Antiallodynic Effects Research Articles

Spinal 5-HT4 and 5-HT6 receptors contribute to the maintenance of neuropathic pain in rats.

Nerve injury promotes release of 5-HT at the spinal cord. Once released, 5-HT may produce antinociceptive or pronociceptive effects depending of the nature of 5-HT receptors. The purpose of this study was to investigate the participation of spinal 5-HT4 and 5-HT6 receptors in the maintenance of neuropathic pain in rats. Tactile allodynia was measured using von Frey hairs in male Wistar rats subjected to L5-L6 spinal nerve injury. Selective 5-HT4 (GR-113808, 0.01-10nmol/rat) and 5-HT6 (SB-258585, 1-1000nmol/rat) receptor antagonists were administered intrathecally to nerve injured rats. Likewise, the most effective dose of 5-HT4 (1nmol/rat) and 5-HT6 (100 nmol/rat) antagonists were co-administered with their respective agonists (ML-10302, 10-100nmol/rat and WAY-208466, 100-1000nmol/rat, respectively). Spinal cord protein expression of both receptors was determined by western blot. Intrathecal administration of 5-HT4 or 5-HT6 receptor antagonists, but not vehicle, decreased in a dose-dependent manner tactile allodynia in neuropathic rats. Moreover, intrathecal co-administration with the agonists prevented in a dose-dependent manner the antagonists-induced antiallodynic effect. Both 5-HT4 and 5-HT6 receptors were expressed in the spinal cord of naïve, sham and neuropathic rats. Nerve injury did not modify expression of any receptor. Data suggests that spinal 5-HT4 and 5-HT6 receptors are expressed in dorsal spinal cord and they participate in the maintenance of neuropathic pain in rats. In this regard, blockade of these receptors could be a useful strategy to treat neuropathic pain states.

Zerumbone Alleviates Neuropathic Pain through the Involvement of l-Arginine-Nitric Oxide-cGMP-K⁺ ATP Channel Pathways in Chronic Constriction Injury in Mice Model.

The present study investigates the involvement of the l-arginine-Nitric Oxide-cGMP-K+ ATP pathways responsible for the action of anti-allodynic and antihyperalgesic activities of zerumbone in chronic constriction injury (CCI) induced neuropathic pain in mice. The role of l-arginine-NO-cGMP-K+ was assessed by the von Frey and the Randall-Selitto tests. Both allodynia and hyperalgesia assessments were carried out on the 14th day post CCI, 30 min after treatments were given for each respective pathway. Anti-allodynic and antihyperalgesic effects of zerumbone (10 mg/kg, i.p) were significantly reversed by the pre-treatment of l-arginine (10 mg/kg), 1H [1,2,4]Oxadiazole[4,3a]quinoxalin-1-one (ODQ), a soluble guanosyl cyclase blocker (2 mg/kg i.p.) and glibenclamide (ATP-sensitive potassium channel blocker) (10 mg/kg i.p.) (p < 0.05). Taken together, these results indicate that systemic administration of zerumbone produces significant anti-allodynic and antihyperalgesic activities in neuropathic pain in mice possibly due to involvement of the l-arginine-NO-cGMP-PKG-K+ ATP channel pathways in CCI model.

Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat

A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.

T-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

Isobolographic Analyses of Proglumide-Celecoxib Interaction in Rats with Painful Diabetic Neuropathy.

