Increase In Nociceptive Threshold Research Articles

Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats.

This study aimed to evaluate the therapeutic potential of amantadine in a vincristine-induced peripheral neuropathy model in rats. Forty-eight male Wistar rats were used. The treated groups received oral amantadine at doses of 2, 5, 12, 25 and 50 mg/kg, with daily applications for 14 days. The mechanical paw withdrawal threshold was measured using a digital analgesimeter. Immunohistochemical analysis of IL-6, TNFα, MIP1α, IL-10, CX3CR1, CXCR4, SOD, CAT and GPx, and enzymatic activity analysis of CAT, SOD and GPx were performed, in addition to quantitative PCR of Grp78, Chop, Ho1, Perk, Bax, Bcl-xL, Casp 3, Casp 9, IL-6, IL-10, IL-18 and IL-1β. The results showed an increase in nociceptive thresholds in animals that received 25 mg/kg and 50 mg/kg amantadine. Immunohistochemistry showed a decrease in the immunostaining of IL-6, TNFα, MIP1α and CX3CR1, and an increase in IL-10. CAT and SOD showed an increase in both immunochemistry and enzymatic analysis. qPCR revealed a reduced expression of genes related to endoplasmic reticulum stress and regulation in the expression of immunological and apoptotic markers. Amantadine demonstrated antinociceptive, anti-inflammatory and antioxidant effects in the vincristine-induced peripheral neuropathy model in rats, suggesting that amantadine may be considered an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

Determination of minimum infusion rate of propofol in combination with electroacupuncture in goats

Total intravenous anesthesia (TIVA) is frequently used anesthetic protocol in animals when inhalation anesthesia is not available. To date, it has not yet been known whether electroacupuncture (EA) can affect propofol-based TIVA in goats. Therefore, the present paper aims to determine the minimum infusion rate (MIR) of propofol, in combination with EA, required to preclude purposeful movement of the extremities in response to standardized noxious stimulation in goats. Twelve clinically healthy goats weighing 17.45 ± 2.15 kg were randomly allocated into two groups with six goats each. Propofol alone (P group) and propofol combined with EA (EA-P group). In the EA-P, propofol was given 30 min after EA stimulation. For induction of anesthesia, a bolus of propofol was administered at 4 mg/kg IV, and an infusion dose of 0.4 mg/kg/min was initially set for maintenance. The MIR of propofol in both groups was determined by testing for responses to stimulation (clamping on a digit with Vulsellum forceps) at 10-min intervals after inducing anesthesia until the end period of the experiment. Cardiorespiratory variables and nociceptive threshold were measured throughout anesthesia. The median propofol MIR was significantly lower in the EA-P group than the P group [0.520 (0.467–0.572) and 0.650 (0.600–0.677)], respectively; p = 0.0013). In the P group, goats anesthetized with MIR showed a significant increase in heart rate and cardiac index (p = 0.0010 and p < 0.0001, respectively), and a decrease in respiratory rate (p = 0.0001). Additionally, the EA-P showed a significant decrease in hemoglobin oxygen saturation following the initial infusion rate at 2 min (p = 0.0023) and 10 min (p = 0.0007) as compared to the P group. A significant increase in nociceptive threshold was recorded in the EA-P threshold than that of the P group (p < 0.005). EA combined with propofol provides antinociception, decreases the MIR of propofol-based TIVA, and subsequently lessens the negative cardiorespiratory consequences related to propofol anesthesia in goats.

