A Comparative Study of Endoscopic versus Percutaneous Epidural Neuroplasty in Lower Back Pain: Outcomes at Six-Month Follow Up.

Background and Objectives: Endoscopic epidural neuroplasty (EEN) facilitates adhesiolysis through direct epiduroscopic visualization, offering more precise neural decompression than that exhibited by percutaneous epidural neuroplasty (PEN). We aimed to compare the effects of EEN and PEN for 6 months after treatment with lower back and radicular pain in patients. Methods: This retrospective study compared the visual analog scale (VAS) and Oswestry disability index (ODI) scores in patients with low back and radicular pain who underwent EEN or PEN with a steering catheter. The medical records of 107 patients were analyzed, with 73 and 34 undergoing EEN and PEN, respectively. Results: The VAS and ODI scores decreased at all time points after EEN and PEN. VAS and ODI scores decreased more in the EEN group than those in the PEN group at 1 day and 1- and 6-months post-procedure, indicating superior pain relief for both lower back and radicular pain through EEN. Conclusions: EEN is a superior treatment of pain control than PEN in lower back and radicular pain patients.

Antinociceptive effects of nefopam activating descending serotonergic modulation via 5-HT2 receptors in the nucleus raphe magnus.

BACKGROUND: Nefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam. METHODS: The effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra-nucleus raphe magnus (NRM) pre-treatment with the serotonin (5-HT) receptor antagonist or 5-HT2 receptor antagonist. The change in extracellular 5-HT levels was measured by spinal cord microdialysis. RESULTS: Intraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre-treatment with 5-HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5-HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5-HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra-NRM cinanserin pre-treatment. The increase in spinal level of 5-HT by systemic nefopam was attenuated by intra-NRM cinanserin pre-treatment. CONCLUSION: The antinociceptive effects of systemically administered nefopam are mediated by 5-HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. SIGNIFICANCE: This study revealed supraspinal mechanisms of nefopam-produced analgesia mediated by 5-HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.

Imbalance in the spinal serotonergic pathway induces aggravation of mechanical allodynia and microglial activation in carrageenan inflammation.

Background: This study investigated the effect of an excess and a deficit of spinal 5-hydroxytryptamine (5-HT) on the mechanical allodynia and neuroglia activation in a rodent pain model of carrageenan inflammation. Methods: Male Sprague-Dawley rats were implanted with an intrathecal (i.t.) catheter to administer the drug. To induce an excess or deficit of 5-HT in the spinal cord, animals were given either three i.t. 5-HT injections at 24-hour intervals or a single i.t. injection of 5,7-dihydroxytryptamine (5,7-DHT) before carrageenan inflammation. Mechanical allodynia was measured using the von Frey test for 0-4 hours (early phase) and 24-28 hours (late phase) after carrageenan injection. The changes in the activation of microglia and astrocyte were examined using immunofluorescence of the dorsal horn of the lumbar spinal cord. Results: Both an excess and a deficit of spinal 5-HT had no or a minimal effect on the intensity of mechanical allodynia during the early phase but prevented the attenuation of mechanical allodynia during the late phase, which was observed in animals not treated with i.t. 5-HT or 5,7-DHT. Animals with an excess or deficit of 5-HT showed stronger activation of microglia, but not astrocyte, during the early and late phases, than did normal animals. Conclusions: Imbalance in the descending 5-HT pathway in the spinal cord could aggravate the mechanical allodynia and enhance the activation of microglia, suggesting that the spinal 5-HT pathway plays an essential role in maintaining the nociceptive processing in balance between facilitation and inhibition in inflammatory pain caused by carrageenan inflammation.

Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain.

Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an urgent need to develop new pharmaceutical agents to treat neuropathic pain. To date, highly specific agents that modulate a single target, such as receptors or ion channels, never progress to the clinic, which may reflect the diverse etiologies of neuropathic pain seen in the human patient population. Therefore, the development of multifunctional compounds exhibiting two or more pharmacological activities is an attractive strategy for addressing unmet medical needs for the treatment of neuropathic pain. To develop novel multifunctional compounds, key pharmacophores of currently used clinical pain drugs, including pregabalin, fluoxetine and serotonin analogs, were hybridized to the side chain of tianeptine, which has been used as an antidepressant. The biological activities of the hybrid analogs were evaluated at the human transporters of neurotransmitters, including serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT), as well as mu (µ) and kappa (κ) opioid receptors. The most advanced hybrid of these multifunctional compounds, 17, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC50 values of 70 nM, 154 nM and 2.01 µM at hSERT, hNET and hDAT, respectively. Additionally, compound 17 showed partial agonism (EC50 = 384 nM) at the µ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound 17 showed significantly reduced allodynia in a spinal nerve ligation (SNL) model by intrathecal administration, indicating that multitargeted strategies in single therapy could considerably benefit patients with multifactorial diseases, such as pain.

Pharmacological interactions between intrathecal pregabalin plus tianeptine or clopidogrel in a rat model of neuropathic pain.

BACKGROUND: There is still unmet need in treating neuropathic pain and increasing awareness regarding the use of drug combinations to increase the effectiveness of treatment and reduce adverse effects in patients with neuropathic pain. METHODS: This study was performed to determine the individual and combined effects of pregabalin, tianeptine, and clopidogrel in a rat model of neuropathic pain. The model was created by ligation of the L5-L6 spinal nerve in male Sprague-Dawley rats; mechanical allodynia was confirmed using von Frey filaments. Drugs were administered to the intrathecal space and mechanical allodynia was assessed; drug interactions were estimated by isobolographic or fixed-dose analyses. RESULTS: Intrathecal pregabalin and tianeptine increased the mechanical withdrawal threshold in a dose-dependent manner, but intrathecal clopidogrel had little effect on the mechanical withdrawal threshold. An additive effect was noted between pregabalin and tianeptine, but not between pregabalin and clopidogrel. CONCLUSIONS: These findings suggest that intrathecal coadministration of pregabalin and tianeptine effectively attenuated mechanical allodynia in the rat model of neuropathic pain. Thus, pregabalin plus tianeptine may be a valid option to enhance the efficacy of neuropathic pain treatment.

Prostaglandin D2 contributes to cisplatin-induced neuropathic pain in rats via DP2 receptor in the spinal cord.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a major reason for stopping or changing anticancer therapy. Among the proposed pathomechanisms underlying CIPN, proinflammatory processes have attracted increasing attention. Here we assessed the role of prostaglandin D2 (PGD2) signaling in cisplatin-induced neuropathic pain. METHODS: CIPN was induced by intraperitoneal administration of cisplatin 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. PGD2 receptor DP1 and/or DP2 antagonists were administered intrathecally and the paw withdrawal thresholds were measured using von Frey filaments. Spinal expression of DP1, DP2, hematopoietic PGD synthase (H-PGDS), and lipocalin PGD synthase (L-PGDS) proteins were analyzed by western blotting. RESULTS: The DP1 and DP2 antagonist AMG 853 and the selective DP2 antagonist CAY10471, but not the DP1 antagonist MK0524, significantly increased the paw withdrawal threshold compared to vehicle controls (P = 0.004 and P < 0.001, respectively). Western blotting analyses revealed comparable protein expression levels in DP1 and DP2 in the spinal cord. In the CIPN group the protein expression level of L-PGDS, but not of H-PGDS, was significantly increased compared to the control group (P < 0.001). CONCLUSIONS: The findings presented here indicate that enhanced PGD2 signaling, via upregulation of L-PGDS in the spinal cord, contributes to mechanical allodynia via DP2 receptors in a cisplatin-induced neuropathic pain model in rats, and that a blockade of DP2 receptor activation may present a novel therapeutic target for managing CIPN.

Systemically administered neurotensin receptor agonist produces antinociception through activation of spinally projecting serotonergic neurons in the rostral ventromedial medulla.