Preclinical Research The aim of the present study was to analyze the antihyperalgesic and antiallodynic interaction between the non-selective cholecystokinin (CCK) antagonist receptor, proglumide, and the selective cyclooxygenase-2 inhibitor, celecoxib in streptozotocin (STZ)-induced diabetic rats. Hyperalgesia was evaluated in the formalin test and tactile allodynia using von Frey filaments. Isobolographic analyses were employed to define the nature of the compound interactions, using a fixed dose ratio (0.5:0.5). Proglumide (20-160 mg/kg) and celecoxib (0.3-30 mg/kg) in these fixed dose ratio combinations induced dose-dependent antihyperalgesia and an antiallodynic effect in diabetic rats. ED40 values were calculated for the treatments and an isobologram was constructed. Theoretical ED40 values for combination proglumide-celecoxib estimated from the isobolograms for antihyperalgesic and antiallodynic activity (30.50 ± 1.90 mg/kg and 45.81 ± 4.55 mg/kg, respectively) were obtained, while experimental ED40 values for this antihyperalgesic and antiallodynic combined effect (13.83 ± 0.65 mg/kg and 17.74 ± 3.57 mg/kg; respectively) were significantly different. Coadministration of proglumide-celecoxib showed an interaction index value of 0.45 ± 0.03 for the antihyperalgesic effect and 0.39 ± 0.08 for the antiallodynic activity, indicating a synergistic interaction. These data suggest that proglumide and celecoxib can interact synergistically to reduce hyperalgesic and allodynic behaviors in diabetic neuropathy. This combination could be useful to treat neuropathic pain in diabetic patients. Drug Dev Res 78 : 116-123, 2017. ©2017 Wiley Periodicals, Inc.

Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF-α Modulation and Activation of Dopaminergic and Opioidergic Systems.

Preclinical Research The aim of this study was to determine the antiallodynic effect of acute administration of the β-lactam antimicrobials, ceftriaxone (CFX) and clavulanic acid (CLAV), for the control of established pain on a model of neuropathic pain (NP). We also investigated the involvement of dopaminergic and opioidergic pathways as well as alterations in serum concentrations of TNF-α in the antiallodynic actions of these drugs. CFX, CLAV, or gabapentin (GAP), a reference drug, were administered i.p. twelve days after constriction of the sciatic nerve in rats. Mechanic and cold allodynia were evaluated for 3 h and alterations in serum concentration of TNF-α determined. Both CFX and CLAV had antiallodynic effects in response to mechanical and cold stimulation, similar to GAP. The antiallodynic effects of CFX and CLAV were blocked by haloperidol (HAL), a D2 receptor antagonist, and by naloxone (NLX), an opioid receptor antagonist. Additionally, serum TNF-α levels were attenuated following CFX and CLAV administration. These results suggest that acute administration of CFX and CLAV may represent a promising approach for treating the acute allodynia of NP, and that the mechanisms involved in these effects involve activation of dopaminergic and opioidergic pathways as well as modulation of TNF-α production. Drug Dev Res 78 : 105-115, 2017. © 2017 Wiley Periodicals, Inc.

Enhancement of Antinociceptive Effect by Co-administration of Amitriptyline and Crocus Sativus in a Rat Model of Neuropathic Pain.

The aim of this study was to evaluate the anti-nociceptive effects of a low, sub-effective dose of amitriptyline, in combination with the different doses of ethanolic and aqueous extracts of Crocus sativus following sciatic nerve chronic constriction injury (CCI) in rats. Amitriptyline (3, 10 and 30 mg/Kg, i.p.) and the extracts (25, 50 and 100 mg/Kg, i.p.), were separately administered at the time of CCI for 7 consecutive days. In combination therapy, the sub-antinociceptive dose of amitriptyline (3 mg/Kg) was given with the three different doses of extracts for seven days. Mechanical allodynia, thermal allodynia and thermal hyperalgesia were evaluated by von Frey, acetone and radiant heat tests, respectively, 1 day before and on days 3, 5 and 7 after surgery. Co-administration of amitriptyline (3 mg/Kg) with aqueous extract (50, 100 mg/Kg,) produced more potent cold anti-allodynic (P < 0.01 and P < 0.001, respectively) as well as thermal anti-hyperalgesic (P < 0.05) effects than that produced by each of them. Amitriptyline (3 mg/Kg) plus ethanolic extract (50, 100 mg/Kg) produced more potent cold anti-allodynic (P < 0.05 and P < 0.001, respectively) as well as thermal anti-hyperalgesic (P < 0.05) effects as compared with the sum effects produced by each of them. Mechanical anti-allodynia effect was only potentiated with the co-administration of amitriptyline with the high dose of aqueous extract (100 mg/Kg, P < 0.001). Our study supports the use of saffron as an adjunctive to amitriptyline to improve the therapeutic outcome in the management of neuropathic pain.