PD05-09 EFFECTS OF SUNOBINOP (V117957) IN A MODEL OF ACUTE CYSTITIS INDUCED BY CYCLOPHOSPHAMIDE

You have accessJournal of UrologyCME1 Apr 2023PD05-09 EFFECTS OF SUNOBINOP (V117957) IN A MODEL OF ACUTE CYSTITIS INDUCED BY CYCLOPHOSPHAMIDE Garth Whiteside, Stamford, CT, Celine Auge, and Philippe Lluel Garth WhitesideGarth Whiteside More articles by this author , Stamford Stamford More articles by this author , CT CT More articles by this author , Celine AugeCeline Auge More articles by this author , and Philippe LluelPhilippe Lluel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003229.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Interstitial Cystitis (IC) is a chronic urological disorder characterized by pain urinary urgency, frequency and nocturia. Not all patients are responsive to existing treatments which are also limited by side-effects. As such new treatments with novel mechanisms of action are needed. Sunobinop (V117957) is a selective partial agonist of the nociceptin/orphanin-FQ (N/OFQ) peptide receptor which is excreted unchanged by the kidneys. The objective of these studies was to examine the effect of sunobinop on visceral pain in a model of interstitial cystitis in female rats. METHODS: Female Sprague-Dawley rats (10/group) were administered sunobinop (30 mg/kg, p.o.), ibuprofen (300 mg/kg, p.o.) or vehicle and 5 minutes later a single dose of cyclophosphamide (CYP; 150 mg/kg i.p). Tactile sensitivity (von Frey fibers) was measured at baseline, 2, 3, 4 and 24 hr after CYP. Parameters analyzed were nociceptive threshold (g), nociceptive scores (%) and area under the nociception curve (AUC) across two fiber ranges (1-6 g and 6-26 g) all of which were expressed as mean±standard error of the mean (SEM) with significance set at p≤0.05. RESULTS: At all evaluated time points CYP induced a significant decrease of nociception measures as compared to saline (p<0.0001) indicating successful model development. Ibuprofen-treated rats displayed a significant overall increase in nociceptive thresholds and significantly decreased nociceptive scores and AUC measures as compared to vehicle (p<0.0001). Post hoc statistical analysis showed a slight and gradual decrease of ibuprofen effect was observed over time. Sunobinop produced an overall inhibitory effect on nociceptive thresholds (significant at 3 hr), a significant decrease in nociceptive scores and a significant decrease in AUCs starting from 2h and up to 24h after CYP injection (p<0.01). After 3h, efficacy of sunobinop decreased slightly and gradually over time. CONCLUSIONS: The positive control, ibuprofen, significantly decreased pain responses, as compared to vehicle in an acute model of CYP induced IC. Likewise, sunobinop was significantly anti-nociceptive. As such this data suggests sunobinop has potential utility in treatment of pain associated with IC. Source of Funding: Imbrium Therapeutics L.P. a subsidiary of Purdue Pharmaceuticals L.P. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e152 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Garth Whiteside More articles by this author Stamford More articles by this author CT More articles by this author Celine Auge More articles by this author Philippe Lluel More articles by this author Expand All Advertisement PDF downloadLoading ...

Central involvement of 5-HT1A receptors in antinociception induced by photobiomodulation in animal model of neuropathic pain.

This study aimed to investigate the central involvement of 5-HT1A receptors in the nociceptive behavior of mice submitted to the chronic constriction injury (CCI) of sciatic nerve and the subsequent application of photobiomodulation (PBM). Male mice (Swiss-albino) were submitted to CCI and subsequently received an infusion of WAY100635 (5-HT1A receptor antagonist) or intracerebroventricular saline (ICV), followed by infrared laser irradiation (808nm), in continuous mode, with the power of 100mW and a dose of 0J/cm2 (control group) or 50J/cm2. The thermal hyperalgesia was evaluated by hot plate test, while mechanical allodynia was evaluated by von Frey filaments. After CCI, animals showed a reduction in the nociceptive threshold (p<0.001) when compared to the sham group. In von Frey test, the CCI + saline + PBM 50J/cm2 group showed an increase in nociceptive threshold (p<0.001) in all measurement moments in comparison with groups CCI + SALINE + PBM 0J/cm2, CCI + WAY100635 + PBM 50J/cm2, and CCI + WAY100635 + PBM 0J/cm2. Similarly, in hot plate test, CCI + SALINE + PBM 50J/cm2 group showed an increase in nociceptive threshold after application of PBM at 120 and 180min. Because of the results found, it can be suggested the involvement of 5-HT1A receptors in the central nervous system, since WAY100635 was able to reverse the antinociceptive effect provided by PBM in animals submitted to CCI.

