Antinociceptive Effects Of Dexmedetomidine Research Articles

Comparative study on epidural administration of dexmedetomidine, dexmedetomidine-lidocaine or lidocaine in conscious rabbits.

The aim of this study was to compare the cardiorespiratory, arterial blood gas and antinociceptive effects of dexmedetomidine (D), dexmedetomidine-lidocaine (DL) or lidocaine (L) administered epidurally on conscious rabbits. Eight six-month-old male New Zealand rabbits were randomly distributed into three treatments: D (2.5 μg/kg); DL (2.5 μg/kg; 2 mg/kg); and L (2 mg/kg). The drugs were injected epidurally via a catheter. Cardiorespiratory, arterial blood gas and antinociceptive variables were recorded before administration, 5 and 10 min after drug administration, then every 10 min until the animals presented a positive response to nociceptive stimulation of perineal dermatomes. Two animals had permanent paralysis after DL treatment due to hemorrhage and congestion with neuron necrosis in spinal cord segments. There was a reduction in mean arterial pressure in treatment L at 5 and 10 min, compared with the baseline, and in treatment DL at 10-30 min. Increases in pH were observed in treatment D at 5 and 10 min, and in DL at all the times evaluated, compared with the baseline. No alterations were observed in other blood gas or electrolyte variables. Antinociceptive effects were evaluated in the perineal, sacral and lumbar regions, and were restricted to the perineal region following D and L treatment. The antinociceptive effects following DL were greater than D and L alone in all of the regions. L and D promotes short-term antinociceptive effects for up to 15 min and, when used in combination with D, increased the duration and extent of sensory block by up to 45 min.

Nrf2 mediates the antinociceptive activity of dexmedetomidine in an acute inflammatory visceral pain rat model by activating the NF-κB sensor.

Dexmedetomidine (DEX) is a highly selective α2 adrenoceptor agonist. In this study, we evaluated the antalgic effect of DEX on acetic acid-induced acute inflammatory visceral pain (AIVP) in rats. Additionally, we evaluated the role of Nrf2 signalling in antinociception. We administered acetic acid to male Sprague Dawley rats that were treated with DEX or saline. Twenty rats were randomly classified into the following groups: normal, model, vehicle, or DEX group. Both q-RT PCR and enzyme-linked immunosorbent assay data suggested that interleukin 1β (IL-1β), tumour necrosis factor α, and IL-6 were upregulated in the spinal cord. Western blotting and q-RT PCR analyses were performed to detect the protein and mRNA expression levels of Nrf2, Keap1, and HO-1 in the spinal cord. The DEX group exhibited a significant downregulation in Nrf2/Keap1/HO-1 signal activation compared with the model group. Furthermore, we used the Nrf2-/- knockout AIVP rat model to determine the role of Nrf2 in the antinociceptive effect of DEX. We observed that the Nrf2 knockout blocked the Keap1/Nrf2/HO-1 signal transduction and partially abated the antinociceptive and the anti-inflammatory effects of DEX. Moreover, our data also indicated that DEX treatment decreased the activation and expression of nuclear factor (NF)-κB. However, Nrf2 silencing restored the expression of NF-κB and its phosphorylated form to physiological levels. In summary, our results suggested that Nrf2 signalling plays an important role in the antinociceptive effect of DEX in the AIVP rat model and that Nrf2 exerts its function by enhancing the activation of the NF-κB sensor. SIGNIFICANCE OF THE STUDY: Currently, using the behavioural parameters is not adequate for the diagnosis of AIVP, and there are no studies that have investigated the role and the mechanism of DEX in ameliorating visceral pain. In this study, we demonstrated that acetic acid stimulation in rats induces AIVP. Additionally, the administration of DEX inhibited the acute inflammation response and decreased the visceromotor reaction (behavioural) to algesia. Further, DEX inhibited the Keap1/Nrf2 pathway, which was activated by acetic acid treatment. We suggest that suppressing the inflammatory response could partially regulate the antinociceptive effect of DEX through Nrf2-mediated NF-κB activation associated with AIVP.

