Level Of Dorsal Horn Research Articles

Modulation of the spinal N13 SEP component by high- and low-frequency electrical stimulation. Experimental pain models matter

ObjectiveThe N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of cervical dorsal horn neurons. Neurophysiological studies in healthy participants showed that capsaicin-induced central sensitization causes an increase of the N13 SEP amplitude. Consequently, in human research, this spinal component may serve as a valuable readout of central sensitization.In this study, we wanted to verify if the sensitivity of the N13 SEP for detecting central sensitization is consistent across different experimental pain models inducing central sensitization and secondary hyperalgesia, namely high and low-frequency electrical stimulation (HFS and LFS). MethodsIn 18 healthy participants, we recorded SEP after bilateral ulnar nerve stimulation before and after secondary hyperalgesia was induced through HFS and LFS applied on the ulnar nerve territory of the hand of one side. The area of secondary hyperalgesia was mapped with a calibrated 128-mN pinprick probe, and the mechanical pain sensitivity with three calibrated 16–64-256-mN pinprick probes. ResultsAlthough both HFS and LFS successfully induced secondary hyperalgesia only LFS increased the amplitude of the N13 SEP. ConclusionsThese findings suggest that the sensitivity of the N13 SEP for detecting dorsal horn excitability changes may critically depend on the different experimental pain models. SignificanceOur results indicate that LFS and HFS could trigger central sensitization at the dorsal horn level through distinct mechanisms, however this still needs confirmation by replication studies.

Caspase-11 contributes to pain hypersensitivity in the later phase of CFA-induced pain of mice

Chronic pain is a common disease that severely disrupts the quality of life. Persistent neuroinflammation and central sensitization play important roles in its pathogenesis. Caspase-11 is a critical modulator of inflammation of central nervous system. However, its role in chronic pain remains elusive. In this study, chronic pain and acute pain were induced via injecting complete Freund’s adjuvant (CFA) and 5 % formalin into the plantar of the right hind paw of wild-type (WT) and Caspase-11 deficient (Caspase-11−/−) mice, respectively. In WT mice, CFA injection significantly decreased the hind paw mechanical pain threshold in Von Frey test on 1–7 days after injection and increased the caspase-11 level of ipsilateral dorsal horn of spinal cord on day 2 and day 5 after injection. Compared to the WT mice, Caspase-11−/− mice showed significantly higher mechanical pain threshold in the later phase of CFA-induced pain, but not in the early phase, and had no significant difference in 5 % formalin induced licking and flinching behavior. In addition, the microglial activation, and the mRNA levels of caspase-1 and IL-18 in the spinal cord of Caspase-11−/− mice restored to baseline on the day 5 after CFA injection, but not in WT mice. Our data indicated that Caspase-11 contributed to persistent inflammation in ipsilateral dorsal horn of spinal cord, and consequently pain hypersensitivity in the later phase of CFA-induced pain.

The analgesic effects of β-elemene in rats with neuropathic pain by inhibition of spinal astrocytic ERK activation.

Neuropathic pain takes a heavy toll on individual well-being, while current therapy is far from desirable. Herein, we assessed the analgesic effect of β-elemene, a chief component in the traditional Chinese medicine Curcuma wenyujin, and explored the underlying mechanisms at the level of spinal dorsal horn (SDH) under neuropathic pain. A spared nerve injury (SNI)-induced neuropathic pain model was established in rats. Intraperitoneal injection (i.p.) of β-elemene was administered for 21 consecutive days. Mechanical allodynia was explored by von Frey filaments. The activation of the mitogen-activated protein kinase (MAPK) family (including ERK, p38, and JNK) in spinal neurons, astrocytes, and microglia was evaluated using immunostaining 29 days after SNI surgery. The expression of GFAP, Iba-1, p-ERK, p-JNK, and p-p38 within the SDH was measured using immunoblotting. The levels of proinflammatory cytokines (including TNF-α, IL-1β, and IL-6) were measured with ELISA. The levels of oxidative stress indicators (including MDA, SOD, and GSH-PX) were detected using biochemical tests. Consecutive i.p. administration of β-elemene relieved SNI-induced mechanical allodynia (with an EC50 of 16.40 mg/kg). SNI significantly increased the expression of p-ERK in spinal astrocytes but not microglia on day 29. β-elemene reversed spinal astrocytic ERK activation and subsequent upregulation of proinflammatory cytokines in SNI rats, with no effect on the expression of p38 and JNK in spinal glia. β-elemene also exerted antioxidative effects by increasing the levels of SOD and GSH-PX and decreasing the level of MDA. Our results suggest that SNI induces robust astrocytic ERK activation within the SDH in the late phase of neuropathic pain. β-elemene exerts remarkable analgesic effects on neuropathic pain, possibly by inhibiting spinal astrocytic ERK activation and subsequent neuroinflammatory processes. Our findings suggest that β-elemene might be a promising analgesic for the treatment of chronic pain.

