One of the significant limiting complications of paclitaxel is
painful peripheral neuropathy during its therapy for several types
of cancers. Our recent study showed that impairment of
Nrf2-antioxidant response element (Nrf2-ARE) and upregulation
of oxidative signals in the dorsal root ganglion (DRG) of rats with
treatment of paclitaxel result in neuropathic pain. The purpose of
this study was to examine the beneficial role played by
electroacupuncture (EA) in modifying neuropathic pain evoked by
paclitaxel via Nrf2-ARE and oxidative mechanisms. Behavioral
test was performed to determine mechanical and thermal
sensitivity in rats. Western Blot analysis and ELISA were used to
examine expression of Nrf2-ARE and superoxide dismutases
(SOD); and the levels of products of oxidative stress in the DRG.
Our data showed that paclitaxel increased mechanical and
thermal sensitivity and this was accompanied with impaired
Nrf2-ARE and SOD in the DRG and amplified products of
oxidative stress (i.e. 8-isoprostaglandin F2α and 8-hydroxy-2’-
deoxyguanosine). EA treatment largely restored the levels of
Nrf2-ARE/SOD and inhibited products of oxidative stress and
thereby attenuated mechanical and thermal hypersensitivity
induced by paclitaxel. In conclusion, we revealed specific
signaling pathways leading to paclitaxel-evoked neuropathic pain,
including impairment of Nrf2-ARE and heightened oxidative
signals. We further provided evidence for the role of EA in
alleviating paclitaxel-neuropathic pain via these molecular
mediators.
Galanin and galanin receptors (GalRs) have been reported to be
involved in the transmission and modulation of nociceptive
information in the central nervous system (CNS). However, the
underlying mechanism of the antinociception of GalRs in
neuropathic pain remains unclear. This study investigated the
antinociception induced by galanin receptor 1 (GalR1) via protein
kinase A (PKA) signaling pathway in the nucleus accumbens
(NAc) of rats with neuropathic pain. A mononeuropathy model
was replicated by ligation of the left sciatic nerve, following which
the expression of phospho-PKA (p-PKA) in the NAc were
markedly up-regulated at 14th and 28th day after ligation of sciatic
nerve, and p-PKA expression was down-regulated by intra-NAc
injection of GalR1 agonist M617, but the GalR1 antagonist M35
did not have an effect. We also found that M35 in the NAc
blocked the M617-induced increase in the hind paw withdrawal
latencies (HWLs) of rats with mononeuropathy, but M35 alone
had no effect on HWLs, and PKA inhibitor H-89 attenuated the
M617-induced an increase in the HWLs. These results suggested
that GalR1 induced an antinociception via inhibiting PKA
activation, implying that GalR agonists may be potential and
potent therapeutic options to treat chronic neuropathic pain.
The aim of this study was to determine the effect and mechanism of low concentration of lidocaine on subthreshold membrane potential oscillations (SMPO) and burst discharges in chronically compressed dorsal root ganglion (DRG) neurons. DRG neurons were isolated by enzymatic dissociation method. SMPO, burst discharges and single spike were elicited by whole cell patch-clamp technique in current clamp mode. Persistent Na+ current (INaP) and transient Na+ current (INaT) were elicited in voltage clamp mode. The results showed that SMPO was suppressed and burst discharges were eliminated by tetrodotoxin (TTX, 0.2 μ mol/l) in current clamp mode, INaP was blocked by 0.2 μ mol/l TTX in voltage clamp mode. SMPO, burst discharges and INaP were also suppressed by low concentration of lidocaine (10 μ mol/l) respectively. However, single spike and INaT could only be blocked by high concentration of lidocaine (5 mmol/l). From these results, it is suggested that INaP mediates the generation of SMPO in injured DRG neurons. Low concentration of lidocaine (10 μ mol/l) suppresses SMPO by selectively inhibiting INaP, but not INaT, in chronically compressed DRG neurons., H. Dong, Y.-H. Fan, Y.-Y. Wang, W.-T. Wang, S.J. Hu., and Obsahuje bibliografii a bibliografické odkazy
We used a model of tibial lengthening in rabbits to study the postoperative pain pattern during limb-lengthening and morphological changes in the dorsal root ganglia (DRG), including alteration of substance P (SP) expression. Four groups of animals (naïve; OG: osteotomized only group; SDG/FDG: slow/fast distraction groups, with 1 mm/3 mm lengthening a day, respectively) were used. Signs of increasing postoperative pain were detected until the 10th postoperative day in OG/SDG/FDG, then they decreased in OG but remained higher in SDG/FDG until the distraction finished, suggesting that the pain response is based mainly on surgical trauma until the 10th day, while the lengthening extended its duration and increased its intensity. The only morphological change observed in the DRGs was the presence of large vacuoles in some large neurons of OG/SDG/FDG. Cell size analysis of the S1 DRGs showed no cell loss in any of the three groups; a significant increase in the number of SP-positive large DRG cells in the OG; and a significant decrease in the number of SP-immunoreactive small DRG neurons in the SDG/FDG. Faster and larger distraction resulted in more severe signs of pain sensation, and further reduced the number of SP-positive small cells, compared to slow distraction., K. Pap, Á. Berta, G. Szöke, M. Dunay, T. Németh, K. Hornok, L. Marosföi, M. Réthelyi, M. Kozsurek, Z. Puskár., and Obsahuje bibliografii
Paclitaxel is used for the treatment of several types of cancers.