Antihyperalgesic, Antiallodynic, and Antinociceptive Effects of Cebranopadol, a Novel Potent Nociceptin/Orphanin FQ and Opioid Receptor Agonist, after Peripheral and Central Administration in Rodent Models of Neuropathic Pain

Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i.pl.), intracerebroventricular (i.c.v.), or intrathecal (i.th.) administration. In STZ-treated rats, cebranopadol (i.pl.) reduced mechanical hypersensitivity in the ipsilateral paw, but had no effect at the contralateral paw. In CCI rats, cebranopadol (i.pl.) showed antiallodynic activity at the ipsilateral paw. After administration to the contralateral paw, cebranopadol also showed ipsilateral antiallodynic activity, but with reduced potency and delayed onset. In diabetic mice, cebranopadol i.th. and i.c.v. decreased heat hyperalgesia with full efficacy and similar potency for both routes. Cebranopadol also produced significant antinociception in nondiabetic controls. Thus, cebranopadol exerts potent and efficacious antihyperalgesic, antiallodynic, and antinociceptive effects after local/peripheral, spinal, and supraspinal administration. The contralateral effects after i.pl. administration were likely due to systemic redistribution. After central administration of cebranopadol, antihyperalgesic efficacy is reached at doses that are not yet antinociceptive. This study shows that cebranopadol is effective after peripheral as well as central administration in nociceptive and chronic neuropathic pain. Thus, it may be well-suited for the treatment of chronic pain conditions with a neuropathic component.

Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1′-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model

Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7–10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7–9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1′-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4–6) [NH2CR(NH)]—in which R=Me, Ph, and NH2—at yields of 60–95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.

Cerebrolysin reduces mechanical allodynia in a rodent model of peripheral inflammation

Cerebrolysin (Cbl) is a neuropeptide preparation of cerebroproteins that crosses the blood brain barrier displaying neuroprotective properties and promoting neurogenesis. Limited evidence exists on the efficacy of Cbl for the treatment of pain, with many studies focusing on neuropathic pain associated to diabetes. Therefore, we designed a study to test the hypothesis that Cbl would reduce mechanical allodynia in a rat model of peripheral inflammation induced by administration of complete Freund’s adjuvant (CFA) in the hind paw. We found that acute administration of Cbl was effective in reducing mechanical allodynia but not peripheral inflammation in the CFA model of inflammatory pain. Our investigation supports further investigation into the therapeutic applications and mechanisms underlying the anti-allodynic effects of Cbl in inflammatory pain.

Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression

BackgroundOxaliplatin, a widely used anticancer drug against metastatic colorectal cancer, can induce acute peripheral neuropathy, which is characterized by cold and mechanical allodynia. Activation of glial cells (e.g. astrocytes and microglia) and increase of pro-inflammatory cytokines (e.g. IL-1β and TNF-α) in the spinal cord play a crucial role in the pathogenesis of neuropathic pain. Our previous study demonstrated that Gyejigachulbu-Tang (GBT), a herbal complex formula, alleviates oxaliplatin-induced neuropathic pain in rats by suppressing spinal glial activation. However, it remains to be elucidated whether and how Buja (Aconiti Tuber), a major ingredient of GBT, is involved in the efficacy of GBT.MethodsCold and mechanical allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) in Sprauge-Dawley rats were evaluated by a tail immersion test in cold water (4 °C) and a von Frey hair test, respectively. Buja (300 mg/kg) was orally administrated for five consecutive days after the oxaliplatin injection. Glial activation in the spinal cord was quantified by immunohistochemical staining using GFAP (for astrocytes) and Iba-1 (for microglia) antibodies. The amount of spinal pro-inflammatory cytokines, IL-1β and TNF-α, were measured by ELISA.ResultsSignificant behavioral signs of cold and mechanical allodynia were observed 3 days after an oxaliplatin injection. Oral administration of Buja significantly alleviated oxaliplatin-induced cold and mechanical allodynia by increasing the tail withdrawal latency to cold stimuli and mechanical threshold. Immunohistochemical analysis showed the activation of astrocytes and microglia and the increase of the IL-1β and TNF-α levels in the spinal cord after an oxaliplatin injection. Administration of Buja suppressed the activation of spinal astrocytes without affecting microglial activation and down-regulated both IL-1β and TNF-α levels in the spinal cord.ConclusionsOur results indicate that Buja has a potent anti-allodynic effect in a rat model of oxaliplatin-induced neuropathic pain, which is associated with the inhibition of activation of astrocytes and release of pro-inflammatory cytokines in the spinal cord. Thus, our findings suggest that administration of Buja could be an alternative therapeutic option for the management of peripheral neuropathy, a common side-effect of oxaliplatin.