BACKGROUND: Supraspinal delivery of neurotensin (NTS), which may contribute to the effect of a systemically administered agonist, has been reported to be either pronociceptive or antinociceptive. Here, we evaluated the effects of systemically administered NTSR1 agonist in a rat model of neuropathic pain and elucidated the underlying supraspinal mechanism. METHODS: Neuropathic pain was induced by L5 and L6 spinal nerve ligation in male Sprague-Dawley rats. The effects of intraperitoneally administered NTSR1 agonist PD 149163 was assessed using von Frey filaments. To examine the role of 5-HT neurotransmission, a serotonin (5-HT) receptor antagonist dihydroergocristine was pretreated intrathecally, and spinal microdialysis studies were performed to measure the change in extracellular level of 5-HT in response to PD 149163 administration. To investigate the supraspinal mechanism, NTSR1 antagonist 48692 was microinjected into the rostral ventromedial medulla (RVM) prior to systemic PD 149163. Additionally, the effect of intrathecal DHE on intra-RVM PD 149163 was assessed. RESULTS: Intraperitoneally administered PD 149163 exhibited a dose-dependent attenuation of mechanical allodynia. This effect was partially reversed by intrathecal pretreatment with dihydroergocristine and was accompanied by an increased extracellular level of 5-HT in the spinal cord. The PD 149163-produced antinociception was also blocked by intra-RVM SB 48692. Direct injection of PD 149163 into the RVM mimicked the maximum effect of the same drug delivered intraperitoneally, which was reversed by intrathecal dihydroergocristine. CONCLUSIONS: These observations indicate that systemically administered NTSR1 agonist produces antinociception through the NTSR1 in the RVM, activating descending serotonergic projection to release 5-HT into the spinal dorsal horn.

Antinociceptive effects of nefopam modulating serotonergic, adrenergic, and glutamatergic neurotransmission in the spinal cord.

The present study investigated the effects of intrathecal nefopam on the pain behavior and on the extracellular levels of serotonin (5-HT), norepinephrine (NE), and glutamate in the spinal cord, in a rat model of pain induced by formalin. Nefopam was intrathecally administered 10 min prior to the formalin test to assess its antinociceptive effects. In another cohorts of animals, dihydroergocristine, yohimbine, or (RS)-α-Methylserine-O-phosphate (MSOP), a serotonergic, α-2 adrenergic receptor, or group III metabotropic glutamate receptor antagonist, respectively, were administered prior to the application of nefopam in the formalin test. Microdialysis studies were conducted to measure the extracellular levels of 5-HT, NE, and glutamate in the spinal cord following nefopam administration. Intrathecal nefopam reduced formalin-induced behavior in both phases of the test. The blockade of serotonergic or adrenergic receptors partially reversed the analgesic effects of nefopam in the first phase of the formalin test whereas MSOP reversed these effects in both phases. The microdialysis results revealed that intrathecal nefopam significantly increased 5-HT and NE levels and attenuated the formalin-induced release of glutamate in the spinal cord. Thus, the present data suggest that the increase in the extracellular levels of 5-HT and NE, and reductions in glutamate release in the spinal cord, may have contributed to the analgesic effects of nefopam.

Febrile convulsions during recovery after anesthesia in an infant with history of MMR vaccination: A case report.

RATIONALE: Seizures are rare during the perioperative period; in most cases, there is a previous history of epilepsy or surgery-associated seizures. Febrile convulsions may occur when the body temperature rises above 38°C; this is the most common cause of seizures in children. Febrile convulsions after general anesthesia in the postanesthetic care unit (PACU) without a past or family history are rare. Some reviews suggest that since anesthesia changes immunity, elective surgery should be postponed three weeks after live vaccination. PATIENT: A 12-month-old female with bilateral hearing loss underwent cochlear implantation under general anesthesia. She did not have any history of convulsions or developmental disorders. However, 1 week before surgery, measles-mumps-rubella (MMR) vaccination was given as a regular immunization. DIAGNOSES: Forty minutes after arrival at the PACU, sudden generalized tonic-clonic movement occurred during recovery and the patient's measured body temperature exceeded 38.0°C. INTERVENTIONS: Thiopental sodium was administered intravenously as an anticonvulsant, and the tonic-clonic movement stopped immediately. Endotracheal intubation was performed to secure the airway, and tepid massage and diclofenac ß-dimethylaminoethanol administration were performed to lower the patient's body temperature. OUTCOMES: There was no further fever and no seizures, and no other neurological deficits were observed until discharge. LESSONS: The anesthesiologist should check the recent vaccination history even if the patient has not developed particular symptoms after vaccination. It is important to know that febrile convulsions may occur in patients who have recently received MMR vaccination.

