scholarly journals Interferon-β suppresses inflammatory pain through activating µ-opioid receptor

2021 ◽  
Vol 17 ◽  
pp. 174480692110452
Author(s):  
Chien Cheng Liu ◽  
I Cheng Lu ◽  
Li Kai Wang ◽  
Jen Yin Chen ◽  
Yu Yu Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Western Blot ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Inflammatory Pain ◽  
Analgesic Effect ◽  
Intrathecal Injection ◽  
Type I ◽  
Withdrawal Threshold ◽  
Withdrawal Latency

Interferons (IFNs) are cytokines secreted by infected cells that can interfere with viral replication. Besides activating antiviral defenses, type I IFNs also exhibit diverse biological functions. IFN-β has been shown to have a protective effect against neurotoxic and inflammatory insults on neurons. Therefore, we aimed to investigate the possible role of IFN-β in reducing mechanical allodynia caused by Complete Freund’s Adjuvant (CFA) injection in rats. We assessed the antinociceptive effect of intrathecal IFN-β in naïve rats and the rats with CFA–induced inflammatory pain. After the behavioral test, the spinal cords of the rats were harvested for western blot and immunohistochemical double staining. We found that intrathecal administration of IFN-β in naïve rats can significantly increase the paw withdrawal threshold and paw withdrawal latency. Further, the intrathecal injection of a neutralizing IFN-β antibody can reduce the paw withdrawal threshold and paw withdrawal latency, suggesting that IFN-β is produced in the spinal cord in normal conditions and serves as a tonic inhibitor of pain. In addition, intrathecal injection of IFN-β at dosages from 1000 U to 10000 U demonstrates a significant transient dose-dependent inhibition of CFA-induced inflammatory pain. This analgesic effect is reversed by intrathecal naloxone, suggesting that IFN-β produces an analgesic effect through central opioid receptor-mediated signaling. Increased expression of phospho-µ-opioid receptors after IFN-β injection was observed on western blot, and immunohistochemical staining showed that µ-opioids co-localized with IFN-α/βR in the dorsal horn of the spinal cord. The findings of this study demonstrate that the analgesic effect of IFN-β is through µ-opioid receptors activation in spial cord.

Spinal Endogenous Acetylcholine Contributes to the Analgesic Effect of Systemic Morphine in Rats

2001 ◽  
Vol 95 (2) ◽  
pp. 525-530 ◽  
Author(s):  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Radiant Heat ◽  
Cholinergic Receptor ◽  
Inhibitory Effect ◽  
Withdrawal Latency ◽  
Aziridinium Ion

Background Systemic morphine is known to cause increased release of acetyicholine in the spinal cord. Intrathecal injection of the cholinergic receptor agonists or acetyicholinesterase inhibitors produces antinociception in both animals and humans. In the present study, we explored the functional importance of spinal endogenous acetylcholine in the analgesic action produced by intravenous morphine. Methods Rats were implanted with intravenous and intrathecal catheters. The antinociceptive effect of morphine was determined by the paw-withdrawal latency in response to a radiant heat stimulus after intrathecal treatment with atropine (a muscarinic receptor antagonist), mecamylamine (a nicotinic receptor antagonist), or cholinergic neurotoxins (ethylcholine mustard aziridinium ion [AF64A] and hemicholinium-3). Results Intravenous injection of 2.5 mg/kg morphine increased significantly the paw-withdrawal latency. Intrathecal pretreatment with 30 microg atropine (n = 7) or 50 microg mecamylamine (n = 6) both attenuated significantly the antinociceptive effect of morphine. The inhibitory effect of atropine on the effect of morphine was greater than that of mecamylanilne. Furthermore, the antinociceptive effect of morphine was significantly reduced in rats pretreated with intrathecal AF64A (n = 7) or hemicholinium-3 (n = 6) to inhibit the high-affinity choline transporter and acetylcholine synthesis. We found that intrathecal AF64A reduced significantly the [3H]hemicholinium-3 binding sites but did not affect its affinity in the dorsal spinal cord. Conclusions The data in the current study indicate that spinal endogenous acetylcholine plays an important role in mediating the analgesic effect of systemic morphine through both muscarinic and nicotinic receptors.