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain.

BackgroundL-acetylcarnitine, a drug marketed for the treatment of chronic pain, causes analgesia by epigenetically up-regulating type-2 metabotropic glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that analgesia could outlast the duration of L-acetylcarnitine treatment in models of inflammatory and neuropathic pain.ResultsA seven-day treatment with L-acetylcarnitine (100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete Freund adjuvant mouse model of chronic inflammatory pain. L-Acetylcarnitine-induced analgesia persisted for at least 14 days after drug withdrawal. In contrast, the analgesic effect of pregabalin, amitryptiline, ceftriaxone, and N-acetylcysteine disappeared seven days after drug withdrawal. L-acetylcarnitine treatment enhanced mGlu2/3 receptor protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting analgesic effect of L-acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with pregabalin, amitryptiline, tramadol, or L-acetylcarnitine produced a significant antiallodynic effect, with pregabalin displaying the greatest efficacy. In mice treated with pregabalin, tramadol or L-acetylcarnitine the analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor protein levels in the dorsal horns of the spinal cord.ConclusionsOur findings suggest that L-acetylcarnitine has the unique property to cause a long-lasting analgesic effect that might reduce relapses in patients suffering from chronic pain.

Antiallodynic effect of intrathecal resiniferatoxin on neuropathic pain model of chronic constriction injury

Injuries and/or dysfunctions in the somatosensory system can lead to neuropathic pain. Transient receptor potential vanilloid sub‑type 1 (TRPV1) play an important role in the development of allodynia and hyperalgesia following injury and the ensuing inflammatory conditions. Resiniferatoxin (RTX) is an ultrapotent synthetic TRPV1 agonist and many different administration routes are available for different mechanisms and different effects. RTX is used intraperitonially as amodel of neuropathic pain or epidurally and topically to produce prolonged analgesic effects. However, the use of RTX is controversial because its neurotoxicity and margin of safety have not been addressed adequately. The present study evaluates the effect of intrathecal RTX on the induction and allodynia behavior of animals submitted to neuropathic pain by chronic constriction injury (CCI). 160 Swiss mice were randomly distributed into two groups: intrathecal pre‑treatment group (PRE) aiming the effect in induction of allodynia and late intrathecal treatment group (POST) to evaluate the antiallodynic effect of the RTX on mechanical nociceptive threshold evaluated by the Von Frey hair filaments. Additionally, we evaluated the expression of TRPV1 in dorsal root ganglia (DRG) by western blotting after PRE‑ and POST‑treatment with RTX. Our results showed that the CCI mice developed prolonged mechanical allodynia‑like behavior in ipsilateral paw after surgery up to 24hours. The PRE‑ and POST‑treatment groups presented significant antiallodynic effects in ipsilateral paw for 24hours. Only the POST‑treatment group showed asignificant reduction of expression of the TRPV1 receptor after CCI. The presented data demonstrated that both PRE‑ and POST‑treatment with RTX given intrathecally produced potent antiallodynic activities in CCI mice and that POST‑treatment can reduce TRPV1 expression in DRG, suggesting that POST‑treatment RTX can revert central sensitization and its associated allodynia.

