAB receptor agonist

baclofen (Chebib and Johnston, 2000). In the present study,

receptor specificity is shown by demonstrating that TPMPA, a

specific GABAC receptor antagonist (Ragozzino et al., 1996),

blocked the peripheral antinociceptive effect of CACA. Further-

more, our results show that neither bicuculline nor GABABreceptor antagonist saclofen blocked the antinociceptive effect

Fig. 5. Antagonism induced by intraplantar administration of picrotoxin of the

peripheralantinociception produced by CACA in hyperalgesic paws (PGE2, 2 g).

Picrotoxin (g) was administered 40 min before CACA (100 g/paw). Each

column represents the mean S.E.M. for 47 rats per group. , # Indicate

significant differences compared to PGE2+Sal+Sal- and PGE2+CACA+Sal-

injected groups, respectively (Pb0.05, ANOVA+Bonferroni test). Veh=vehicle.

Fig. 6. Effect of intraplantar administration of tetraethylammonium (TEA),

4-aminopyridine (4-AP), glibenclamide (GLI), tolbutamide (TOL), charybdo-

toxinin (ChTX), dequalinium (DQ) and cesium (Cs) on the peripheral

antinociception produced by CACA in hyperalgesic paws (PGE2, 2 g). Drugs

(g) were administered 30 min before CACA (100 g/paw). Each column

represents the meanS.E.M. for 47 rats per group. , # Indicate significant

differences compared to PGE2

+Sal+ Sal- and PGE2

+CACA+Sal-injectedgroups, respectively (Pb0.05, ANOVA+Bonferroni test). Veh=vehicle.



5/6

induced by CACA (data not shown), further supporting the

argument that the antinociceptive response induced by CACA in

the paw pressure test is mediated by a GABAC mechanism.

The present work suggested for the first time, based on

pharmacological evidence, the peripheral occurrence of

GABAC receptors and their antinociceptive function/activation.

According to Bormann (2000) the Cl- channel blockerpicrotoxin is a strong antagonist on GABAA and 1 homomeric

GABAC receptors. The present results demonstrated that the

intraplantar administration of picrotoxin antagonized the

peripheral antinociception induced by CACA, suggesting that

chloride channel coupled GABAC receptors play an important

role in this effect. In neurons of the major pelvic ganglion in

rats, picrotoxin blocked the biphasic response (depolarization

followed by hyperpolarization) induced by CACA indicating

that GABAC receptors mediate this effect (Akasu et al., 1999).

In this study, we propose that activation of chloride channel

coupled GABAC receptors cause a hyperpolarization of

peripheral terminals of primary afferents, leading to a decreasein action potential generation.

In contrast, K+ channel blockers, in effective doses

(Rodrigues and Duarte, 2000; Soares and Duarte, 2001;

Pacheco and Duarte, 2005) did not exhibit any effect in the

peripheral antinociception induced by CACA. The lack of

antagonism of peripheral antinociceptive effect of CACA by K+

channel blockers was expected, as CACA does not open K+

channels in neurons, but does open Cl- channels (Bormann,

2000). In addition, K+ channel blockers seem to antagonize

only the antinociception due to drugs that activate receptors

linked to K+ channel (see Ocaa et al., 2004).

More recently, we demonstrated the participation of voltage-

dependent K+ channel or G-protein-coupled inwardly rectifyingK+ channel in the peripheral antinociception induced by

baclofen (Reis and Duarte, 2006).

In conclusion, the present study shows that the peripheral

chloride channels coupled to GABAC receptors play an

important role in the antinociception induced by CACA and

that K+ channel do not appear to be involved in this effect.

Acknowledgements

The authors were supported by a fellowship from the

Coordenao de Aperfeioamento de Pessoal de Nvel Superior

(CAPES) and the Conselho Nacional de Pesquisa (CNPq).

References

Akasu, T., Munakata, Y., Tsurusaki, M., Hasuo, H., 1999. Role of GABAA and

GABAC receptors in the biphasic GABA responses in neurones of the rat

major pelvic ganglia. Journal of Neurophysiology 82, 14891496.

Aran, S., Hammond, D.L., 1991. Antagonism of baclofen-induced antinocicep-

tion by intratecal administration of phaclofen or 2-hydroxy-saclofen, but not

-aminovaleric acid in the rat. Journal of Pharmacology and Experimental

Therapeutics 257, 360368.

Barnard, E.A., Skolnick, P., Olsen, H., Mohler, H., Sieghart, W., Biggio, C.,

Bateson, A.N., Braestrup, A.N., Langer, S.Z., 1998. International Union of

Pharmacology XV. Subtypes of-aminobutyric acidA: classification on the

basis of subunit structure and receptor function. Pharmacological Reviews

50, 291313.

Battaglia, G., Rustioni, A., 1988. Coexistence of glutamate and substance P in

dorsal root ganglion neurons of the rat and monkey. The Journal of

Comparative Neurology 277, 302312.

Bormann, J., 2000. The ABC of GABA receptors. Trends in Pharmacological

Sciences 21, 1619.

Bowery, N.G., Enna, S.J., 2000. Gamma-aminobutyric (B): first of the

functional metabotropic heterodimers. Journal of Pharmacology and

Experimental Therapeutics 292, 27.Bowery, N.G., Doble, A., Hill, D.R., Hudson, A.L., Shaw, J.S., Turnbull, M.J.,

Warrington, R., 1981. Bicuculline-insensitiveGABA receptors on peripheral

autonomic nerve terminals. European Journal of Pharmacology 71, 5370.