Ultrastructural Evidence for Oxytocin and Oxytocin Receptor at the Spinal Dorsal Horn: Mechanism of Nociception Modulation

Oxytocin is a hypothalamic neuropeptide involved in the inhibition of nociception transmission at spinal dorsal horn (SDH) level (the first station where the incoming peripheral signals is modulated). Electrophysiological, behavioral, and pharmacological data strongly support the role of this neuropeptide and its receptor (the oxytocin receptor, OTR) as a key endogenous molecule with analgesic properties. Briefly, current data showed that oxytocin release from the hypothalamus induces OTR activation at the SDH, inducing selective inhibition of the nociceptive Aδ- and C-fibers (probably peptidergic) activity, but not the activity of proprioceptive fibers (i.e. Aβ-fibers). The above inhibition could be a direct presynaptic mechanism, or a mechanism mediated by GABAergic interneurons. However, the exact anatomical localization of oxytocin and OTR remains unclear. In this context, the present study set out to analyze the role of OTRs, GABAergic cells and CGRP fibers in the SDH in rats by using electron microscopy. Ultrastructural analyses of the SDH tissue show that: (i) oxytocin and OTR are found in asymmetrical synapsis; (ii) OTR is found in GABAergic interneurons (near unmyelinated fibers), CGRPergic fibers and glial cells; (iii) whereas oxytocin is present in supraspinal descending projection fibers. These anatomical data strongly support the notion that oxytocin released at the SDH could presynaptically inhibit the nociceptive input from the peripheral primary afferent fibers. This inhibitory action could be direct or use a GABA interneuron. Furthermore, our findings that OTR is exhibited in glial tissue at the SDH requires further exploration in nociception assays.

Targeting spinal TRAF6 expression attenuates chronic visceral pain in adult rats with neonatal colonic inflammation.

BackgroundIrritable bowel syndrome is one of the most common gastrointestinal disorders. It is featured by abdominal pain in conjunction with altered bowel habits. However, the pathophysiology of the syndrome remains largely unknown. Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been reported to be involved in neuropathic pain. The aim of this study was to investigate roles and mechanisms of TRAF6 in the chronic visceral hypersensitivity.MethodsVisceral hypersensitivity was induced by neonatal colonic inflammation and was identified by colorectal distention. The protein level, RNA level, and cellular distribution of TRAF6 and its related molecules were detected with Western blot, quantitative polymerase chain reaction, and immunofluorescence. In vitro spinal cord slice recording technique was performed to determine the synaptic transmission activities.ResultsNeonatal colonic inflammation rats displayed visceral hypersensitivity at the age of six weeks. The expression of TRAF6 was obviously upregulated in spinal cord dorsal horn of neonatal colonic inflammation rats at the age of six weeks. Immunofluorescence study showed that TRAF6 was dominantly expressed in spinal astrocytes. Intrathecal injection of TRAF6 small interfering RNA (siRNA) significantly reduced the amplitude of spontaneous excitatory postsynaptic currents at the spinal dorsal horn level. Furthermore, knockdown of TRAF6 led to a significant downregulation of cystathionine β synthetase expression in the spinal dorsal horn of neonatal colonic inflammation rats. Importantly, intrathecal injection of TRAF6 siRNA remarkably alleviated visceral hypersensitivity of neonatal colonic inflammation rats.ConclusionsOur results suggested that the upregulation of TRAF6 contributed to visceral pain hypersensitivity, which is likely mediated by regulating cystathionine β synthetase expression in the spinal dorsal horn. Our findings suggest that TRAF6 might act as a potential target for the treatment of chronic visceral pain in irritable bowel syndrome patients.