Chemogenetic Activation of Parasubthalamic nucleus Corticotropin‐Releasing Factor Neurons recapitulates Alcohol Withdrawal‐Related Behavioral Symptomatology

Negative reinforcing effects of alcohol, driven by negative affect during withdrawal, are thought to be crucial to drinking escalation in alcohol use disorders. While the brain regions and neurotransmitter signaling affected by chronic alcohol use are well characterized, our understanding of the specific neural circuits driving drinking escalation and negative affect during withdrawal remains limited. Animal studies have highlighted a critical role of corticotropin‐releasing factor (CRF) signaling in the behavioral symptomatology of alcohol dependence. Hence, the present study sought to examine the role of a cluster of CRF neurons located in the parasubthalamic nucleus (PSTN), a small region of the posterior hypothalamus, which has received little attention in behaviors related to alcohol dependence. Adult male Crh‐IRES‐Cre mice were bilaterally injected in the PSTN with a viral vector encoding the excitatory designer receptor hM3D(Gq) fused to the fluorescent reporter mCherry upon Cre recombination. Injection of the hM3D(Gq) agonist clozapine‐N‐oxide (CNO, 1 mg/kg) significantly increased alcohol and saccharin consumption but did not change food and water consumption compared to vehicle. CNO had no effect in mice expressing mCherry only. CNO also increased locomotor and digging activity but did not alter open arm exploration in the elevated plus maze. CNO also decreased grooming duration in the splash test and immobility duration in the tail suspension test. Interestingly, the increased alcohol consumption, digging activity, active coping and reduced grooming all recapitulate phenotypes observed in mice withdrawn from chronic intermittent ethanol vapor inhalation, a model of alcohol dependence. However, CNO injection caused a significant increase in nociceptive thresholds in both the tail immersion and tail pressure tests, which is at odds with the hyperalgesia typically associated with alcohol withdrawal.The PSTN sends a strong projection to the central amygdala (CeA), a region that plays a critical role in the transition to alcohol dependence. We therefore tested whether the effects of PSTN CRF neuron chemogenetic activation may be mediated by the activation of CeA neurons carrying CRF1 receptors. However, CNO did not affect alcohol drinking, locomotion and digging in Crhr1‐IRES‐Cre mice expressing hM3D(Gq) in the CeA. Combined with our recent finding that PSTN neurons become activated during alcohol withdrawal, our results suggest that PSTN CRF neurons contribute to the behavioral symptomatology of ethanol withdrawal, but CRF1 signaling in the CeA may not be relevant to their mechanism of action.Support or Funding InformationThis work was funded by the following grants from the National Institutes of Health: AA026685 (CC), P60 AA006420 (CC), and University of Benin, Benin City, Nigeria, (AO).

Sepsis-induced encephalopathy impairs descending nociceptive pathways in rats

Sepsis-associated encephalopathy (SAE) is a significant problem in patients with sepsis, and it is associated with a decrease in cognitive and sensitivity capability induced by systemic inflammation. SAE is implicated in reversible brain damage of several regions related to cognition, emotion, and sensation; however, it is not well established if it could affect brain regions associated with nociceptive modulation. Here were evaluated the nociceptive thresholds in rats with systemic inflammation induced by cecal ligation puncture (CLP). After 24 h of CLP, it was observed an increase in nociceptive threshold in all tests. Periaqueductal gray, rostroventral medulla, critical regions for descending nociceptive modulation, were evaluated and showed enhanced pro-inflammatory cytokines as well as glial activation. These results suggest that systemic inflammation could compromise descending facilitatory pathways, impairing nociceptive sensory functioning.

Pomegranate supplementation attenuates inflammation, joint dysfunction via inhibition of NF-κB signaling pathway in experimental models of rheumatoid arthritis.