Comparison of vocal cord view between neutral and sniffing position during orotracheal intubation using fiberoptic bronchoscope: a prospective, randomized cross over study.

BACKGROUND: In intubation using fiberoptic bronchoscope (FOB), partial or complete obstruction of upper airway makes the FOB insertion difficult. Thus, maneuvers to relieve such obstructions are recommended. There have been no studies to determine whether the sniffing or neutral position is superior for this purpose. Therefore, this study was performed to examine the effects of these two positions including vocal cord view. METHODS: Fifty-four patients scheduled to receive general anesthesia by orotracheal intubation were eligible for inclusion in the study with informed consent. After confirmation of proper head positioning depending on the group, the view of the vocal cord was acquired in each position. Images were reviewed using the percentage of glottic opening (POGO) score. RESULTS: A total of 106 images of vocal cords from 53 patients were obtained. The mean of difference of POGO score was 11.09, higher for the neutral position and standard deviation was 23.73 (p = 0.002). Neutral position increased POGO score in 31 patients and decreased POGO score in 13 patients compare to sniffing position (p = 0.017). There were no significant differences between the two head positions with regard to intubation time or degree of convenience during intubation. CONCLUSIONS: Neutral position improved the view of glottic opening than sniffing position during oral fiberoptic intubation. However, there was no difference in the difficulty of tube insertion between the two positions. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT02931019 , registered on October 12, 2016.

Activation of spinal macrophage-inducible C-type lectin induces mechanical allodynia and microglial activation in rats.

Macrophage-inducible C-type lectin (Mincle), a pattern recognition receptor, is a critical component of the innate immune system that is involved in the pathogenesis of chronic pain. Previous studies have reported the expression of Mincle in neuronal and glial cells of the brain, but its expression and role in pain processing at the spinal level remain to be determined. The current study was performed to identify Mincle in the spinal cord and to investigate the effect of Mincle activation on spinal sensitization. Most Mincle immunoreactivity was localized within the grey matter and the dorsal and ventral horns of the lumbar spinal cord in naïve rats. A single intrathecal (i.t.) injection of trehalose-6,6-dibehenate (TDB), a Mincle ligand, induced mechanical allodynia. Immunoreactivity to Mincle and Iba-1 in the spinal cord significantly increased after i.t. injection of TDB. Mechanical allodynia was attenuated by daily i.t. injection of minocycline. However, double immunofluorescence revealed that Mincle co-localizes with NeuN (neurons), but not with Iba-1 (microglia) or GFAP (astrocytes). In conclusion, we found that Mincle was present in spinal cord neurons, but not microglia or astrocytes, and may play a role in microglia-induced spinal sensitization.

Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats.

This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and α2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days). Paw withdrawal thresholds (PWT) were mechanically assessed using von Frey filaments. The involvement of 5-HT and α2-adrenergic receptors in antiallodynia was determined using antagonists with the following receptor specificities: nonselective 5-HT (dihydroergocristine), 5-HT7 (SB269970), nonselective α2-adrenoceptor (yohimbine), α-2A (BRL 44408), α-2B (ARC 239), and α-2C (JP 1302). Intrathecal areca nut significantly increased the PWT in both spinal nerve-ligated and chemotherapy-induced NP (‡ p < 0.001). Intrathecal dihydroergocristine, SB269970, yohimbine, BRL 44408, ARC 239, and JP 1302 significantly reversed the antiallodynic effects of areca nut in both NP states (‡ p < 0.001). Collectively, intrathecal areca nut suppressed mechanical allodynia induced by spinal nerve ligation and cisplatin injection. Furthermore, spinal 5-HT7 receptor and α2A, α2B, and α2C-adrenoceptors contributed to the antiallodynic effects of areca nut.

The role of inversely operating glutamate transporter in the paradoxical analgesia produced by glutamate transporter inhibitors.