Neonatal Colonic Inflammation Increases Spinal Transmission and Cystathionine β-Synthetase Expression in Spinal Dorsal Horn of Rats with Visceral Hypersensitivity.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and alteration of bowel movements. The pathogenesis of visceral hypersensitivity in IBS patients remains largely unknown. Hydrogen sulfide (H2S) is reported to play an important role in development of visceral hyperalgesia. However, the role of H2S at spinal dorsal horn level remains elusive in visceral hypersensitivity. The aim of this study is designed to investigate how H2S takes part in visceral hypersensitivity of adult rats with neonatal colonic inflammation (NCI). Visceral hypersensitivity was induced by neonatal colonic injection of diluted acetic acid. Expression of an endogenous H2S synthesizing enzyme cystathionine β-synthetase (CBS) was determined by Western blot. Excitability and synaptic transmission of neurons in the substantia gelatinosa (SG) of spinal cord was recorded by patch clamping. Here, we showed that expression of CBS in the spinal dorsal horn was significantly upregulated in NCI rats. The frequency of glutamatergic synaptic activities in SG was markedly enhanced in NCI rats when compared with control rats. Application of NaHS increased the frequency of both spontaneous and miniature excitatory post-synaptic currents of SG neurons in control rats through a presynaptic mechanism. In contrast, application of AOAA, an inhibitor of CBS, dramatically suppressed the frequency of glutamatergic synaptic activities of SG neurons of NCI rats. Importantly, intrathecal injection of AOAA remarkably attenuated visceral hypersensitivity of NCI rats. These results suggest that H2S modulates pain signaling likely through a presynaptic mechanism in SG of spinal dorsal horn, thus providing a potential therapeutic strategy for treatment for chronic visceral pain in patients with IBS.

Effects of intraplantar botulinum toxin-B on carrageenan-induced changes in nociception and spinal phosphorylation of GluA1 and Akt.

Increasing evidence suggests that botulinum neurotoxins (BoNTs) delivered into the skin and muscle in certain human and animal pain states may exert antinociceptive efficacy though their uptake and transport to central afferent terminals. Cleavage of soluble N-methylaleimide-sensitive attachment protein receptor by BoNTs can impede vesicular mediated neurotransmitter release as well as transport/insertion of channel/receptor subunits into plasma membranes, an effect that can reduce activity-evoked facilitation. Here, we explored the effects of intraplantar botulinum toxin- B (BoNT-B) on peripheral inflammation and spinal nociceptive processing in an inflammatory model of pain. C57BL/6 mice (male) received unilateral intraplantar BoNT (1U, 30μL) or saline prior to intraplantar carrageenan (20μL, 2%) or intrathecal N-methyl-D-aspartate (NMDA), substance P or saline (5μL). Intraplantar carrageenan resulted in edema and mechanical allodynia in the injected paw and increased phosphorylation of a glutamate subunit (pGluA1ser845) and a serine/threonine-specific protein kinase (pAktser473) in spinal dorsal horn along with an increased incidence of spinal c-Fos positive cells. Pre-treatment with intraplantar BoNT-B reduced carrageenan evoked: (i) allodynia, but not edema; (ii) pGluA1 and pAkt and (iii) c-Fos expression. Further, intrathecal NMDA and substance P each increased dorsal horn levels of pGluA1 and pAkt. Intraplantar BoNT-B inhibited NMDA, but not substance P evoked phosphorylation of GluA1 and Akt. These results suggest that intraplantar toxin is transported centrally to block spinal activation and prevent phosphorylation of a glutamate receptor subunit and a kinase, which otherwise contribute to facilitated states.