scholarly journals Regulation of Neurotrophin-3 and Interleukin-1βand Inhibition of Spinal Glial Activation Contribute to the Analgesic Effect of Electroacupuncture in Chronic Neuropathic Pain States of Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Wenzhan Tu ◽  
Wansheng Wang ◽  
Haiyan Xi ◽  
Rong He ◽  
Liping Gao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Analgesic Effect ◽  
Dorsal Root ◽  
Interleukin 1 ◽  
Chronic Neuropathic Pain ◽  
Western Blots ◽  
Withdrawal Threshold ◽  
Withdrawal Latency ◽  
Neurotrophin 3

Growing evidence indicates that neurotrophin-3, interleukin-1β, and spinal glia are involved in neuropathic pain derived from dorsal root ganglia to spinal cord. Electroacupuncture is widely accepted to treat chronic pain, but the precise mechanism underlying the analgesic effect of EA has not been fully demonstrated. In this study, the mechanical withdrawal threshold and thermal withdrawal latency were recorded. We used immunofluorescence and western blots methods to investigate the effect of EA on the expression of NT-3 and IL-1βin DRG and spinal cord of CCI rats; we also examined the expression of spinal GFAP and OX-42 in spinal cord. In present study, the MWT and TWL of CCI group rats were lower than those in the Sham CCI group rats, but EA treatment increased the pain thresholds. Furtherly, we found that EA upregulates the expression of NT-3 in DRG and spinal cord of CCI rats, while EA downregulates the expression of IL-1β. Additionally, immunofluorescence exhibited that CCI-induced activation of microglia and astrocytes was inhibited significantly by EA treatment. These results demonstrated that the analgesic effect of EA may be achieved through promoting the neural protection of NT-3 as well as the inhibition of IL-1βproduction and spinal glial activity.

scholarly journals Galanin Receptor 2 Is Involved in Galanin-Induced Analgesic Effect by Activating PKC and CaMKII in the Nucleus Accumbens of Inflammatory Pain Rats

2021 ◽  
Vol 14 ◽  
Author(s):  
Mengnan Li ◽  
Xiaomin Zhang ◽  
Chongyang Li ◽  
Yanan Liu ◽  
Shuang Yang ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Protein Kinase ◽  
Inflammatory Pain ◽  
Analgesic Effect ◽  
Signaling Mechanism ◽  
Withdrawal Threshold ◽  
Calcium Calmodulin Dependent ◽  
Kinase C ◽  
Dependent Protein ◽  
Galanin Receptors

It has been reported that galanin has an analgesic effect via activating galanin receptors (GALRs). This study focused on the involvement of GALR2 in the galanin-induced analgesic effect and its signaling mechanism in the nucleus accumbens (NAc) of inflammatory rats. Animal models were established through injecting carrageenan into the plantar of rats’ left hind paw. The results showed that GALR2 antagonist M871 weakened partially the galanin-induced increases in hind paw withdrawal latency (HWL) to thermal stimulation and hind paw withdrawal threshold (HWT) to mechanical stimulation in NAc of inflammatory rats. Moreover, the GALR2 agonist M1145 prolonged the HWL and HWT, while M871 blocked the M1145-induced increases in HWL and HWT. Western blotting showed that the phosphorylation of calcium/calmodulin-dependent protein kinase II (p-CaMKII) and protein kinase C (p-PKC) in NAc were upregulated after carrageenan injection, while p-PKC and p-CaMKII were downregulated after intra-NAc administration of M871. Furthermore, the CaMKII inhibitor KN93 and PKC inhibitor GO6983 attenuated M1145-induced increases in HWL and HWT in NAc of rats with inflammatory pain. These results prove that GALR2 is involved in the galanin-induced analgesic effect by activating CaMKII and PKC in NAc of inflammatory pain rats, implying that GALR2 agonists probably are potent therapeutic options for inflammatory pain.