Incisive search of innovative compounds for regulating pain, inflammation, and bone damage, with nominal side effects has focused on nutritional supplements. The endeavor of this research work was to investigate, for first time, the inhibitory effect of pomegranate rind extract in established models of nociception and inflammation. Pomegranate (50, 100, and 200mg/kg) and indomethacin (3mg/kg) was assessed in eddy's hot plate-induced algesia, carrageenan, and Complete Freund's adjuvant-induced models in Wistar rats. Results of study conclude that pomegranate at a dose of 200mg/kg showed significant (p<0.001) reduction in paw swelling in both inflammatory experimental models. In addition, observations recorded a significant (p<0.05) increase in nociceptive threshold. Henceforth, we might say that pomegranate (200mg/kg) decline pain and inflammation by downregulating the activation of TNF-R1, TNF-α, IL-1β, IL-6, NF-κB, oxidative stress markers, and tissue histology. PRACTICAL APPLICATIONS: The research work represents the first report on inhibitory mechanism of NF-κB by pomegranate rind extract, enriched in tannins and flavanoids. The findings of the study provide satisfactory evidence of pomegranate rind in amelioration of adjuvant-induced arthritis. Pomegranate rind, being enrich in bioactive compounds like phenolics and flavanoids possess potent antioxidant activity that might contribute in attenuating rheumatoid arthritis.

Sedative and antinociceptive effects of different combinations of detomidine and methadone in standing horses

ObjectiveTo evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects. Study designRandomized, placebo-controlled, blinded, crossover. AnimalsA group of eight adult healthy horses aged (mean ± standard deviation) 7 ± 2 years and 372 ± 27 kg. MethodsA total of six treatments were administered IV: saline (SAL); detomidine (5 μg kg−1; DET); methadone (0.2 mg kg−1; MET) alone or combined with detomidine [2.5 (MLD), 5 (MMD) or 10 (MHD) μg kg−1]. Thermal, mechanical and electrical nociceptive thresholds were measured, and sedation, head height above ground (HHAG), cardiopulmonary variables and intestinal motility were evaluated at 5, 15, 30, 45, 60, 75, 90, 120 and 180 minutes. Normal data were analyzed by mixed-model analysis of variance and non-normal by Kruskal–Wallis (p < 0.05). ResultsNociceptive thresholds in horses administered methadone with the higher doses of detomidine (MMD, MHD) were increased above baseline to a greater degree and for longer duration (MMD: 15–30 minutes, MHD: 30–60 minutes) than in horses administered low dose with methadone or detomidine alone (MLD, DET: 5–15 minutes). No increases in nociceptive thresholds were recorded in SAL or MET. Compared with baseline, HHAG was lower for 30 minutes in MMD and DET, and for 45 minutes in MHD. No significant sedation was observed in SAL, MET or MLD. Intestinal motility was reduced for 75 minutes in MHD and for 30 minutes in all other treatments. ConclusionsMethadone (0.2 mg kg−1) potentiated the antinociception produced by detomidine (5 μg kg−1), with minimal sedative effects. Clinical relevanceDetomidine (5 μg kg−1) with methadone (0.2 mg kg−1) produced antinociception without the adverse effects of higher doses of detomidine.

µ1 -Opioid receptors in the dorsomedial and ventrolateral columns of the periaqueductal grey matter are critical for the enhancement of post-ictal antinociception.

Generalised tonic and tonic-clonic seizures are followed by significant increase in nociceptive thresholds in both laboratory animals and humans. The endogenous opioid peptides play a role in antinociceptive signalling, and the periaqueductal grey matter (PAG) is recruited to induce analgesia. Thus, the aim of this investigation was to evaluate the role of µ1 -opioid receptors in the dorsomedial (dm) and ventrolateral (vl) columns of PAG in post-ictal antinociception. Pentylenetetrazole (PTZ; 64 mg/kg), which is an ionotropic GABA-mediated Cl- influx antagonist, was intraperitoneally (IP) administered to induce tonic-clonic seizures in Wistar rats. The tail-flick test was used to measure the nociceptive threshold. Microinjections of naltrexone (5.0 µg/0.2 µL), which is a non-selective opioid receptor antagonist, in both dmPAG and vlPAG decreased the tonic-clonic seizure-induced antinociception in seizing animals from 10 to 120 min after seizures. Furthermore, microinjections of the µ1 -opioid receptor-selective antagonist naloxonazine (5.0 µg/0.2 µL) into the dmPAG decreased post-ictal antinociception immediately after convulsive reactions and from 10 to 90 min after seizures. However, vlPAG-pretreatment with naloxonazine at the same concentration decreased the post-ictal antinociception 30 min after the onset of tonic-clonic seizures and the nociceptive threshold returned to basal values 120 min after seizures. These findings indicate that µ1 -opioid receptor-signalling mechanisms in both dmPAG and vlPAG play a relevant role in the organisation of post-ictal antinociception. In addition, µ1 -opioid receptors in the dmPAG rather than in vlPAG seem to be more critically recruited during the antinociception induced by generalised tonic-clonic seizures.