Carlton, S.M., Zhou, S., 1998. Attenuation of formalin-induced nociceptive

behaviours following local peripheral injection of gabapentin. Pain 76,

201207.

Carlton, S.M., Zhou, S., Coggeshall, R.E., 1999. Peripheral GABA (A) receptors:

evidence for peripheral afferent despolarization. Neuroscience 93, 713722.

Chebib, M., Johnston, G.A., 2000. GABA activated ligand gated ion channels:

medicinal chemistry and molecular biology. Journal of Medicinal Chemistry

43, 14271447.

Enz, R., Cutting, G.R., 1999. Identification of 70 amino acids important for

GABA (C) receptor rho 1 subunit assembly. Brain Research 846, 177185.

Enz, R., Branstatter, J.H., Wassle, H., Bormann, J., 1996. Immunocytochemical

localization of the GABAC receptor rho subunits in the mammalian retina.Journal of Neuroscience 16, 44794490.

Fields, H.L.,Heinricher, M.M.,Mason, P., 1991. Neurotransmitter in nociceptive

modulatory circuits. Annual Review of Neuroscience 14, 219245.

Fletcher, E.L., Koulen, P., Wssle, H., 1998. GABAA and GABAB receptors on

mammalian rod bipolar cells. The Journal of Comparative Neurology 396,

351365.

Hammond, D.L., 2001. J. J. Bonica Lecture-2001: Role of spinal GABA in

acute and persistent nociception. Regional Anesthesia and Pain Medicine

26, 551557.

Koulen, P., Brandstatter, J.H., Kroger, S., Enz, R., Bormann, J., Wassle, H.,

1997. Immunocytochemical localization on the GABAC receptor subunits

in the cat, goldfish, and chicken retina. The Journal of Comparative

Neurology 380, 520532.

Lukasiewicz, P.D., 1996. GABAC receptors in the vertebrate retina. Molecular

Neurobiology 12, 181194.Malcangio, M., Bowery, N.G., 1996. GABA and its receptors in the spinal cord.

Trends in Pharmacological Sciences 17, 457462.

Millan, M.J., 2002. Descending control of pain. Progress in Neurobiology 66,

355474.

Motta, P.G., Veiga, A.P.C., Francischi, J.N., Tatsuo, M.A.K.F., 2004. Evidence

for participation of GABAA receptors in a rat model of secondary

hyperalgesia. European Journal of Pharmacology 483, 233239.

Ocaa, M., Cendan, C.M., Cobos, E.J., Entrena, J.M., Baeyens, J.M., 2004.

Potassium channels and pain: present realities and future opportunities.

European Journal of Pharmacology 500, 203219.

Pacheco, D.F., Duarte, I.D.G., 2005. -opioid receptor agonist SNC80 induces

peripheral antinociception via activation of ATP-sensitive K+ channels.

European Journal of Pharmacology 512, 2328.

Quian, H., Dowling, J.E., 1993. Novel GABA responses from roddriven retinal

horizontal cells. Nature 361, 162164.Ragozzino, D., Woodward, R.M., Murata, Y., Eusebi, F., Overman, L.E., Miled,

R., 1996. Design and in vitro pharmacology of a selective gammaamino-

butyric acid c receptor antagonist. Molecular Pharmacology 50, 10241030.

Randall, L.O., Selitto, J.J., 1957. A method for measurement of analgesic

activity on inflamed tissues. Archives Internationales de Pharmacodynamie

et de Therapie 111, 409419.

Reis, G.M.L., Duarte, I.D.G., 2006. Baclofen, an agonist at peripheral GABABreceptors, induces antinociception via activation of TEA-sensitive potassium

channel. British Journal of Pharmacology 149, 733739.

Rodrigues, A.R.A., Duarte, I.D.G., 2000. The peripheral antinociceptive effect

induced by morphine is associated with ATP sensitive K+ channels. British

Journal of Pharmacology 129, 110114.

Sabetkasai, M., Ahang, S., Shafaghi, B., Zarrindast, M.R., 1999. Baclofen-

induced antinociception and nicotinic receptor mechanism. Pharmacology

and Toxicology 85, 247251.

1272 G.M.L. Reis, I.D.G. Duarte / Life Sciences 80 (2007) 12681273


6/6

Sawynok, J., 1987. GABAergic mechanisms of analgesia: an update.

Pharmacology, Biochemistry and Behavior 26, 463474.

Schlicker, K., Boller, M., Schmidt, M., 2004. GABAC receptor mediated

inhibition in acutely isolated neurons of the rat dorsal lateral geniculate

nucleus. Brain Research Bulletin 63, 9197.

Shafizadeh, M., Semmanian, S., Zarrinsdast, M.R., Hashemi, B., 1997.

Involvement of GABAB receptors in the antinociception induced by

baclofen in the formalin test. General Pharmacology 28, 611615.

Soares, A.C., Duarte, I.D.G., 2001. Dibutyryl-cyclic GMP induces peripheral

antinociception via activation of ATP-sensitive K+ channels in the PGE2-

induced hyperalgesic paw. British Journal of Pharmacology 134, 127131.

Stoyanova, I., 2004.-Aminobutiric acid immunostaining in trigeminal, nodose

and spinal ganglia of the cat. Acta Histochemica 106, 309314.

Zheng, W., Xie, W., Zhang, J., Strong, J.A., Wang, L., Yu, L., Xu, M., Lu, L.,

2003. unction of GABA receptor/channel 1 subunits in spinal cord. Journal

of Biological Chemistry 278, 4832148329.


Canales Cloro Acoplados GABA

Documents

Transcript of Canales Cloro Acoplados GABA