Intrathecal injection of dexmedetomidine ameliorates chronic neuropathic pain via the modulation of MPK3/ERK1/2 in a mouse model of chronic neuropathic pain

ABSTRACTObjective: Despite the application of dexmedetomidine (DEX) as a perioperative adjuvant in local analgesia, the exact analgesic mechanism underpinning chronic neuropathic pain (CNP) awaits our elucidation.Methods: We investigated the molecular mechanisms of the anti-nociceptive effect of DEX on neuropathic pain in a mouse model induced by chronic constriction injury (CCI).Results: DEX administration significantly increased the paw withdrawal latency (PWL) values 0.5 to 2 h post-injection in CCI-induced CNP mice at day 5 to 21 versus dimethyl sulfoxide (DMSO)-treated mice, confirming its analgesic effect. The c-Fos expression was significantly elevated in CCI mice versus the sham-operated group, whereas the elevation was mitigated by DEX injection. Subsequently, the involvement of MKP1 and MKP3 in the pathogenesis of chronic neuropathic pain was evaluated. Western blotting analyses revealed significant decrease in both MKP1 and MKP3 in the spinal cord in CCI group versus the sham group. DEX markedly elevated the MKP3 expression and modestly reduced the MKP1 expression, with insignificant difference in the latter. Co-injection of BCI (an MKP3 inhibitor) and DEX evidently reduced the PWL values in CCI mice. Furthermore, DEX significantly downregulated the phosphorylation of extracellular-signal-regulated kinase (ERK) 1/2, down-stream effector of MKP3 in CCI mice, whereas the downregulation was reversed by BCI.Conclusion: We confirmed that DEX exerts the analgesic effect on chronic neuropathic pain via the regulation of MKP3/ERK1/2 signaling pathway, which may contribute to clarification of the molecular mechanism and novel therapy for chronic neuropathic pain.

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats.

α2-Adrenoceptor agonists attenuate hypersensitivity under neuropathic conditions. However, the mechanisms underlying this attenuation remain largely unknown. In the present study, we explored the potential roles of purinergic receptor 7 (P2X7R)/extracellular signal-regulated kinase (ERK) signaling in the anti-nociceptive effect of dexmedetomidine in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. An animal model of CCI was adopted to mimic the clinical neuropathic pain state. Behavioral hypersensitivity to mechanical and thermal stimuli was determined by von Frey filament and Hargreaves' tests, and the spinal P2X7R expression level and ERK phosphorylation were analyzed using western blot analysis and immunohistochemistry. In parallel with the development of mechanical and thermal hyperalgesia, a significant increase in P2X7R expression was noted in the ipsilateral spinal cord on day 7 after CCI. Intrathecal administration of dexmedetomidine (2.5 µg) for 3 days not only attenuated neuropathic pain but also inhibited the CCI-induced P2X7R upregulation and ERK phosphorylation. Intrathecal dexmedetomidine administration did not produce obvious effects on locomotor function. The present study demonstrated that dexmedetomidine attenuates the neuropathic pain induced by CCI of the sciatic nerve in rats by inhibiting spinal P2X7R expression and ERK phosphorylation, indicating the potential therapeutic implications of dexmedetomidine administration for the treatment of neuropathic pain.

Anti-nociceptive effect of dexmedetomidine in a rat model of monoarthritis via suppression of the TLR4/NF-κB p65 pathway.