scholarly journals EFFECTS OF NEW PIPERIDINE DERIVATIVES WITH SUBSTITUTIONS IN THE 1ST AND 4TH POSITIONS IN NALOXONE SENSITIVE ANALGESY

2021 ◽  
Vol 19 (5) ◽  
pp. 501-505
Author(s):  
A. A. Vasilyuk ◽  
◽  
V. I. Kozlovsky ◽  
G. S. Akhmetova ◽  
V. K. Yu ◽  
...  
Keyword(s):  
Pain Relief ◽  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Effect ◽  
Chemical Stimulation ◽  
Analgesic Action ◽  
Preliminary Administration ◽  
Chemical Irritation

Background. Despite the wide arsenal of painkillers, pain relief is an urgent interdisciplinary problem that requires a search for new solutions. Purpose of the study. To establish the role of opioid receptors in the mechanism of the analgesic action of the piperidine derivatives AGV-22 and AGV-23. Material and methods. The studies were carried out on 96 white mice of both sexes weighing 30-40 g. The analgesic effect of the compounds was tested on models of thermal and chemical irritation with preliminary administration of the opioid receptor antagonist naloxone. Results. The pain reactions of mice with models of thermal and chemical stimulation in the AGV-22 / AGV-23 + naloxone and AGV-22 / AGV-23 groups were comparable. Conclusions. The mechanism of the analgesic action of the piperidine derivatives AGV-22 and AGV-23 is not associated with the activation of opioid receptors.

scholarly journals Ipsi- and Contralateral Moxibustion Generate Similar Analgesic Effect on Inflammatory Pain

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Chuan-Yi Zuo ◽  
Peng Lv ◽  
Cheng-Shun Zhang ◽  
Ru-Xue Lei ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Pain Relief ◽  
Phase I ◽  
Phase Ii ◽  
Inflammatory Pain ◽  
Analgesic Effect ◽  
Withdrawal Latency ◽  
Significant Difference ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant ◽  
Biting Time

The aim of this study was to investigate whether contralateral moxibustion would generate a similar analgesic effect with ipsilateral moxibustion. Contra- and ipsilateral moxibustion were separately applied to Zusanli (ST36) acupoints of inflammatory pain mice. The analgesic effect was evaluated, respectively, by licking/biting time (LBT) of formalin-induced inflammatory pain and thermal withdrawal latency (TWL) of complete Freund’s adjuvant- (CFA-) induced inflammatory pain. For formalin-induced pain, compared with formalin group, the total LBT of ipsi- and contralateral moxibustion reduced in both phase I and phase II, but there was no significant difference between ipsi- and contralateral moxibustion. For CFA-induced inflammatory pain, compared with CFA group, TWL of ipsi- and contra-Moxi groups increased immediately after moxibustion intervention; however there was no obvious difference between ipsi- and contralateral moxibustion at any timepoint. It indicated that contralateral moxibustion had a similar analgesic effect with ipsilateral moxibustion in both formalin- and CFA-induced pain. These results suggest that both ipsi- and contralateral moxibustion could be applied for pain relief.

scholarly journals Effects of Hyperbaric Oxygen on Pain-Related Behaviours and Nitric Oxide Synthase Expression in a Rat Model of Neuropathic Pain

2013 ◽  
Vol 18 (3) ◽  
pp. 137-141 ◽  
Author(s):  
Guang Han ◽  
Lu Li ◽  
Ling-xin Meng
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nitric Oxide Synthase ◽  
Hyperbaric Oxygen ◽  
Rat Model ◽  
Withdrawal Threshold ◽  
Withdrawal Latency ◽  
Oxide Synthase ◽  
Inducible Nos