Nerve transfers for brachial neuralgia

Motor function, rather than sensory function, is the primary concern for most brachial plexus surgeons. After root avulsions from the spinal cord, numbness in the affected limb may be associated with extreme, almost unbearable, intractable pain. Deafferent pain is the result of avulsion of the root from the spinal cord. Pain from the brachial plexus avulsion probably arises from the disinhibition of neurons within the substantia gelatinosa that fire spontaneously. The convulsive pain of the brachial plexus injury may correlate with the burst pattern of firing in lamina V also observed in higher levels of the central nervous system including the thalamus. It has been postulated that the lack of sensory input into the spinal cord leads to spontaneous discharges of the neurons in the dorsal horn, therebycausing pain. In our experience, one-third of patients with C5 and C6 root avulsion presented with pain on the dorsal radial aspect of the hand correlated with the superficial radial nerve distribution. Nerve transfer may inhibit abnormal electrical activity in the dorsal horn or higher levels of the central nervous system such as the thalamus by restoring the input to the damaged limb. In 2011 we described the technique “End-to-Side Radial Sensory to Median Nerve Transfer to Restore Sensation and Relieve Pain in C5 and C6Nerve Root Avulsion” in 8 patients. Six patients had S2 and 2 patients had S3. All patients perceived at least one number lower of the Semmes-Weinstein filament in the dorsal radial aspect of the affected hand compared with the preoperative status. The best result was perception of the 3.61 filament in 2 patients. No downgrading of the donor nerve was observed after surgery. All patients had relief of pain 2 weeks after surgery, and the pain decreased dramatically at the last follow-up. An interesting finding in our patients is that we observed no cross-misperception between the injured nerve and donor nerve territories. One hypothesis is that the induced collateral axons are specifically aimed to their new target reconnecting with the spinal cord neurons; another explanation is that there is an unknown mechanism of brain plasticity. Recently, we performed end-to-side median nerve into contralateral C7 transfer to relieve pain at the median nerve distribution area of the hand in late total arm type brachial plexus injury in 7 patients. All patients perceived at least 2 number lower of the Visual Analog Scale (VAS) for pain at the median nerve distribution area of the affected hand and at least 20% decrease in the PSRS compared with the preoperative status. The mean VAS was decreased from 7.8 to 4.1 and the mean PSRS was decrease from 28.4 to 17.5 at last F/U. No downgrading of the donor nerve was observed after surgery. None of the patients experienced any major complication. This nerve transfer could be an alternative method to treat refractory deafferent pain in total arm type brachial plexus injury without major complications.

Inhibitory effect of spinal mGlu5 receptor antisense oligonucleotide on the up-regulated expression of spinal G protein associated with chronic morphine treatment

Knockdown of spinal metabotropic glutamate 5 (mGlu5) receptor was shown to inhibit the development of intrathecal morphine antinociceptive tolerance. The present work was designed to evaluate the expression of spinal G-protein during morphine tolerance and knockdown of spinal mGlu5 receptor with antisense oligonucleotide (ODN). Rats were treated with saline, morphine, mGlu5 receptor antisense or mismatch ODN intrathecally. Behavioral tests were employed to test the thermal and mechanical pain thresholds. Five days later, rats were scarified and spinal expression of spinal Gαi, Gαo, Gαq and Gβ were detected. Consistent with the previous results, knockdown of spinal mGlu5 receptor could inhibit spinal morphine antinociceptive tolerance in behavioral tests (P<0.05). The mGlu5 receptor antisense ODN produced a significant reduction in mGlu5 receptor protein of about 56.6% compared with the control group (P<0.05). Expression of spinal Gαi, Gαo, Gαq and Gβ were up-regulated while morphine tolerance developed (P<0.05). Antisense ODN of spinal mGlu5 receptor, but not mismatched ODN, reduced the spinal dorsal horn levels of Gαi, Gαo, Gαs, Gαq and Gβ (P<0.05). We conclude that expression of spinal G (αi, αo, αs, αq and β) protein may be up-regulated after chronic morphine treatment which could be attenuated by knockdown of spinal mGlu5 receptor with antisense ODN.

The Pain Pathway in the Rat following Noxious Thermal Stimulation: Effect of Morphine on pERK1/2 and TRPV1 at the Dorsal Horn Level, and on Hyperalgesia

The aim of the present study was to investigate the phosphorylation of ERK1/2 in the lumbar dorsal horn of the rat by fluorescence immunohistochemistry following a noxious thermal stimulation of the hind paw. The protein level of TRPV1 in the dorsal spinal cord and the development of a heat hyperalgesia after the acute noxious thermal stimulation were also measured. The protein content of TRPV1 was determined by Western blot and heat hyperalgesia by the plantar test. At 2 and 10 min after the thermal stimulation a 4-fold increase in pERK1/2 immunoreactivity was observed in cells of lamina I/II of the L3-L5 dorsal horn. A pretreatment with the opioid analgesic morphine markedly attenuated ERK1/2 phosphorylation. The protein content of TRPV1 in the lumbar dorsal spinal cord was not significantly altered at 1 and 4 h after the thermal hind paw stimulation and by the morphine pretreatment. Heat hyperalgesia in the plantar test was observed at 8 h, but not at 24 h after the noxious stimulation. This temporary hyperalgesia was prevented by the morphine pretreatment. The present findings indicate that ERK1/2 activation in dorsal horn nociceptive neurons may be linked to the development of hyperalgesia, and that opioid analgesics are effective agents to prevent sensitization in the pain pathway at spinal level.

Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats

Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 μg/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR.

