[Mechanism of antinociceptive action of calcitonin--involvement of descending serotonergic system].
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Analgesics↗
Biomedical subjects
Megumu Yoshimura
Publications and source records attributed to Megumu Yoshimura.
Electrophysiological mapping of the nociceptive inputs to the substantia gelatinosa in rat horizontal spinal cord slices.
To study the functional projection patterns of the primary afferents in the spinal cord, the postsynaptic responses of substantia gelatinosa (SG) neurones evoked by L5 dorsal root stimulation (DRS) were examined from the neurones located at L2 to S1 in horizontal slices of the adult rat spinal cord using a blind whole-cell patch-clamp technique. In the voltage-clamp mode, the L5 DRS evoked the Adelta- and C-afferent-mediated excitatory postsynaptic currents (EPSCs) in more than 70% of the neurones tested at the L5 level. Both Adelta- and C-afferent EPSCs were also recorded in more than 50% of the neurones at L4. At L3 and L6, the number of neurones receiving the C-afferent EPSCs (> 40%) was significantly greater than that of Adelta-afferent EPSCs (< 20%). On the other hand, the Adelta- and C-afferent-mediated inhibitory postsynaptic currents (IPSCs) elicited by L5 DRS were almost equally observed from L2 to S1. In the current-clamp mode, L5 DRS evoked Adelta- and C-afferent-mediated EPSPs, some of which initiated action potentials (APs). Most of the Adelta-afferent-mediated APs were limited at the L5 level, while C-afferent-mediated APs were observed at L5 and L4. As the L2 DRS-evoked APs in the L2 SG neurones were suppressed by L5 DRS, the widespread distribution of the inhibitory inputs was considered to be functional. These findings suggest that the excitatory projection of the C afferents to the SG neurones was thus spread more rostrocaudally than that of the Adelta afferents, thereby contributing to more diffuse pain transmission. In addition, the widespread distribution of the inhibitory inputs may thus play a role as a lateral inhibitory network and thereby prevent the expansion of the excitatory inputs of noxious stimuli.
Action Potentials↗
Presynaptic modulation by neuromedin U of sensory synaptic transmission in rat spinal dorsal horn neurones.
Neuromedin U (NMU) is a brain-gut peptide first isolated from the spinal cord. Recent studies on NMU and its receptors have suggested a role of NMU in sensory transmission. Here we report on the localization of NMU in sensory neurones, and the actions of NMU in the substantia gelatinosa (SG) and the deep layer of the dorsal horn (laminae III-V) in adult rat spinal cord slices using the patch-clamp technique. An immunohistochemical study revealed that NMU peptide was present in most of the dorsal root ganglion neurones. In the spinal cord, NMU-immunoreactive neurones were located in the deep layer (laminae III-V), but not in the SG. However, NMU-positive axon terminals were observed in the SG as well as the deep layer. Bath-applied NMU (10 microm) increased the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) in the SG and deep layer neurones by 146 +/- 14% (P < 0.01, n = 17) and 174 +/- 21% (P < 0.01, n = 6), respectively, without inducing any postsynaptic membrane currents recorded in tetrodotoxin. On the other hand, NMU did not affect miniature inhibitory postsynaptic currents recorded in tetrodotoxin. These findings, taken together, suggest that NMU acts on the presynaptic terminals of the primary afferent fibres working as an autocrine/paracrine neuromodulator to increase mEPSC frequency of the SG and deep layer neurones. This may account for the spinal mechanisms of the NMU-induced hyperalgesia reported previously.
Animals↗
Administration of estrogen shortly after ovariectomy mimics the anti-nociceptive action and change in 5-HT1A-like receptor expression induced by calcitonin in ovariectomized rats.