However, one of the significant limiting complications of
paclitaxel is painful peripheral neuropathy during its therapy. In
this study we examined the engagement of antioxidative signal
pathway of the dorsal root ganglion (DRG) in mechanical and
thermal hypersensitivity evoked by paclitaxel. Behavioral test was
performed to determine mechanical and thermal sensitivity in
rats. Western blot analysis and ELISA were used to examine
expression of Nrf2-antioxidant response element (ARE) and
superoxide dismutases (SOD); and the levels of products of
oxidative stress in the DRG. Our results show that paclitaxel
increased mechanical and thermal sensitivity as compared with
vehicle control animals. Paclitaxel also impaired Nrf2-ARE and
SOD in the DRG and amplified products of oxidative stress,
namely 8-isoprostaglandin F2α and 8-hydroxy-2’-
deoxyguanosine. Systemic administration of SOD mimetic using
tempol, antioxidant vitamin C or blocking oxidative pathway
using NADPH oxidase inhibitor (GKT137831) attenuated
mechanical and thermal hypersensitivity induced by paclitaxel.
This inhibitory effect was accompanied with decreases of
proinflammatory cytokines (PICs) such as IL-1β, IL-6 and TNF-α
in the DRG. In conclusion, the data revealed impairment of
Nrf2-ARE and heightened oxidative and PIC signals in the DRG of
paclitaxel rats, leading to neuropathic pain. Balancing of reactive
oxygen species by supplying antioxidants and/or inhibiting
NADPH oxidase appears significant to yield beneficial effects in
neuropathic pain conditions after chemotherapeutic paclitaxel.
Animal models are important for the investigation of mechanisms and therapeutic approaches in various human diseases, including schizophrenia. Recently, two neurodevelopmental rat models of this psychosis were developed based upon the use of subunit selective N-methyl-D-aspartate receptor agonists - quinolinic acid (QUIN) and N-acetyl-aspartyl-glutamate (NAAG). The aim of this study was to evaluate pain perception in these models. QUIN or NAAG was infused into lateral cerebral ventricles neonatally. In the adulthood, the pain perception was examined. The rats with neonatal brain lesions did not show any significant differences in acute mechanical nociception and in formalin test compared to controls. However, the neonatally lesioned rats exhibited significantly higher pain thresholds in thermal nociception. Increased levels of mechanical hyperalgesia, accompanying the sciatic nerve constriction (neuropathic pain), were also observed in lesioned rats. Although hyperalgesia was more pronounced in QUIN-treated animals, the number of c-Fos-immunoreactive neurons of the lumbar spinal cord was similar in experimental and control rats. We conclude that neonatal brain lesions attenuated the thermal perception in both nociceptive and neuropathic pain whereas mechanical pain was increased in the model of neuropathic pain only. Thus, nociceptive and neuropathic pain belongs - in addition to behavioral changes - among the parameters which are affected in described animal models of schizophrenia., M. Franěk ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Ketamine, an N-methyl-D-aspartate antagonist, reduces pain by decreasing central sensitization and pain windup. However, chronic ketamine use can cause tolerance, dependency, impaired consciousness, urinary symptoms, and abdominal pain. This study aimed to investigate the effects of repeated ketamine injections and ketamine readministration after discontinuation in a rat model of neuropathic pain. To induce neuropathic pain, partial sciatic nerve ligation (PSNL) was performed in 15 male Wistar rats, and these animals were divided into three groups: PSNL (control), PSNL + ketamine 5 mg/kg (K5), and PSNL + ketamine 10 mg/kg (K10; n=5 each). Ketamine was injected intraperitoneally daily for 4 weeks, discontinued for 2 weeks, and then readministered for 1 week. Following PSNL, the mechanical withdrawal threshold was determined weekly using the Von Frey. The K10 group showed a significant increase in the mechanical withdrawal threshold, presented here as the target force (in g), at 21 and 28 days compared to the time point before ketamine injection (mean±SE, 276.0±24.0 vs. 21.6±2.7 and 300.0±0.0 vs. 21.6±2.7, respectively; P<0.01) and at 14, 21, and 28 days compared to the control group (108.2±51.2 vs. 2.7±1.3, 276.0±24.0 vs. 2.5±1.5, and 300.0±0.0 vs. 4.0±0.0, respectively; P<0.05). However, in the K10 group, the ketamine effects decreased significantly at 7 days after readministration compared to those after 28 days of repeated injections (P<0.05). In the K10 group, repeated ketamine injections showed a significant increase in antinociceptive effect for >2 weeks, but this ketamine effect decreased after drug readministration.