As a therapeutic target for neuropathic pain, the anti-nociceptive effects of α 2-adrenoceptors (α2AR) have attracted attention. Dexmedetomidine (DEX), a potent and highly selective α2AR agonist, has exhibited significant analgesic effects in neuropathic pain, but the underlying mechanism has remained elusive. The present study investigated the effect of DEX on Toll-like receptor (TLR)4 and nuclear factor (NF)-κB p65 expression, as well as the production of pro-inflammatory cytokines. The rat monoarthritis (MA) model was induced by intra-articular injection of complete Freund's adjuvant (CFA) at the ankle joint. After induction of MA, the rats were intrathecally treated with normal saline or DEX (2.5 µg) for 3 consecutive days. The concentration of interleukin-1β and −6 as well as tumor necrosis factor-α was examined by ELISA. The expression levels of TLR4 and NF-κB p65 were determined by western blot analysis and immunohistochemistry. The results indicated that the pro-inflammatory cytokines TLR4 and NF-κB p65 were significantly upregulated in MA rats. DEX treatment markedly reduced mechanical and thermal hyperalgesia, suppressed MA-induced elevation of the pro-inflammatory cytokines and inhibited the TLR4/NF-κB p65 pathway, while these effects were blocked by pre-treatment with the selective α2AR antagonist BRL44408 (15 µg) at 30 min prior to CFA injection. These results suggested that DEX has an anti-nociceptive effect via suppressing the TLR4/NF-κB p65 pathway.

Antinociceptive effects of dexmedetomidine via spinal substance P and CGRP.

The aim of this study was to examine the role played by substance P and calcitonin gene-related peptide (CGRP) within the dorsal horn of the spinal cord in engagement of antinociception evoked by dexmedetomidine (DEX). Paw withdrawal threshold (PWT) to mechanical stimulation was determined after chronic intrathecal infusion of DEX and enzyme-linked immunosorbent assay (ELISA) was employed to examine the levels of spinal substance P and CGRP. Our results show that PWT was significantly increased by intrathecal administration of DEX in rats (P < 0.05 vs. vehicle control, n = 20 in each group). Also, intrathecal infusion of DEX significantly decreased the concentrations of substance P and CGRP as compared with vehicle control (P < 0.05 DEX vs. vehicle control, n = 20 in each group). Blocking α2-adrenoreceptors (α2-AR) blunted the decreases of substance P and CGRP levels and the enhancement of PWT evoked by DEX. Additionally, a linear relationship was observed between PWT and the levels of spinal substance P (r = 0.87; P < 0.005) and CGRP (r = 0.85; P < 0.005). Moreover, blocking individual substance P and CGRP receptors amplified PWT without altering substance P and CGRP levels. Thus, DEX plays a role in stimulating α2-AR receptors, which thereby decreases substance P and CGRP levels within the dorsal horn. This contributes to DEX-evoked antinociception.

Cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone, morphine or tramadol in dogs

ObjectiveTo evaluate the cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone, morphine or tramadol in dogs. Study designExperimental, blinded, randomized, crossover study. AnimalsSix mixed breed dogs (two males and four females) weighing 10 ± 4 kg. MethodsThe animals were randomly divided into four treatments: D (10 μg kg−1 of dexmedetomidine), DM (dexmedetomidine 10 μg kg−1 and methadone 0.5 mg kg−1); DMO (dexmedetomidine 10 μg kg−1 and morphine 0.5 mg kg−1), and DT (dexmedetomidine 10 μg kg−1 and tramadol 2 mg kg−1). The combinations were administered intramuscularly in all treatments. The variables evaluated were heart rate (HR), respiratory rate (fR), rectal temperature (RT), systolic arterial pressure (SAP), sedation scale and pedal withdrawal reflex. These variables were measured at T0 (immediately before the administration of the protocol) and every 15 minutes thereafter until T105. ResultsA decrease in HR and fR occurred in all the treatments compared with T0, but no significant difference was observed between the treatments. The RT decreased from T45 onward in all the treatments. The SAP did not show a difference between the treatments, but in the DT treatment, the SAP was lower at T30 and T45 compared with T0. The D treatment had lower scores of sedation at T15 to T75 compared with the other treatments, and the DMO and DM treatments showed higher scores at T60 and T75 compared with DT. Conclusions and clinical relevanceThe treatments with morphine and methadone added to the dexmedetomidine showed higher sedation scores than the control treatment and the treatment with tramadol added to the dexmedetomidine showed no relevant differences in any of the variables evaluated in the study.