Although many clinical reviews are consistent with the view that hormone replacement therapy should be recommended for increasing bone mass of osteoporotic patients, calcitonin administration is preferable to hormone replacement therapy for the alleviation of pain accompanying osteoporosis, despite the fact that osteoporosis and the accompanying pain are accelerated by the reduction in estrogen levels. Distinct from the clinical view, animal studies have shown that estrogen treatment reduces ovariectomy-induced hyperalgesia, although the mechanism of this phenomenon is unknown. The discrepancy in clinical and animal study outcomes may be due to the timing of administration of estrogen after depletion of the hormone. To address this possibility, the anti-nociceptive effect of estrogen was compared with calcitonin using the tail withdrawal test in rats injected with estrogen or calcitonin at 3 weeks (short term) or 15 weeks (long term) after ovariectomy. Furthermore, we analyzed the change in [3H]8-OH-DPAT binding in the spinal cord, addressing whether estrogen exerts its anti-nociceptive effect by the expression of 5-HT receptors attributable to calcitonin-induced analgesia, as has been reported in our previous animal studies. The present study demonstrates that the administration of estrogen injected in the short term, but not long term, after ovariectomy mimicked the effects of calcitonin-induced anti-nociception and prevention of ovariectomy-induced decrease in 5-HT receptor expression in the spinal cord, although the effects of calcitonin were observed regardless of the timing of calcitonin injection. These results suggest that the estrogen receptor is downregulated gradually after ovariectomy. Disappearance of the estrogen receptor may be one of the reasons that estrogen is not recommended for the treatment for chronic pain associated with osteoporosis.
Analgesics↗
Sensory processing and functional reorganization of sensory transmission under pathological conditions in the spinal dorsal horn.
The superficial dorsal horn, particularly substantia gelatinosa (SG) in the spinal cord, receives inputs from small-diameter primary afferents that predominantly convey noxious sensation. This sensory information via the high-threshold Adelta and C afferents is modified and integrated in SG, and consequently regulates the outputs of projection neurons located in lamina I and laminae IV-V. Recent studies using slice and in vivo patch-clamp recordings indicate that the sensory inputs to SG are functionally reorganized during post-natal development. Even in the mature state, the synaptic connectivity and receptor expression in SG can be altered easily following peripheral tissue damage. In addition, the descending pain inhibitory system to SG is also modified under certain pathological conditions. Considering that the pain system is phylogenetically primitive, it is, therefore, not surprising that the system easily exhibits a plastic change in response to inflammation or nerve damage. Because such plastic changes in the neuronal circuit or receptor expression in SG are now generally accepted to be one of the explanations for the induction of pathological pain, SG is thought to be a primary therapeutic target for chronic pain. We review here recent results demonstrating plastic changes in SG under pathological conditions.
Animals↗
Application of in vivo patch-clamp technique to pharmacological analysis of synaptic transmission in the CNS.
Slice preparations as well as acutely dissociated and cultured neurons from various regions in the CNS have been widely used to analyze pharmacological properties of synaptic responses and receptors expressed at the pre- and post-synaptic sites. However, the essential properties are not obviously different from neuron to neuron. These characteristics of neurons in the CNS make it difficult to elucidate their functional significances. It is, therefore, preferable that the pharmacological analysis should be made from identified neurons by stimulation of identified inputs. The in vivo patch-clamp recording technique allows us to clarify the synaptic responses evoked by the various known natural stimuli applied to the skin or other parts and makes it possible to interpret with more certainty the behavioral changes by synaptic plasticity observed at the single cell level. Although the in vivo technique has obvious advantages in analysis of physiological responses, this method is, however, confined so far to neurons located at the near surface of the CNS for pharmacological analysis, because of the diffusion problem of the chemical to deeper neurons. Thus, combinatorial studies with dissociated or cultured neurons or with slice preparations are clearly required for further understanding of pharmacological properties of neurons in the CNS.
Animals↗
Alterations in primary afferent input to substantia gelatinosa of adult rat spinal cord after neonatal capsaicin treatment.
Primary afferent fibers are divided into three main subgroups: Abeta-, Adelta-, and C-fibers. Morphological studies have demonstrated that neonatal capsaicin treatment (NCT) depletes C-fiber inputs in the spinal dorsal horn; the electrophysiological features of the NCT-induced changes, however, remain unclear. This issue was addressed by performing whole-cell voltage-clamp recordings from substantia gelatinosa (SG) neurons in dorsal root-attached spinal cord slices. When estimated from excitatory postsynaptic currents (EPSCs) evoked by stimulating primary afferent fibers, 24 (49%) of 49 neurons examined exhibited C-fiber EPSCs that were either monosynaptic (n = 15) or polysynaptic (n = 9) in origin; only two of the neurons had Abeta-fiber responses. In NCT rats, however, SG neurons exhibiting C-fiber-mediated EPSCs decreased to 7% (3 of 41 neurons tested), whereas Abeta-fiber EPSCs were observed in 21 (51%) of the neurons, and 14 (67%) of them exhibited monosynaptic ones. There was no change in the cell proportion having Adelta-fiber innervation after NCT. Our electrophysiological data suggest that NCT diminishes primary afferent C-fiber inputs while enhancing Abeta-fiber direct innervation in the SG in adulthood.