The efficacy of combination treatment of gabapentin and electro-acupuncture on paclitaxel-induced neuropathic pain.

Paclitaxel, a chemotherapeutic drug, induces severe peripheral neuropathy. Gabapentin (GBT) is a first line agent used to treat neuropathic pain, and its effect is mediated by spinal noradrenergic and muscarinic cholinergic receptors. Electro-acupuncture (EA) is used for treating various types of pain via its action through spinal opioidergic and noradrenergic receptors. Here, we investigated whether combined treatment of these two agents could exert a synergistic effect on paclitaxel-induced cold and mechanical allodynia, which were assessed by the acetone drop test and von Frey filament assay, respectively. Significant signs of allodynia were observed after four paclitaxel injections (a cumulative dose of 8 mg/kg, i.p.). GBT (3, 30, and 100 mg/kg, i.p.) or EA (ST36, Zusanli) alone produced dose-dependent anti-allodynic effects. The medium and highest doses of GBT (30 and 100 mg/kg) provided a strong analgesic effect, but they induced motor dysfunction in Rota-rod tests. On the contrary, the lowest dose of GBT (3 mg/kg) did not induce motor weakness, but it provided a brief analgesic effect. The combination of the lowest dose of GBT and EA resulted in a greater and longer effect, without inducing motor dysfunction. This effect on mechanical allodynia was blocked by spinal opioidergic (naloxone, 20 μg), or noradrenergic (idazoxan, 10 μg) receptor antagonist, whereas on cold allodynia, only opioidergic receptor antagonist blocked the effect. In conclusion, the combination of the lowest dose of GBT and EA has a robust and enduring analgesic action against paclitaxel-induced neuropathic pain, and it should be considered as an alternative treatment method.

Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain.

PurposeBaclofen and morphine have shown efficacy against mechanical allodynia after infraorbital nerve chronic constriction injury (IoN-CCI). No drug effects have yet been reported on spontaneous trigeminal neuropathic pain. It has been proposed that the directed face grooming behavior that also develops following IoN-CCI offers a measure of spontaneous trigeminal neuropathic pain.Subjects and methodsWe examined the effects of a continuous 1-week infusion of 30 mg/day carbamazepine (the first-line drug treatment for trigeminal neuralgia), 1.06 mg/day baclofen, 4.18 mg/day clomipramine, and 5 mg/day morphine on spontaneous and mechanically evoked pain behavior (ie, directed face grooming and von Frey testing) in IoN-CCI rats.ResultsIsolated face grooming was significantly reduced in rats receiving carbamazepine and baclofen but not in clomipramine- or morphine-treated rats. All drugs showed significant antiallodynic effects; carbamazepine showed the strongest effects, whereas clomipramine had only minor efficacy.ConclusionThe tested drugs have differential effects in the IoN-CCI model, and different neuropathological mechanisms may underlie the different somatosensory symptoms in this model. A mechanism-based approach may be needed to treat (trigeminal) neuropathic pain. The present data support IoN-CCI as a model of trigeminal neuralgia in which isolated face grooming is used as a measure of spontaneous neuropathic pain.