Controlling extracellular glutamate level in a physiological range is important to maintain normal sensory transmission. Here, we investigated the paradoxical action of glutamate transporters in the rat formalin test to elucidate a possible role of inversely operating transporters in its analgesic mechanism. The effects of glutamate transporter inhibitor on formalin-induced pain behavior were examined. Then we performed a microdialysis study to clarify the differential change in extracellular glutamate concentration by intrathecal administration of transportable and non-transportable blockers. And we further investigated the mechanism pharmacologically via pretreatment with antagonists of various receptors and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining. Intrathecally-injected glutamate transporter inhibitors, non-transportable DL-threo-ß-benzyloxyaspartat (TBOA) and transportable trans-pyrrolidine-2,4-dicarboxylic acid (t-PDC), produced paradoxical antinociception in the formalin test. In normal rats, inhibition of the glutamate transporter increased extracellular glutamate. In the formalin model rats, TBOA suppressed while t-PDC enhanced glutamate release. When tPDC was pretreated 30min prior to formalin injection, glutamate release was blocked. Blocking α-2 adrenergic receptors reversed the tPDC analgesia. Increased apoptosis was not apparent in the spinal dorsal horn of tPDC-treated rats compared to the control group. These data suggest that glutamate transporters in a formalin-induced pain state work in a reverse mode and can be blocked from releasing glutamate by TBOA and preloaded tPDC. The analgesic mechanism of TBOA may be related to the blockade of inversely operating transporter, and that of tPDC may be associated with the activation of noradrenergic neurotransmission but not with dorsal horn neurotoxicity.

Femoral nerve block for patient undergoing total knee arthroplasty: Prospective, randomized, double-blinded study evaluating analgesic effect of perineural fentanyl additive to local anesthetics.

BACKGROUND: The existence of peripheral opioid receptors and its effectiveness in peripheral nerve block remain controversial. The aim of this prospective, randomized, double-blinded study was to examine the analgesic effects of adding fentanyl to ropivacaine for continuous femoral nerve block (CFNB) using patient-controlled analgesia after total knee arthroplasty (TKA). METHODS: The patients were divided into 2 groups, each with n = 40 in ropivacaine (R) group and n = 42 in R with fentanyl (R + F) group. After operation, the patients in each group received R + F and R alone via a femoral nerve catheter, respectively. We assessed the visual analog scale (VAS) pain immediately before administration (baseline) and at 15, 30, and 60 minutes on postanesthesia care unit (PACU), and resting and ambulatory VAS score up to 24 hours. RESULTS: Overall, the average VAS scores in the R + F group were slightly lower than those of the R group. However, the VAS score differences between groups were not statistically significant, except for 30 minutes (P = 0.009) in PACU. R group showed higher supplemental analgesics consumption in average compared with R + F group, but not significant. CONCLUSION: Additional fentanyl did not show prominent enhancement of analgesic effect in the field of CFNB after TKA.

Effects of tianeptine on the development and maintenance of mechanical allodynia in a rat model of neuropathic pain.

We validate the analgesic efficacy of tianeptine by different administration routes and timing in a rat model of neuropathic pain. Neuropathic pain was induced by ligating the L5 and L6 spinal nerves in male Sprague-Dawley rats, and mechanical allodynia was assessed using von Frey filaments. The effects of orally administered tianeptine and pretreatment with tianeptine (intrathecally or intraperitoneally) on mechanical allodynia were assessed. Oral and preemptive intrathecal administration of tianeptine significantly increased the paw withdrawal threshold but preemptive intraperitoneal administration did not. Nevertheless, intraperitoneal pretreatment of tianeptine potentiated the antiallodynic effects of subsequently administered tianeptine. These findings suggest that tianeptine may be effective for preventing and treating neuropathic pain and that it can be used more widely in clinical pain practice.

The Role of Spinal Dopaminergic Transmission in the Analgesic Effect of Nefopam on Rat Inflammatory Pain.