Action Potentials↗
Actions of noradrenaline on substantia gelatinosa neurones in the rat spinal cord revealed by in vivo patch recording.
To elucidate the mechanisms of antinociception mediated by the descending noradrenergic pathway in the spinal cord, the effects of noradrenaline (NA) on noxious synaptic responses of substantia gelatinosa (SG) neurones, and postsynaptic actions of NA were investigated in rats using an in vivo whole-cell patch-clamp technique. Under urethane anaesthesia, the rat was fixed in a stereotaxic apparatus after the lumbar spinal cord was exposed. In the current-clamp mode, pinch stimuli applied to the ipsilateral hindlimb elicited a barrage of EPSPs, some of which initiated an action potential. Perfusion with NA onto the surface of the spinal cord hyperpolarized the membrane (5.0-9.5 mV) and suppressed the action potentials. In the voltage-clamp mode (V(H), -70 mV), the application of NA produced an outward current that was blocked by Cs(+) and GDP-beta-S added to the pipette solution and reduced the amplitude of EPSCs evoked by noxious stimuli. Under the blockade of postsynaptic actions of NA, a reduction of the evoked and spontaneous EPSCs of SG neurones was still observed, thus suggesting both pre- and postsynaptic actions of NA. The NA-induced outward currents showed a clear dose dependency (EC(50), 20 microM), and the reversal potential was -88 mV. The outward current was mimicked by an alpha(2)-adrenoceptor agonist, clonidine, and suppressed by an alpha(2)-adrenoceptor antagonist, yohimbine, but not by alpha(1)- and beta-antagonists. These findings suggest that NA acts on presynaptic sites to reduce noxious stimuli-induced EPSCs, and on postsynaptic SG neurones to induce an outward current by G-protein-mediated activation of K(+) channels through alpha(2)-adrenoceptors, thereby producing an antinociceptive effect.
Adrenergic alpha-Agonists↗
Endotoxin inhibitor blocks heat exposure-induced expression of brain cytokine mRNA in aged rats.
To investigate the age-related changes in the expression of interleukin-1beta (IL-1beta) and its related substances in the brain during heat stress, we measured amounts of mRNAs for IL-1beta, cyclooxygenase-2 (COX-2), and an inhibitor of nuclear factor (NF)-kappaB-beta (IkappaB-beta) that is known to reflect an activation of NF-kappaB, in the cortex, cerebellum, and hippocampus using a quantitative real-time capillary PCR method. The basal levels of IL-1beta mRNA in aged rats (108-110 weeks old) was significantly higher than those in young animals (10-11 weeks old) in these brain regions. Heat exposure (33 degrees C) for 1 h enhanced the expression of IL-1beta and COX-2 mRNAs in aged rats but not in young ones. The amount of lipopolysaccharide (LPS) assessed by its bioactivity in the cortex increased by heat exposure only in aged rats. To further examine an involvement of LPS in the increase in mRNAs, an endotoxin inhibitor (EI), a synthetic peptide that detoxifies LPS by binding to the toxic component of LPS, lipid A, was intraperitoneally injected before heat exposure in aged rats. An intraperitoneal injection of EI significantly attenuated the heat exposure-induced increases in mRNAs for IL-1beta, COX-2, IkappaB-beta, and the LPS activity. Administration of EI also debilitated the heat exposure-induced hyperthermia and responses of plasma ACTH and catecholamines. These findings, taken together, suggest that the bacterial translocation is involved in the mechanisms of the responses to heat exposure in aged rats including the increased expression of mRNAs for IL-1beta and its related substances in the brain.
Adrenocorticotropic Hormone↗
Pre- and postsynaptic inhibition mediated by GABA(B) receptors in rat ventrolateral periaqueductal gray neurons.