The Effects of Dexmedetomidine Alone and in Combination with Tramadol or Amitriptyline in a Neuropathic Pain Model

Background: Interactions between the sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The α2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Multidrug therapy is potentially valuable to decrease side effects. Objective: The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain, i.e., amitriptyline or tramadol, in a chronic constriction injury (CCI) model of the sciatic nerve in rats. Study Design: Controlled animal study. Methods: Following unilateral ligation of the left sciatic nerve, the effect of intraperitoneal (i.p.) dexmedetomidine (5μg/kg), tramadol (5 mg/kg), and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied. Results: The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests confirmed the development of neuropathic pain after CCI. All individual drugs and dexmedetomidine combination with either tramadol or amitriptyline were effective in reducing mechanical allodynia and hyperalgesia. Dexmedetomidine, amitriptyline, tramadol, amitriptyline+dexmedetomidine, and tramadol+dexmedetomidine combination did not produce any sedation/motor impairment (P &gt; 0.05). Limitations: Although the combination of these drugs improved the CCI model of neuropathic pain in this study, an additional interpretation of the underlying mechanism(s) will be needed to confirm these findings. Conclusion: The combination of these drugs appears to be more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone and should be considered as a possible alternative to decrease side effects of individual drug therapy. Key words: Allodynia, amitriptyline, chronic constriction injury, dexmedetomidine, hyperalgesia, neuropathic pain, rat, tramadol

Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats

ObjectiveTo compare sedation and antinociception after oral transmucosal (OTM) and intramuscular (IM) administration of a dexmedetomidine-buprenorphine combination in healthy adult cats. Study designRandomized, ‘blinded’ crossover study, with 1 month washout between treatments. AnimalsSix healthy neutered female cats, weighing 5.3–7.5 kg. MethodsA combination of dexmedetomidine (40 μg kg−1) and buprenorphine (20 μg kg−1) was administered by either the OTM (buccal cavity) or IM (quadriceps muscle) route. Sedation was measured using a numerical rating scale, at baseline and at various time points until 6 hours after treatment. At the same time points, analgesia was scored using a dynamic and interactive visual analogue scale, based on the response to an ear pinch, and by the cat’s response to a mechanical stimulus exerted by a pressure rate onset device. Physiological and adverse effects were recorded, and oral pH measured. Signed rank tests were performed, with significance set at p < 0.05. Data are presented as median and range. ResultsThere were no differences in sedation or antinociception scores between OTM and IM dosing at any of the time points. Nociceptive thresholds increased after both treatments but without significant difference between groups. Buccal pH remained between 8 and 8.5. Salivation was noted after OTM administration (n = 2) and vomiting after both OTM (n = 4), and IM (n = 3) dosing. Conclusions and clinical relevanceIn healthy adult cats, OTM administration of dexmedetomidine and buprenorphine resulted in comparable levels of sedation and antinociception to IM dosing. The OTM administration may offer an alternative route to administer this sedative-analgesic combination in cats.

Involvement of spinal microglia and interleukin-18 in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI

Dexmedetomidine, a selective alpha 2-adrenoceptor (α2AR) agonist, has provided significant analgesia in neuropathic pain. However, its underlying molecular mechanism has not been fully elucidated. In the present study, we found that intrathecal administration of dexmedetomidine alleviated mechanical allodynia induced by chronic constriction injury (CCI), and pretreatment with BRL44408 significantly reversed the dexmedetomidine-induced anti-nociceptive effect. Western blotting revealed that dexmedetomidine reduced the activation of microglia and the upregulation of interleukin-18 (IL-18) protein expression in the ipsilateral lumbar spinal dorsal horn, while BRL44408 pretreatment significantly blocked these effects of dexmedetomidine. Immunocytochemistry/immunohistochemistry indicated that the α2A-adrenoceptor was localised to microglia in primary culture, and IL-18 predominantly colocalised with the microglial marker Iba-1 in the dorsal horn of the spinal cord. These results suggest that the IL-18 signalling pathway in microglia may be involved in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI.