Low-level laser therapy as a treatment for chronic pain.

Low-level laser therapy as a treatment for chronic pain.

Long-Term Changes in Pain Sensitivity in an Animal Model of Social Anxiety

Animal models with an eco-ethological relevance can help in identifying novel and reliable stress-related markers. To this end, 3-month-old C57BL/6J male mice were exposed to social defeat (SD) stress for 10 days as this stressor shows good face and predictive validity for several models of human affective disorders including depression, social phobia and post-traumatic stress disorder. Social avoidance and pain threshold were assessed 24 h and 4 weeks after the end of SD stress, while corticosterone was assayed at the beginning and at the end of the stressful procedure (days 1 and 10). SD subjects were characterized by increased corticosterone levels (30 min following stress exposure), increased latency to approach the social target in the short-term as well as increased emotionality in the long-term. Moreover, an increase in nociceptive threshold (stress-induced analgesia) was found both in the short-term and 4 weeks after the end of stress. These data indicate that the SD paradigm is able to induce emotional changes associated with a stressful/traumatic event. In addition, they indicate that variations in the nociceptive threshold might represent a physiological marker of both short- and long-term effects of stress.

Antinociceptive effect of d-Lys2, Dab4N-(ureidoethyl)amide, a new cyclic 1-4 dermorphin/deltorphin analog

BackgroundA preliminary evaluation of antinociceptive activity of a new cyclic dermorphin/deltorphin tetrapeptide analog restricted via a urea bridge and containing C-terminal ureidoethylamid {[H-Tyr-d-Lys(&1)-Phe-Dab(&2)-CH2CH2NHCONH2][&1CO&2]} (cUP-1) revealed a significant and long-lasting increase of pain threshold to thermal stimulation after systemic application. The current studies were aimed at further evaluation of cUP-1 activity in animal models of somatic and visceral pain. The influence of cUP-1 on motor functions was also investigated. MethodsThe influence of cUP-1 (0.5–2mgkg−1, iv) on nociceptive threshold to mechanical pressure and analgesic efficacy in formalin and acetic acid-induced writhing tests were estimated. The antinociceptive effect of cUP-1 was compared to that of morphine (MF). The influence of cUP-1 (1, 4 and 8mgkg−1, iv) on locomotor activity, motor coordination and muscle strength was estimated using open field and rota-rod tests and a grip strength measurement. ResultsAdministration of cUP-1 in doses of 1 and 2mgkg−1 elicited a significant increase of nociceptive threshold to mechanical pressure. MF applied in the same doses induced an antinociceptive effect only at the higher dose (2mgkg−1). There were no marked differences between the effect of cUP-1 and MF at each dose, at relative time points. In the writhing test and both phases of the formalin test, cUP-1 showed a significant, dose-dependent antinociceptive effect which did not markedly differ from that of MF. cUP-1 did not significantly affect motor functions of mice. ConclusionsSystemic application of cUP-1 elicited a dose-dependent antinociceptive effect. The analgesic efficacy of cUP-1 on mechanical nociception, visceral and formalin-induced pain was comparable to that of MF. cUP-1 did not impair motor functions of mice.

Blockade of substance P receptor attenuates osteoporotic pain, but not bone loss, in ovariectomized mice