The Synergistic Effect of Intrathecally Administered Dexmedetomidine and Ketorolac on Mechanical Allodynia in Rats with Spinal Nerve Ligation

Objectives This research was carried out to identify the synergistic effect of dexmedetomidine and ketorolac on neuropathic pain alleviation. Methods The anti-allodynic effect of intrathecal dexmedetomidine and ketorolac was investigated in rats after L5 spinal nerve ligation (SNL). Mechanical allodynia was assessed using Von Frey filaments. Every day for 3 consecutive days, beginning on the 10th day after SNL, behavioral tests were carried out at 1, 2, and 4 hr after drug injection. Results Significant increases in ipsilateral paw withdrawal thresholds (PWTs) were observed 1, 2, and 4 hr after drug injection in the groups of rats which received intrathecal injection of either dexmedetomidine (group D) or ketorolac (group K), compared to group S (P&amp;lt; 0.05). And group DK, which received simultaneous intrathecal injection of both dexmedetomidine and ketorolac, showed statistically significantly higher ipsilateral PWTs than groups D and K, which received only one of them (P&amp;lt; 0.05). Conclusions The results of this research demonstrated the anti-allodynic effect of dexmedetomidine and ketorolac on neuropathic pain induced by SNL in rats. They also suggest that synergistic analgesia can be induced by the simultaneous injection of dexmedetomidine and ketorolac, and that combination therapy is an effective approach to treating chronic neuropathic pain syndrome.

Participation of central GABAA receptors in the trigeminal processing of mechanical allodynia in rats.

Here we investigated the central processing mechanisms of mechanical allodynia and found a direct excitatory link with low-threshold input to nociceptive neurons. Experiments were performed on male Sprague-Dawley rats weighing 230-280 g. Subcutaneous injection of interleukin 1 beta (IL-1β) (1 ng/10 µL) was used to produce mechanical allodynia and thermal hyperalgesia. Intracisternal administration of bicuculline, a gamma aminobutyric acid A (GABAA) receptor antagonist, produced mechanical allodynia in the orofacial area under normal conditions. However, intracisternal administration of bicuculline (50 ng) produced a paradoxical anti-allodynic effect under inflammatory pain conditions. Pretreatment with resiniferatoxin (RTX), which depletes capsaicin receptor protein in primary afferent fibers, did not alter the paradoxical anti-allodynic effects produced by the intracisternal injection of bicuculline. Intracisternal injection of bumetanide, an Na-K-Cl cotransporter (NKCC 1) inhibitor, reversed the IL-1β-induced mechanical allodynia. In the control group, application of GABA (100 µM) or muscimol (3 µM) led to membrane hyperpolarization in gramicidin perforated current clamp mode. However, in some neurons, application of GABA or muscimol led to membrane depolarization in the IL-1β-treated rats. These results suggest that some large myelinated Aβ fibers gain access to the nociceptive system and elicit pain sensation via GABAA receptors under inflammatory pain conditions.

Cardamonin attenuates hyperalgesia and allodynia in a mouse model of chronic constriction injury-induced neuropathic pain: Possible involvement of the opioid system

Neuropathic pain arises from the injury of nervous system. The condition is extremely difficult to be treated due to the ineffectiveness and presence of various adverse effects of the currently available drugs. In the present study, we investigated the antiallodynic and antihyperlagesic properties of cardamonin, a naturally occurring chalcone in chronic constriction injury (CCI)-induced neuropathic pain mice model. Our findings showed that single and repeated dose of intra-peritoneal administration of cardamonin (3, 10, 30mg/kg) significantly inhibited (P<0.001) the chronic constriction injury-induced neuropathic pain using the Hargreaves plantar test, Randall-Selitto analgesiometer test, dynamic plantar anesthesiometer test and the cold plate test in comparison with the positive control drug used (amitriptyline hydrochloride, 20mg/kg, i.p.). Pre-treatment with naloxone hydrochloride (1mg/kg, i.p.) and naloxone methiodide (1mg/kg, s.c) significantly reversed the antiallodynic and antihyperalgesic effects of cardamonin in dynamic plantar anesthesiometer test and Hargreaves plantar test, respectively. In conclusion, the current findings demonstrated novel antiallodynic and antihyperalgesic effects of cardamonin through the activation of the opioidergic system both peripherally and centrally and may prove to be a potent lead compound for the development of neuropathic pain drugs in the future.

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain.

BackgroundThere is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP.MethodsThe reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min.ResultsThe coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h.ConclusionsThese results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects.

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.