Ameliorative effect of dexmedetomidine and its combination with tramadol or amitriptyline in rat model of neuropathic pain

Event Abstract Back to Event Ameliorative effect of dexmedetomidine and its combination with tramadol or amitriptyline in rat model of neuropathic pain Hannan Farghaly1, Rasha Abd-ellatief1, Marie Z. MOFTAH2, Mostafa Galal3, Hassan Kotb4 and Eman M. Khedr5* 1 Department of Pharmacology, Faculty of medicine., Pharmacology, Egypt 2 Zoology Department, Faculty of Science, Alexandria University, Egypt 3 South Egypt Cancer Institute, Assiut University , faculty of Medicine, Egypt 4 Department of Anaesthesia, Faculty of Medicine, Assiut University, Egypt, Egypt 5 Department of Neurology, Faculty of Medicine, Assiut University Hospital, Faculty of medicine, Neurology, Egypt Interactions between sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain i.e. amitriptyline or tramadol in chronic constriction injury (CCI) model of sciatic nerve in rats. The effect of intraperitoneal (i.p.) dexmedetomidine (5μg/kg), tramadol (5 mg/kg) and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied after CCI. The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests, confirmed the development of neuropathic pain after CCI. Dexmedetomidine, amitriptyline, tramadol, amitriptyline + dexmedetomidine and tramadol + dexmedetomidine combination did not produce any sedation/motor impairment (p>0.05). The combination of these drugs is more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone at several time points. Figure 1 Figure 2 Figure 3 Keywords: neuropathic pain, Amitriptyline, Dexmedetomidine, rat, Tramadol Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Poster Presentation Topic: Abstracts Citation: Farghaly H, Abd-ellatief R, MOFTAH MZ, Galal M, Kotb H and Khedr EM (2013). Ameliorative effect of dexmedetomidine and its combination with tramadol or amitriptyline in rat model of neuropathic pain. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00030 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Mar 2013; Published Online: 11 Apr 2013. * Correspondence: Prof. Eman M Khedr, Department of Neurology, Faculty of Medicine, Assiut University Hospital, Faculty of medicine, Neurology, Assiut city, Egypt, emankhedr99@yahoo.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Hannan Farghaly Rasha Abd-ellatief Marie Z MOFTAH Mostafa Galal Hassan Kotb Eman M Khedr Google Hannan Farghaly Rasha Abd-ellatief Marie Z MOFTAH Mostafa Galal Hassan Kotb Eman M Khedr Google Scholar Hannan Farghaly Rasha Abd-ellatief Marie Z MOFTAH Mostafa Galal Hassan Kotb Eman M Khedr PubMed Hannan Farghaly Rasha Abd-ellatief Marie Z MOFTAH Mostafa Galal Hassan Kotb Eman M Khedr Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Pharmacological mechanisms involved in the antinociceptive effects of dexmedetomidine in mice