Spinal Cord GABA Receptors Inhibit the Exercise Pressor Reflex in Decerebrate Rats

Neurotransmitters and neuromodulators released by contraction‐activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Evidence suggests that transmission at this synapse is mainly mediated by excitatory amino acids (i.e., glutamate). However, whether GABA, a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of the dorsal horn remains to be determined. To test this hypothesis, we performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to determine the effect of these GABA receptor antagonists on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots or passive stretch in decerebrate rats. We found that microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to either static contraction or passive stretch in decerebrate rats. Data are presented in the table. In addition, microinjection of these two antagonists also caused a temporary increase in the baseline blood pressure and heart rate which returned to normal level in 2–3 min. These data suggest that GABA evokes a tonic inhibition of the EPR at the level of dorsal horn in spinal cord.

Antisense oligonucleotide knockdown of mGlu5 receptor attenuates the antinociceptive tolerance and up-regulated expression of spinal protein kinase C associated with chronic morphine treatment

Spinal metabotropic glutamate receptor 5 (mGlu5 receptor) is known to influence the development of intrathecal morphine antinociceptive tolerance. However, the signaling mechanisms remain unknown. We carried out intrathecal administration of an antisense oligodeoxynucleotide (ODN), which results in reduced expression of spinal mGlu5 receptor, to determine its effects on morphine tolerance and spinal protein kinase C (PKC) expression. Rats were treated intrathecally with saline, morphine, mGlu5 receptor antisense ODN or mGlu5 receptor mismatched ODN. Behavioral tests were used to test the thermal and mechanical pain thresholds. Eight days later, rats were sacrificed and spinal cords were harvested to assess the expression of spinal PKC (α, γ and ε) by Western blotting and real-time polymerase chain reaction (PCR). Compared to control, intrathecal mGlu5 receptor antisense ODN resulted in a ~53.9% reduction of spinal mGlu5 receptor after 8days treatment. The mGlu5 receptor antisense ODN prevented the development of morphine tolerance. Expression of spinal PKC (α, γ and ε) was up-regulated at the mRNA and protein levels during the development of tolerance. Meanwhile, antisense ODN but not mismatched ODN reduced the spinal dorsal horn levels of PKC (α, γ and ε) which had been up-regulated after morphine exposure. We conclude that mGlu5 receptor participates in the development of morphine tolerance. Expression of spinal PKC (α, γ and ε) at the mRNA and protein levels increased during morphine tolerance. Antisense ODN of mGlu5 receptor prevented the tolerance and inhibited the altered expression of spinal PKC (α, γ and ε) during the development of tolerance.

Transplantation and follow-up of human iPSc-derived neural progenitors in a rat model of ALS

Transplantation and follow-up of human iPSc-derived neural progenitors in a rat model of ALS

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms—spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.Descending dopaminergic controls exert a tonic inhibition of trigeminal nociceptive information via D2-like receptors within superficial medullary dorsal horn. Dopamine-dependent tonic inhibition is dynamically modulated by pain.

Progresses of CAMKII signal transduction in pathological pain

Background Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ),a multifunctional serine/threonine protein kinase,which is abundant in both peripheral and central nervous system.Objective To overview that CaMKⅡ plays an important role in the input and integration of sensory information,especially nociceptive information.Content In this review,we focused on the progress of CaMK Ⅱ expressed in dorsal root ganglia,spinal dorsal horn and supraspinal levels in pathological pain,and its associated adjustment factors.Trend CaMK Ⅱ may provide the basis for clarifying the pain mechanisms,and provide directions and ideas for clinical treatment of pain. Key words: Ca2+calmodulin-dependent protein kinase; Inflammatory pain; Neuropathic pain; Dorsal root ganglion; Spinal dorsal horn

How triggers trigger acute migraine attacks: A hypothesis

A trigger is an integral part of any acute migraine attack. In this article, the author argues that triggers, identifiable or not, must be present in all attacks of migraine headache. It is hypothesized that triggers, internal or external, induce the onset of cortical spreading depression (CSD) in a pre-existing hyper-excitable cortex of a migraine brain, initiating the process of pain generation. The author hypothesizes on a second site of action of triggers at the level of trigeminal nuclear complex (TNC) in brain stem, the cell station of second order neuron pathway for migraine pain transmission to the sensory cortex. The author suggests existence of a hypothetical 'gate' at TNC level where incoming trigeminal migraine pain impulses would 'compete' with descending inhibitory signals from brain stem pain modulatory neurons, to get entry into the central nervous system. The author draws analogy with the 'gate control' mechanism operative at the dorsal horn level for spinally transmitted somatic and visceral pain. It is suggested that the hypothetical 'gate' at TNC level is controlled by activity of 5HT receptors, thus supporting the concept of an additional site of action of triptans in aborting acute migraine pain. The suggested hypothesis on mechanism of action of triggers, offers theoretical basis for efficacy of currently available pharmacologic and non-pharmacologic therapies for abortive and prophylactic treatment of migraine.