The present study examined the actions of a GABA(B)-receptor agonist, baclofen, on synaptic transmission in rat ventrolateral periaqueductal gray (PAG) neurons of brainstem slices by using whole-cell voltage-clamp recordings. Baclofen (10 microM) induced a slow outward current (peak amplitude: 30.1+/-3.1pA, n=13) at -70mV, which persisted in the presence of tetrodotoxin (0.5 microM) and was diminished in the presence of postsynaptic intracellular K(+)-channel blockers (Cs(+) and TEA) and GDP-beta-S, indicating a direct postsynaptic depression mediated by K(+) channels and G proteins. Baclofen (10 microM) also decreased the frequency of both glutamatergic spontaneous EPSC (by 36+/-7%, n=11) and GABAergic spontaneous IPSC (by 37+/-12%, n=6) without changes in their amplitudes, indicating its presynaptic inhibitions. Taken together, the activation of postsynaptic GABA(B) receptors inhibits ventrolateral PAG neurons directly. At the same time, activating presynaptic GABA(B) receptors on glutamatergic and GABAergic nerve terminals inhibits glutamate and GABA release, respectively. The overall effects might influence an output of ventrolateral PAG neurons that build up the descending pain control system to the spinal dorsal horn.
Animals↗
Somatostatin directly inhibits substantia gelatinosa neurons in adult rat spinal dorsal horn in vitro.
Effects of somatostatin (SST) on the synaptic transmission to substantia gelatinosa (SG) neurons of adult spinal cord slices were investigated using intracellular recording and blind whole-cell patch-clamp technique. Bath application of SST (1 microM) induced the membrane hyperpolarization that was accompanied by a decrease in input resistance and had the reversal potential of -92 +/- 3 mV (n=5) in the intracellular recording experiment. In patch-clamp experiment, SST (1 microM) induced an outward current with amplitude of 14 +/- 2 pA (n=60) at the holding potential of -60 mV, and was not affected by TTX (n=3). The effect was dose-dependent with EC50 value of 0.82 microM (Hill coefficient: 0.89). The outward current was suppressed when the patch-pipette solution containing potassium channel blockers, Cs+ and tetraethylammonium (TEA), and was inhibited by Ba2+ (200 microM) to 15 +/- 6% of the control (n=3). In addition, the SST current reversed its polarity at potential close to the equilibrium potential of K+ channel calculated by the Nernst equation. No significant changes were found in amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) and dorsal root evoked EPSC (eEPSC) by SST. Also, SST did not affect both of the miniature inhibitory postsynaptic currents (mIPSCs) and evoked inhibitory postsynaptic currents (eIPSCs), mediated by either the GABA or glycine receptor. We conclude that SST activates the K+ channel resulting in postsynaptic hyperpolarization in adult rat SG neurons without affecting presynaptic component of the transmission, which are considered to account, at least a part, for the analgesic effects of SST reported previously.
Action Potentials↗
Alpha 2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat substantia gelatinosa neurons.
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 microm) 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 A delta-fiber and C-fiber excitatory postsynaptic currents in a reversible manner. When compared in magnitude between the A delta-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 alpha2 adrenoceptor agonist, clonidine (10 microm), and an alpha 2A agonist, oxymetazoline (10 microm), but not by an alpha1 agonist, phenylephrine (10 microm), and a beta agonist, isoproterenol (40 microm). The inhibitory actions were antagonized by an alpha 2 antagonist, yohimbine (1 microm), all of the results of which indicate an involvement of alpha 2 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 A delta-fiber- and C-fiber-mediated sensory transmission to substantia gelatinosa neurons through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in A delta-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.
Animals↗
GABA-mediated inhibition of glutamate release during ischemia in substantia gelatinosa of the adult rat.