Dexmedetomidine (DEX) is a α₂ -adrenoceptor (α₂ -AR) agonist used as an anesthetic adjuvant and as sedative in critical care settings. Typically, α₂ -AR agonists release nitric oxide (NO) and subsequently activate NO-GMPc pathway and have been implicated with antinociception. In this study, we investigate the pharmacological mechanisms involved in the antinociceptive effects of DEX, using an acetic acid-induced writhing assay in mice. Saline or DEX (1, 2, 5, or 10 μg/kg) was intravenously injected 5 min before ip administration of acetic acid and the resulting abdominal constrictions were then counted for 10 min. To investigate the possible mechanisms related to antinociceptive effect of DEX (10 μg/kg), the animals were also pretreated with one of the following drugs: 7-nitroindazole (7-NI; 30 mg/kg ip); 1H-[1,2,4] oxadiazole [4,3-a] quinoxaline-1-one (ODQ; 2.5 mg/kg, ip); yohimbine (YOH; 1 mg/kg, ip); atropine (ATRO; 2 mg/kg, ip); glibenclamide (GLIB; 1 mg/kg, i.p.) and naloxone (NAL; 0.2 mg/kg, ip). A rotarod and open-field performance test were performed with DEX at 10 μg/kg dose. DEX demonstrated its potent antinociceptive effect in a dose-dependent manner. The pretreatment with 7-NI, ODQ, GLIB, ATRO, and YOH significantly reduced the antinociceptive affects of DEX. However, NAL showed no effecting DEX-induced antinociception. The rotarod and open-field tests confirmed there is no detectable sedation or even significant motor impairment with DEX at 10 μg/kg dose. Our results suggest that the α₂ -AR and NO-GMPc pathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain. Furthermore, the antinociceptive effect exerted by DEX appears to be dependent on KATP channels, independent of opioid receptor activity.

Effects of opioid receptor and α 2-adrenoceptor agonists on slow ventral root potentials and on capsaicin and formalin tests in neonatal rats

The inhibitory effects of morphine and α 2-adrenoceptor agonists on slow ventral root potentials (slow VRP) following ipsilateral dorsal root stimulation in neonatal rat spinal cord were compared with the analgesic effects of these drugs on formalin and capsaicin tests in neonatal rats. Morphine, (D-Phe 2, D-Pen 5)-enkephalin (DPDPE), dexmedetomidine, clonidine and xylazine showed concentration-related inhibition of slow VRP. The order of potency was dexmedetomidine > morphine = DPDPE > clonidine > xylazine. The inhibitory effects of opioid agonists and α 2-adrenoceptor agonists were abolished by naloxone, an opioid antagonist, and atipamezole, an α 2-adrenoceptor antagonist, respectively. There was no cross antagonism. Morphine, dexmedetomidine and xylazine dose-dependently inhibited body movement induced by formalin or capsaicin. The order of potency was dexmedetomidine > morphine > xylazine. Although morphine and dexmedetomidine inhibited formalin- and capsaicin-induced body movement in the same dose range, xylazine inhibited formalin-induced body movement at lower concentrations than capsaicin-induced one. The inhibitory potency for slow VRP by these drugs seems to be correlated with that for capsaicin-induced body movement but not that for formalin-induced one. Dexmedetomidine and morphine in combination inhibited slow VRP and body movement induced by capsaicin in an additive manner. It is suggested that the antinociceptive effects of dexmedetomidine and morphine but not xylazine on the capsaicin test are mainly due to spinal effects and that there is no synergistic interaction between dexmedetomidine and morphine in the neonatal rat.

The role of μ-opioid receptors in inflammatory hyperalgesia and α2-adrenoceptor-mediated antihyperalgesia