P.2.c.006 Survival rates of maintenance treatment with venlafaxine extended-release in patients with somatic symptoms

The present study, by the use of in vivo electrochemical detection of 5-hydroxyindole (peak ‘3’) in the bulbo spinal serotonergic system at the medullary dorsal horn (MDH) level, investigated the effects of the new tricyclic antidepressant (TCA) tianeptine, which has been shown to be a specific serotonin (5-HT) uptake enhancer. It was found that acutely administered tianeptine (10 mg/kg, i.p.) induced a marked significant increase in peak 3 within the dorsal horn, an in vivo observation which is in accordance with the biochemical properties of tianeptine as studied in forebrain structures. In addition, the effect of tianeptine on the morphine-induced increase in 5-HT metabolism was investigated, by comparison with the previous data obtained with the specific 5-HT uptake inhibitor femoxetine in the MDH. It was shown that tianeptine can display additive effect with morphine (10 mg/kg, i.p.) on 5-HT metabolism at the MDH level. These results are discussed in relation to the effects of classical TCAs and the particular properties of tianeptine.

Antihyperalgesic Effect of a Recombinant Herpes Virus Encoding Antisense for Calcitonin Gene–related Peptide

Calcitonin gene-related peptide (CGRP) is contained in and released by small-diameter, nociceptive primary afferent sensory neurons. Upon spinal release, one of the effects of CGRP seems to be to sensitize dorsal horn neurons to subsequent input from nociceptive afferents and, consequently, to induce a behavioral hyperalgesia. Therefore, attenuating evoked release of CGRP from central terminals of nociceptors should have an antihyperalgesic effect. The authors applied a recombinant herpes vector, encoding an antisense sequence to the whole CGRP gene, to the dorsal surface of the hind paw of mice to knock down expression of the peptide selectively in primary afferents innervating this tissue. Herpes virus-based vector encoding an antisense sequence for the whole CGRP clearly reduced CGRP immunoreactivity in the infected spinal dorsal horn levels as well as in cultured dorsal root ganglia neurons. Selective knockdown of CGRP in primary afferents significantly attenuated the thermal, C-fiber hyperalgesia normally observed after topical application of capsaicin. The effect of viral vector-mediated knockdown of CGRP was comparable to the effect of intrathecal application of the CGRP antagonist CGRP8-37, but lasted for 14 weeks after one single application. Viral vector-mediated knockdown of CGRP in primary afferent neurons provides a promising tool for treatment of chronic pain states as well as for studies investigating the pathophysiology underlying these conditions.

Modulation of Gamma-Aminobutyric AcidA Receptor Function by Thiopental in the Rat Spinal Dorsal Horn Neurons

To assess the actions of thiopental at the spinal dorsal horn level, we examined the effects of thiopental using the whole cell patch-clamp technique on mechanically dissociated rat spinal dorsal horn neurons. Thiopental, at large concentrations, elicited a current (I(Thio)) through activation of chloride conductance, and its threshold concentration was approximately 50 microM. I(Thio) was sensitive to bicuculline, a gamma-aminobutyric acid (GABA)A receptor antagonist, but not to strychnine, a glycine receptor antagonist. At a clinically relevant concentration (30 muM), thiopental markedly enhanced the peak amplitude of a subsaturating GABA-induced current (I(GABA)) but not that of a saturating GABA-induced current. Furthermore, thiopental prolonged the time constants of both desensitization and deactivation of I(GABA). At a large concentration (300 muM), it inhibited the peak amplitude of I(GABA), which may be the result of open-channel blockade. In addition, at 30 microM, thiopental increased the duration and decreased the frequency of GABAergic miniature inhibitory postsynaptic currents. These results indicate that thiopental enhances GABAergic inhibitory transmission and suggest that GABA(A) receptors in the spinal cord are a potential target through which thiopental causes immobility and depresses the response to noxious stimuli.