An ischemia-induced change in glutamatergic transmission was investigated in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by use of the whole cell patch-clamp technique; the ischemia was simulated by superfusing an oxygen- and glucose-free medium (ISM). Following ISM superfusion, 21 of 37 SG neurons tested produced an outward current (23 +/- 4 pA at a holding potential of -70 mV), which was followed by a slow and subsequent rapid inward current; the remaining neurons had only inward currents. During such a change in holding currents, spontaneous excitatory postsynaptic currents (EPSCs) were remarkably decreased in a frequency with time (half-decay time of the frequency: about 65 s). The frequency of spontaneous EPSCs was reduced to 28 +/- 13% (n = 37) of the control level during the generation of the slow inward current (about 4 min after the beginning of ISM superfusion) without a change in the amplitude of spontaneous EPSCs. When ISM was superfused together with either bicuculline (10 microM) or CGP35348 (20 microM; GABA(A) and GABA(B) receptor antagonists, respectively), spontaneous EPSC frequency reduced by ISM recovered to the control level and then the frequency markedly increased [by 325 +/- 120% (n = 22) and 326 +/- 91% (n = 17), respectively, 4 min after ISM superfusion]; this alteration in the frequency was not accompanied by a change in spontaneous EPSC amplitude. Superfusing TTX (1 microM)-containing ISM resulted in a similar recovery of spontaneous EPSC frequency and following increase (by 328 +/- 26%, n = 12) in the frequency; strychnine (1 microM) did not affect ISM-induced changes in spontaneous EPSC frequency (n = 5). It is concluded that the ischemic simulation inhibits excitatory transmission to SG neurons, whose action is in part mediated by the activation of presynaptic GABA(A) and GABA(B) receptors, probably due to GABA released from interneurons as a result of an ischemia-induced increase in neuronal activities. This action might protect SG neurons from an excessive excitation mediated by L-glutamate during ischemia.
Age Factors↗
Anandamide inhibits excitatory transmission to rat substantia gelatinosa neurones in a manner different from that of capsaicin.
Actions of anandamide (10 microM) were examined on monosynaptic glutamatergic transmission from the periphery to substantia gelatinosa (SG) neurones in adult rat spinal cord slices using the whole-cell patch-clamp technique. In 64% of neurones examined, Adelta-fibre-evoked excitatory postsynaptic currents (EPSCs) were depressed (in amplitude; by 32 +/- 4%, n=21) by anandamide. On the contrary, an inhibitory action on C-fibre-evoked EPSCs was observed in only 31% of neurones tested; this magnitude (17 +/- 3%, n=4) was less than that of Adelta-fibre EPSCs (P<0.05). A cannabinoid-receptor agonist, WIN 55,212-2 (5 microM), exhibited similar actions on the EPSCs. In a neurone with minimal effects of anandamide on C-fibre EPSCs, capsaicin (1 microM) largely depressed the EPSCs (n=3); Adelta-fibre EPSCs were little affected by capsaicin. It is concluded that unlike capsaicin, anandamide inhibits more effectively Adelta-fibre than C-fibre-mediated excitatory transmission in the SG, possibly through the activation of the cannabinoid receptor.
Animals↗
Activation of central terminal vanilloid receptor-1 receptors and alpha beta-methylene-ATP-sensitive P2X receptors reveals a converged synaptic activity onto the deep dorsal horn neurons of the spinal cord.
Using a spinal cord slice preparation and patch-clamp recordings from spinal cord dorsal horn neurons, we examined excitatory and inhibitory circuits connecting to lamina V neurons after the activation of afferent central terminal vanilloid receptor-1 (VR1) receptors and P2X receptors. We found that single neurons in lamina V often received excitatory inputs from two chemically defined afferent pathways. One of these pathways was polysynaptic from capsaicin-sensitive afferent terminals. In this pathway the capsaicin-sensitive afferent input first activated interneurons in superficial laminas, and then the excitatory activity was transmitted onto lamina V neurons. The second excitatory input was monosynaptic from alpha(beta)m-ATP-sensitive/capsaicin-insensitive afferent terminals. Both capsaicin-sensitive and alpha(beta)m-ATP-sensitive/capsaicin-insensitive pathways also recruited polysynaptic inhibitory inputs to lamina V neurons. Furthermore, we demonstrated that simultaneous activation of both capsaicin-sensitive afferent pathways and alpha(beta)m-ATP-sensitive/capsaicin-insensitive pathways could generate a temporal summation of excitatory inputs onto single lamina V neurons. These convergent pathways may provide a mechanism of sensory integration for two chemically defined sensory inputs and may have implications in different sensory states.