BACKGROUND: Neuropathic pain is complex, and a satisfactory therapeutic method of treatment has yet to be developed; therefore, finding a new and effective therapeutic method is an important issue in the field of neuropathic pain.OBJECTIVE: To determine the effects of hyperbaric oxygen (HBO) on pain-related behaviours and nitric oxide synthase (NOS) expression in a rat model of neuropathic pain.METHODS: Forty male Sprague Dawley rats were randomly divided into five groups (eight rats per group) including control, sham operation, sciatic nerve with chronic constriction injury (CCI), HBO pretreatment (pre-HBO) and HBO post-treatment (post-HBO) groups. Pain-related behaviours and NOS expression in the spinal cord were compared among the five groups.RESULTS: Compared with the CCI group, the mechanical withdrawal threshold was significantly increased and thermal withdrawal latency was significantly extended in the pre-HBO and post-HBO groups (all P<0.05). After CCI, expression of spinal neuronal NOS and inducible NOS were increased. Expression of spinal neuronal NOS and inducible NOS were significantly decreased in the pre-HBO and post-HBO groups compared with the CCI group (all P<0.05). Spinal eNOS expression changed very little.DISCUSSION: HBO has been used as an effective and noninvasive method for the treatment of spinal cord injuries and high-altitude sickness, and in immunosuppression and stem-cell research; however, it has yet to be applied to the treatment of neuropathic pain. The present study indicated that HBO effectively increased mechanical withdrawal threshold and thermal withdrawal latency, demonstrating that HBO has therapeutic effects on neuropathic pain.CONCLUSION: HBO inhibits pain in rats with CCI through the regulation of spinal NOS expression.

scholarly journals Sex differences in central inflammatory pain sensitization are associated with differential expression of glycine receptors and GLP-1 at the spinal cord

2020 ◽  
Author(s):  
TA. Mariqueo ◽  
G. Améstica ◽  
J. Pino ◽  
R. Barra ◽  
J. Stehberg ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sex Differences ◽  
Western Blot ◽  
Inflammatory Pain ◽  
Glycine Receptor ◽  
Female Rats ◽  
Central Pain ◽  
Nociceptive Threshold ◽  
Zymosan A ◽  
Pain Sensitization

AbstractBackgroundFemales have higher inflammatory pain representation. However, sex differences in central pain sensitization and the regulation of nociceptive response to peripheral inflammation remain unclear. The central pain sensitization is mediated by inhibitory neurotransmission and glial cell activity dysregulation where spinal glycine and GLP-1 receptors have described play a critical role.ObjectivesThe aim of this study was to compare the mechanical withdrawal nociceptive threshold with spinal glycine receptor subunits and GLP-1 expression in adult male and female rats after inflammatory hypersensitivity.MethodsSex differences in inflammatory nociception were evaluated before and after intraplantar hindpaw Zymosan A injection in Sprague-Dawley rats. Mechanical paw withdrawal thresholds were tested using von Frey filaments.Western blot was used to measure GlyRs subunits protein levels in the spinal cord. GLP-1 was determined using the Magnetic Luminex Assay.ResultsA reduced nociceptive threshold was observed in males and females rats after 4 hours of inflammatory Zymosan A injection. However, this reduction was significantly major in females. Western blot analysis demonstrated significantly increased α1, α2, α3 and β GlyR subunit levels in male rats. Female rats only increased α3 and β GlyR subunits after Zymosan A injection. GLP-1 was reduced in female spinal tissues after an inflammatory injury.ConclusionsOur study indicates that sex differences in nociceptive threshold after inflammatory Zymosan A rat pain sensitization is related to the sex differences in glycine receptor subunits and GLP-1 expression at the spinal cord.

scholarly journals Effects of Intrathecal Ketamine in the Neonatal Rat

2010 ◽  
Vol 113 (1) ◽  
pp. 147-159 ◽  
Author(s):  
Suellen M. Walker ◽  
B. David Westin ◽  
Ronald Deumens ◽  
Marjorie Grafe ◽  
Tony L. Yaksh
Keyword(s):  
Spinal Cord ◽  
Calcium Binding ◽  
Dose Range ◽  
Intrathecal Injection ◽  
Neonatal Rat ◽  
Glial Fibrillary Acid Protein ◽  
Percutaneous Injection ◽  
Withdrawal Threshold ◽  
Rat Pups ◽  
Relative Safety