The aim of this study was to investigate the effect of a substance P (SP) receptor (NK1 receptor [NK1-R]) antagonist on hyperalgesia and bone metabolism in ovariectomized mice. Thirty-six 9-week-old mice were subjected to either bilateral ovariectomy or sham surgery. Three weeks after the operation, the mice were treated with either a single-dose injection or 2-week repeated daily administration of L-703606, an NK1-R antagonist. Behavioral tests were performed for pain assessment; tibiae and the third lumbar vertebrae were dissected and assessed for microarchitectural or biomechanical properties. The expressions of SP and NK1-R in the dorsal root ganglia and spinal cord were also evaluated. Both single-dose injection and 2-week repeated injections of L-703606 led to a significant increase in nociceptive threshold in ovariectomized mice. However, the antihyperalgesic effect faded at 2 hours and almost disappeared at 5 hours after a single-dose injection. With the 14-day repeated treatment of ovariectomized mice, the effect was not detectable at 24 hours after the first injection but was obvious at 24 hours after 1-week and 2-week administrations and still existed at 48 hours after the last injection. Ovariectomized mice at the hyperalgesic state had enhanced SP immunoreactivity in the dorsal root ganglia and up-regulated SP and NK1-R expressions in the spinal cord. However, no significant change in serum SP level was detected. Two-week treatment with L-703606 could down-regulate these expressions but failed to salvage the deteriorated trabecular microstructure and reduced compressive strength in ovariectomized mice. Estrogen deficiency-induced hyperalgesia is achieved through up-regulation of SP and NK1-R expressions. Blockade of SP receptor can alleviate pain but cannot ameliorate bone loss. NK1-R antagonist is not recommended for the treatment of estrogen deficiency osteoporosis.

The Novel Reversible Fatty Acid Amide Hydrolase Inhibitor ST4070 Increases Endocannabinoid Brain Levels and Counteracts Neuropathic Pain in Different Animal Models

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor α antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain.

Comparison of the analgesic efficacy of oral ABT-116 administration with that of transmucosal buprenorphine administration in dogs

To evaluate the analgesic efficacy of ABT-116, a transient receptor potential cation channel vanilloid subfamily V member 1 antagonist, and compare it with that of buprenorphine by measurement of mechanical and thermal nociceptive thresholds in dogs. Six 7- to 8-month-old dogs (3 males and 3 females). In a crossover study design, all dogs received ABT-116 (30 mg/kg, PO) and buprenorphine (0.03 mg/kg, orotransmucosally), with each treatment separated by 1 week. Physiologic variables were recorded prior to and 1, 6, and 24 hours after drug administration. Thermal (thoracic) and mechanical (dorsolateral aspect of the radius [proximal] and dorsopalmar aspect of the forefoot [distal]) nociceptive thresholds were assessed prior to (baseline) and 15 minutes and 1, 2, 4, 6, 12, 18, and 24 hours after treatment. Buprenorphine administration resulted in higher overall thermal and proximal mechanical nociceptive thresholds, compared with ABT-116. Distal mechanical nociceptive thresholds after treatment were higher than baseline values for both treatments, but the magnitude of change was greater for buprenorphine at 1 hour after administration. Whereas HR and RR sporadically differed from baseline values after ABT-116 administration, rectal temperature increased from a baseline value of 39 ± 0.2°C (mean ± SD) to a peak of 40.6 ± 0.2°C at 6 hours. In dogs without inflammation or nerve injury, PO administration of ABT-116 did not consistently result in an increase in nociceptive thresholds. However, clinically relevant increases in rectal temperature were identified after ABT-116 administration.

Panic-like defensive behavior but not fear-induced antinociception is differently organized by dorsomedial and posterior hypothalamic nuclei of Rattus norvegicus (Rodentia, Muridae)

The hypothalamus is a forebrain structure critically involved in the organization of defensive responses to aversive stimuli. Gamma-aminobutyric acid (GABA)ergic dysfunction in dorsomedial and posterior hypothalamic nuclei is implicated in the origin of panic-like defensive behavior, as well as in pain modulation. The present study was conducted to test the difference between these two hypothalamic nuclei regarding defensive and antinociceptive mechanisms. Thus, the GABAA antagonist bicuculline (40 ng/0.2 µL) or saline (0.9% NaCl) was microinjected into the dorsomedial or posterior hypothalamus in independent groups. Innate fear-induced responses characterized by defensive attention, defensive immobility and elaborate escape behavior were evoked by hypothalamic blockade of GABAA receptors. Fear-induced defensive behavior organized by the posterior hypothalamus was more intense than that organized by dorsomedial hypothalamic nuclei. Escape behavior elicited by GABAA receptor blockade in both the dorsomedial and posterior hypothalamus was followed by an increase in nociceptive threshold. Interestingly, there was no difference in the intensity or in the duration of fear-induced antinociception shown by each hypothalamic division presently investigated. The present study showed that GABAergic dysfunction in nuclei of both the dorsomedial and posterior hypothalamus elicit panic attack-like defensive responses followed by fear-induced antinociception, although the innate fear-induced behavior originates differently in the posterior hypothalamus in comparison to the activity of medial hypothalamic subdivisions.