Action Potentials↗
[Functional analysis of pain pathway in posterior horn cells using spinal cord slice and in-vivo patch clamp method].
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Animals↗
Adenosine inhibits excitatory transmission to substantia gelatinosa neurons of the adult rat spinal cord through the activation of presynaptic A(1) adenosine receptor.
Although intrathecal administration of adenosine analogues or A(1) adenosine receptor agonists is known to result in antinociception, this has not been examined yet at the cellular level. In the present study, we examined in pharmacology an action of adenosine on glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in substantia gelatinosa (SG) neurons of an adult rat spinal cord slice; this was done under the condition where a postsynaptic action of adenosine was blocked. In 65% of the neurons examined (n=72), adenosine at a concentration of 100 microM depressed the frequency of mEPSC in a reversible manner; the remaining neurons exhibited an inhibition followed by potentiation of the frequency. When examined quantitatively in extent in some cells (n=25), the inhibition was 40+/-3% (n=25) while the potentiation was 42+/-8% (n=6). These actions were not accompanied by a change in mEPSC amplitude. The inhibitory action on mEPSC frequency was dose-dependent in a range of 10-500 microM with an EC(50) value of 277 microM. The inhibitory action of adenosine was mimicked by a selective A(1) adenosine receptor agonist, CPA (1 microM; depression: 54+/-9%, n=4); this action of adenosine (100 microM) was not observed in the presence of a specific A(1) adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (1 microM; 94+/-4% of control, n=3). The facilitatory action of adenosine (100 microM) was unaffected by an A(2a) antagonist, ZM 241385 (0.1 microM, n=3); an A(2a) agonist, CGS 21680 (0.1-10 microM; n=6), was without actions on mEPSC frequency. It is concluded that adenosine inhibits excitatory transmission to SG neurons through the activation of presynaptic A(1) adenosine receptor and that some of the inhibition is followed by a potentiation of the transmission. It remains to be examined which subtypes of adenosine receptors except for the A(1)- and A(2a)-subtypes are involved in the potentiating action. Considering that adenosine-like immunoreactivity and adenosine receptors are expressed at a high density in the SG, which is thought to play an important role in modulating nociceptive transmission from the periphery to the central nervous system, this inhibitory action of adenosine could contribute to a negative modulation of pain transmission.
Adenosine↗
Baclofen inhibits more effectively C-afferent than Adelta-afferent glutamatergic transmission in substantia gelatinosa neurons of adult rat spinal cord slices.
Although intrathecal administration of baclofen, a selective GABA(B)-receptor agonist, is known to have an antinociceptive effect on various pain models, the role of presynaptic GABA(B) receptors in antinociception is not well characterized. In the present study, the action of baclofen on primary afferent-evoked glutamatergic excitatory transmission was examined in substantia gelatinosa (SG) neurons of an adult rat spinal cord slice with an attached dorsal root, prepared from the lumbar segment, by use of the blind whole-cell patch-clamp technique. Under the condition where a postsynaptic action of baclofen was inhibited, baclofen (1 microM) reduced the amplitudes of excitatory postsynaptic currents (EPSCs; V(H)=-70 mV) which were monosynaptically evoked by stimulating primary-afferent C- and/or Adelta-fibers and which were remarkably depressed by CNQX (10 microM). The identification of the C-fiber or Adelta-fiber EPSC was based on antidromic action potentials recorded from neurons of isolated dorsal root ganglia. The C-fiber EPSC was depressed in peak amplitude by baclofen (1 microM) to a larger extent than the Adelta-fiber EPSC (20 and 45% of control, respectively). Each of the baclofen actions was suppressed by a selective GABA(B)-receptor antagonist, CGP 35348 (50 microM). Baclofen (1 microM) did not affect a response of SG neurons to bath-applied AMPA (10 microM). These results indicate that baclofen inhibits the release of L-glutamate from Adelta and C primary-afferent terminals in the SG through the activation of GABA(B) receptor; this action is more effective to C-fiber than Adelta-fiber transmission. Considering that the SG is the main part of termination of Adelta- and C-fibers transmitting nociceptive information, the present finding would account for at least a part of the inhibitory action of baclofen on pain transmission.
Animals↗