Background Systemic ketamine can trigger apoptosis in the brain of rodents and primates during susceptible developmental periods. Clinically, spinally administered ketamine may improve the duration or quality of analgesia in children. Ketamine-induced spinal cord toxicity has been reported in adult animals but has not been systematically studied in early development. Methods In anesthetized rat pups, intrathecal ketamine was administered by lumbar percutaneous injection. Changes in mechanical withdrawal threshold evaluated dose-dependent antinociceptive and carrageenan-induced antihyperalgesic effects in rat pups at postnatal day (P) 3 and 21. After intrathecal injection of ketamine at P3, 7, or 21, spinal cords were examined for apoptosis (Fluoro-Jade C and activated caspase-3), histopathologic change, and glial responses (ionized calcium-binding adapter molecule 1 and glial fibrillary acid protein). After maximal doses of ketamine or saline at P3 or P21, sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection of 3 mg/kg ketamine at P3 and 15 mg/kg at P21 reverses carrageenan-induced hyperalgesia. Baseline neuronal apoptosis in the spinal cord was greater at P3 than P7, predominantly in the dorsal horn. Intrathecal injection of 3-10 mg/kg ketamine in P3 pups (but not 15 mg/kg at P21) acutely increased apoptosis and microglial activation in the spinal cord and altered spinal function (reduced mechanical withdrawal threshold and altered static gait parameters) at P35. Conclusions Because acute pathology and long-term behavioral change occurred in the same dose range as antihyperalgesic effects, the therapeutic ratio of intrathecal ketamine is less than one in the neonatal rat. This measure facilitates comparison of the relative safety of spinally administered analgesic agents.

scholarly journals Functional and anatomical characterization of corticotropin-releasing factor receptor subtypes of the rat spinal cord involved in somatic pain relief

2021 ◽  
Author(s):  
Shaaban Mousa ◽  
Mohammed Shaqura ◽  
Baled Khalefa ◽  
Li Li ◽  
Mohammed Al-madol ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Western Blot ◽  
Opioid Receptor ◽  
Radioligand Binding ◽  
Corticotropin Releasing Factor ◽  
Receptor Subtypes ◽  
Inhibitory Interneurons ◽  
Rat Spinal Cord ◽  
Somatic Pain ◽  
Antinociceptive Effects

Abstract Corticotropin-releasing factor (CRF) orchestrates our body’s response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptors of subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. This study aimed to examine CRF-R1 and CRF-R2 expression within spinal cord of rats with Freund’s complete adjuvant-induced hindpaw inflammation using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis, Western blot, immunohistochemistry, and radioligand binding. Moreover, paw pressure algesiometry examined antinociceptive effects of intrathecal (i.t.) CRF and their possible antagonism through CRF-R1 and/or CRF-R2 selective antagonists as well as opioid receptor antagonist naloxone. Our results demonstrated mainly CRF-R2 mRNA, protein, binding sites and immunoreactivity in dorsal horn of rat spinal cord. In parallel, i.t. CRF as well as CRF-R2 agonists elicited potent antinociceptive effects which are dose-dependent and antagonized exclusively by i.t. CRF-R2 (K41498), but not CRF-R1 (NBI35965) antagonist. Moreover, i.t. CRF elicited inhibition of somatic pain that was dose-dependently reversed by the opioid antagonist naloxone. Consistently, double immunofluorescence confocal microscopy showed CRF-R2 on enkephalin (ENK) containing inhibitory interneurons in close opposition of incoming, mu-opioid receptor-immunoreactive nociceptive neurons but not on pre- nor on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonist inhibits inflammatory somatic pain which occurs most predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons resulting in endogenous opioid-mediated pain inhibition.

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