Antinociception by neutrophil-derived opioid peptides in noninflamed tissue—Role of hypertonicity and the perineurium

Inflammatory pain can be controlled by intraplantar opioid injection or by secretion of endogenous opioid peptides from leukocytes in inflamed rat paws. Antinociception requires binding of opioid peptides to opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic opioid peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic opioid peptides (i.e. Met-Enkephalin and β-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of opioid peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered opioid peptide release from neutrophils in vitro, nociceptive thresholds were unchanged in vivo. In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and opioid peptide release from neutrophils. These inhibitory effects were fully reversible by washout . In vivo, return to normotonicity occurred within 30 min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced opioid peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for opioid peptide access and (ii) opioid peptide release from neutrophils involving p38 MAPK.

Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system

Epidural motor cortex stimulation (MCS) has been used for treating patients with neuropathic pain resistant to other therapeutic approaches. Experimental evidence suggests that the motor cortex is also involved in the modulation of normal nociceptive response, but the underlying mechanisms of pain control have not been clarified yet. The aim of this study was to investigate the effects of epidural electrical MCS on the nociceptive threshold of naive rats. Electrodes were placed on epidural motor cortex, over the hind paw area, according to the functional mapping accomplished in this study. Nociceptive threshold and general activity were evaluated under 15-min electrical stimulating sessions. When rats were evaluated by the paw pressure test, MCS induced selective antinociception in the paw contralateral to the stimulated cortex, but no changes were noticed in the ipsilateral paw. When the nociceptive test was repeated 15min after cessation of electrical stimulation, the nociceptive threshold returned to basal levels. On the other hand, no changes in the nociceptive threshold were observed in rats evaluated by the tail-flick test. Additionally, no behavioral or motor impairment were noticed in the course of stimulation session at the open-field test. Stimulation of posterior parietal or somatosensory cortices did not elicit any changes in the general activity or nociceptive response. Opioid receptors blockade by naloxone abolished the increase in nociceptive threshold induced by MCS. Data shown herein demonstrate that epidural electrical MCS elicits a substantial and selective antinociceptive effect, which is mediated by opioids.

Chronic unpredictable stress inhibits nociception in male rats

Chronic stress elicits remarkable alterations to the structure and function of several areas of the central nervous system. Nociception is known to be affected by chronic stress and age, although the observations are contradictory. Herein we report that both young and old rats submitted to a chronic unpredictable stress paradigm have reduced nociception in the tail-flick nociceptive test. Moreover, stressed animals show an increase in nociceptive threshold after three successive exposures to noxious stimulation (within a 2 min interval). While the sustained stress-induced analgesia is usually attributed to the resulting hypercorticalism, the immediate exacerbation of tolerance to pain displayed by stressed animals is most likely mediated through other mechanisms due to the very rapid antinociceptive effect observed.

Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of diabetic neuropathic pain

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, has been recognised as one of the most difficult types of pain to treat. Lack of understanding of etiology involved, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve pain. The aim of the present study was to explore the antinociceptive effect of a bioflavonoid, quercetin, both in control and streptozotocin (STZ)-induced diabetic mice. After 4 weeks of a single intraperitoneal injection of STZ (200 mg/kg), both control and diabetic mice were subjected to test thermal hyperalgesia by tail-immersion assay (warm water). Diabetic mice exhibited a significant hyperalgesia as compared with control mice. Quercetin (100 but not 50 mg/kg po) produced a marked increase in tail-flick latencies in both diabetic and nondiabetic mice. Quercetin-induced increase in nociceptive threshold was reversed by naloxone (2 mg/kg ip), an opioid receptor antagonist. These preliminary results indicate an antinociceptive activity of quercetin, probably through modulation of opioidergic mechanism and point towards its potential to attenuate diabetic neuropathic pain.