The purpose of the present study was to investigate the role of μ-opioid receptor in inflammatory hyperalgesia in intact and in spinalized animals and the interaction between μ-opioid and α2-adrenergic receptor in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and heat stimuli were studied in μ-opioid receptor knockout mice and wildtype control mice. Thermal nociception was evaluated by measuring paw withdrawal latencies to radiant heat applied to the hindpaws. Mechanical nociception was measured by von Frey monofilament applications to the hindpaws. Intraplantar carrageenan-induced (1 mg/40 μl) mechanical and heat hyperalgesia were compared in μ-opioid knockout and wildtype mice. The effect of systemically administered α2-adrenergic receptor agonist dexmedetomidine (1–10 μg/kg) was evaluated on mechanical and thermal withdrawal responses under normal and inflammatory state in knockout and wildtype mice. The role of μ-opioid receptor in descending modulation of nociception was studied by assessing mechanical and heat withdrawal responses before and after mid-thoracic spinalization. Withdrawal responses to radiant heat and von Frey monofilaments were similar in μ-opioid knockout and wildtype mice before and after the carrageenan induced hindpaw inflammation. Also, antinociceptive effects of dexmedetomidine in thermal and mechanical nociceptive tests were similar before carrageenan induced hindpaw inflammation. However, the potency of dexmedetomidine was significantly reduced in carrageenan-induced mechanical hyperalgesia in μ-opioid knockout mice compared to the wildtype control mice. Thermal and mechanical withdrawal responses were similar between μ-opioid knockout and wildtype mice before and after mid-thoracic spinalization. Our observations indicate that the μ-opioid receptors do not play an important role in α2-adrenergic receptor agonist-mediated acute antinociception. In addition, μ-opioid receptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia, and the supraspinal control of spinal reflexes. However, in the presence of inflammation, μ-opioid receptors play an important role in the antihyperalgesic actions of an α2-adrenergic receptor agonist.

The antinociceptive actions of dexmedetomidine on dorsal horn neuronal responses in the anaesthetized rat

The actions of the selective α 2-adrenoceptor agonist dexmedetomidine were examined on the nociceptive C and innocuous Aβ fibre-evoked responses of dorsal horn neurones to transcutaneous electrical stimulation in the intact anaesthetized rat. C fibre-evoked responses were dose dependently reduced by intrathecal dexmedetomidine - to a maximum 86 ± 6% inhibition by 10 μg of the agonist. The ED 50 for inhibition of C fibre responses was estimated to be 2.5 μg. Aβ-evoked responses were inhibited to a lesser degree - a maximum 54 ± 8% inhibition after 10 μg dexmedetomidine. The antinociceptive effects of dexmedetomidine were reversed by the α 2-adrenoceptor antagonist atipamezole and the opioid antagonist naloxone. The results are discussed with reference to adrenergic and opioid mechanisms in the spinal cord.

Spinal Antinociception by Dexmedetomidine, a Highly Selective α2‐Adrenergic Agonist

The antinociceptive effects of dexmedetomidine, a highly selective new alpha 2-adrenoceptor agonist, were evaluated in rats after intrathecal, intraperitoneal and subcutaneous administration. Antinociception was tested using the tail-flick method. Both 3 and 6 micrograms of intrathecal dexmedetomidine produced maximal antinociception within 10 min. The effect lasted for up to 6 hr. The smaller dose of 1.5 micrograms produced a mean antinociception of 50% (of the maximum possible effect, MPE%) which lasted for about 2 hr. Subcutaneous atipamezole, a specific alpha 2-adrenergic antagonist completely abolished the antinociception produced by intrathecal dexmedetomidine. When given intraperitoneally, dexmedetomidine produced on average a 50% antinociceptive effect with the highest dose of 60 micrograms/kg. The lower doses of 10 and 30 micrograms/kg were ineffective. After subcutaneous administration a maximal effect was achieved with 120 micrograms/kg, a 70% effect, on average, with 60 micrograms/kg and a short lasting effect of 60% with 30 micrograms/kg. In conclusion, dexmedetomidine is a very potent antinociceptive agent when given intrathecally to rats.

Comparative Effects of Hypoxia on Respiratory and Cardiac Function in Reptiles

reptiles show similar organ system responses to hypoxia and, by doing so, determine the relative importance of organ system responses compared to anaerobiosis in making the turtles so resistant. Accordingly, studies were made in snakes, lizards, and an alligator, of the effects of decreasing levels of ambient oxygen upon oxygen uptake, breathing rate, and heart rate. Certain analyses were also made of changes in duration of parts of the cardiac cycle.