BACKGROUND: Nefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of nefopam administered intravenously or intrathecally. METHODS: The effects of intravenously and intrathecally administered nefopam were examined using the rat formalin test. Then we performed a microdialysis study to confirm the change of extracellular dopamine concentration in the spinal dorsal horn by nefopam. To determine whether the changes of dopamine level are associated with the nefopam analgesia, its mechanism was investigated pharmacologically via pretreatment with sulpiride, a dopaminergic D2 receptor antagonist. RESULTS: When nefopam was administered intravenously the flinching responses in phase I of the formalin test were decreased, but not those in phase II of the formalin test were decreased. Intrathecally injected nefopam reduced the flinching responses in both phases of the formalin test in a dose dependent manner. Microdialysis study revealed a significant increase of the level of dopamine in the spinal cord by intrathecally administered nefopam (about 3.8 fold the baseline value) but not by that administered intravenously. The analgesic effects of intrathecally injected nefopam were not affected by pretreatment with sulpiride, and neither were those of the intravenous nefopam. CONCLUSIONS: Both the intravenously and intrathecally administered nefopam effectively relieved inflammatory pain in rats. Nefopam may act as an inhibitor of dopamine reuptake when delivered into the spinal cord. However, the analgesic mechanism of nefopam may not involve the dopaminergic transmission at the spinal level.

Corrigendum: Expression of the spinal 5-HT7 receptor and p-ERK pathway in the carrageenan inflammatory pain of rats (Korean J Anesthesiol 2015 April 68(2): 170-174).

[This corrects the article on p. 170 in vol. 68, PMID: 25844136.].

Expression of the spinal 5-HT7 receptor and p-ERK pathway in the carrageenan inflammatory pain of rats.

BACKGROUND: Although the inhibitory role of the 5-hydroxytrypatmine receptor 7(5-HT7R) on nociceptive processing is generally recognized, an excitatory effect associated with a reduced 5-HT7R expression has also been observed in the nerve injury model. In the carrageenan model, no significant effect is produced by the 5-HT7R activation, but the change in 5-HT7R expression has not been examined. Lesioning of the spinal serotonergic pathway enhances allodynia in the carrageenan model, but it also relieves several other pain states, including in the formalin model. While lesioning suppresses the activation of the extracellular signal-regulated kinase (ERK) of the spinal cord in the formalin model, its role in the carrageenan model has not been reported. METHODS: Following intraplantar injections of carrageenan, the spinal 5-HT7R expression was examined using Western blotting in male Sprague-Dawley rats. The effect of serotonergic pathway lesioning with intrathecal 5,7-dihydroxytryptamine (5,7-DHT) on the expression of the phospho-ERK was measured. RESULTS: The expression of the 5-HT7R in the carrageenan model was not significantly different from that of naive animals. The expression of the spinal p-ERK in the carrageenan model was significantly increased, but returned to the level of a naive rat 1 hour after the carrageenan injection. However, it remained significantly higher 1 hour after the injection in the animals treated with 5,7-DHT than in the naive and control rats. CONCLUSIONS: The expression of the spinal 5-HT7R is not altered by peripheral inflammation with carrageenan, suggesting that the lack of antinociceptive effect of the 5-HT7R activation is partly attributable to the absence of changes in the expression of the 5-HT7R in the spinal cord. The extended increase of the spinal p-ERK might be related to the enhanced pain behavior in the animals with lesions of the spinal serotonergic pathway in the carrageenan model.

Intrathecal nefopam-induced antinociception through activation of descending serotonergic projections involving spinal 5-HT7 but not 5-HT3 receptors.

We examined the involvement of spinal 5-HT(5-hydroxytryptamine) receptor 3(5-HT3R) and 7(5-HT7R) as well as the overall role of descending serotonergic projections in the analgesic effects of intrathecal(i.t.) nefopam for two rat models of formalin and paw incision test. I.t. nefopam produced an antinociceptive effect in a dose-dependent manner in both tests. Lesioning the spinal serotonergic projections using i.t. 5,7-dihydroxytryptamine(5,7-DHT) did not influence the intensity of allodynia in the paw incision test, but i.t. 5,7-DHT abolished the effect of nefopam. In the formain test, i.t. 5,7-DHT alone significantly diminished the flinches, but the effect of nefopam was not affected by i.t. 5,7-DHT. Antagonism study showed that i.t. 5-HT7R antagonist, SB269970 significantly blocked the antinociceptive effect of nefopam in both tests, but i.t. 5-HT3R antagonist, ondansetron has no influence on the effect of nefopam. The present study demonstrates that descending spinal serotonergic projections play a vital role in antinociceptive effect of i.t. nefopam in the paw incision test, but indeterminate in the formalin test. In both tests, the antinociceptive effect of i.t. nefopam involves the spinal 5-HT7R, but not 5-HT3R.