Evaluation Of Antinociceptive Effects Research Articles

The Anti-Calcitonin Gene-Related Peptide (Anti-CGRP) Antibody Fremanezumab Reduces Trigeminal Neurons Immunoreactive to CGRP and CGRP Receptor Components in Rats.

Treatment with the anti-CGRP antibody fremanezumab is successful in the prevention of chronic and frequent episodic migraine. In preclinical rat experiments, fremanezumab has been shown to reduce calcitonin gene-related peptide (CGRP) release from trigeminal tissues and aversive behaviour to noxious facial stimuli, which are characteristic pathophysiological changes accompanying severe primary headaches. To further decipher the effects of fremanezumab that underlie these antinociceptive effects in rats, immunohistochemistry and ELISA techniques were used to analyse the content and concentration of CGRP in the trigeminal ganglion, as well as the ratio of trigeminal ganglion neurons which are immunoreactive to CGRP and CGRP receptor components, 1-10 days after subcutaneous injection of fremanezumab (30 mg/kg) compared to an isotype control antibody. After fremanezumab treatment, the fraction of trigeminal ganglion neurons which were immunoreactive to CGRP and the CGRP receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) was significantly lowered compared to the control. The content and concentration of CGRP in trigeminal ganglia were not significantly changed. A long-lasting reduction in CGRP receptors expressed in trigeminal afferents may contribute to the attenuation of CGRP signalling and antinociceptive effects of monoclonal anti-CGRP antibodies in rats.

Evaluation of antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide in rats.

Acute pain is the most common type of pain. The aim of the present work was carried out to study the antinociceptive effect and pharmacological mechanisms of thiocyanoacetamide (Thm) in rats exposed to thermal pain stimulus. The anti-nociceptive effect of the newly synthesized compound, Thm was studied in comparison to that of paracetamol (Para), dexamethasone (Dex), and morphine (Morph) at different doses using a hot plate test at a constant temperature of 48.0 ± 0.5°C. During this test, the latency time (LT) was measured when rats express pain behavior. Then, the pharmacological mechanisms were determined using receptor-antagonist drugs. Firstly, the obtained result showed pain modulation of the pretreated rats with Thm at 10 mg/kg dose proved by the delay of latency time during the thermal test. This significant antinociceptive activity of the thiocyanoacetamide was more effective than that of paracetamol or dexamethasone and less than that of morphine. Second, the pretreatment with acebutolol or risperidone antagonist drugs of, respectively, adrenergic and serotonin receptors demonstrated the elimination of pain modulation with Thm 10 mg/kg dose proved by a short latency time of rat's response in hot plate test. In this case, the pharmacological mechanism of Thm was characterized by the involvement of adrenergic and serotoninergic systems. It may be concluded that Thm constitutes a promising antinociceptive drug including beta-adrenergic and serotoninergic targets. The present study warrants further investigation to determine the side effects of this compound.

Effect of Pregabalin and Gabapentin on Nociceptive Behaviors Induced by Spinal Nerve Ligation

Pain is defined as an unpleasant sensory and emotional experience, associated with actual or potential tissue damage. According to its neurobiological mechanism, pain is classified into nociceptive, inflammatory, dysfunctional, and neuropathic. Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory nervous system. Both pregabalin and gabapentin are pharmaceuticals used as validation drugs in experimental models of NP. Pregabalin was shown to produce significant antihyperalgesic and antiallodynic effects. Gabapentin is used as a reference compound for new analgesics and reduces tactile allodynia in rats. The aim of this work is to evaluate pregabalin and gabapentin effects on nociceptive behaviors induced by spinal nerve ligation (SNL). Female Wistar rats of 140 - 160 g were used, divided into five groups: Naive, SHAM, SNL rats treated with saline solution, SNL rats treated with pregabalin 30 mg/kg p.o., SNL rats treated with gabapentin 300 mg/kg p.o. Nociceptive behaviors were determined by the up and down method. In the establishment of SNL-induced allodynic behavior, a reduction in paw withdrawal threshold was observed in the time course, which was present from day 1 and it was maintained for 28 days post-ligation. With the administration of pregabalin and gabapentin, anti-allodynic behavior was observed in the time course and in the areas under the curve (AUC) of the time course of anti-allodynic behavior, significant difference was observed between pregabalin, and gabapentin groups compared to vehicle with a value of p < 0.0001. The results showed pregabalin and gabapentin induce an antinociceptive effect in rats subjected to SNL.

Mechanism of Ginkgolide B Amelioration of Neuropathic Pain Induced by Chronic Constriction Injury

Activation of NOD-like receptor protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of neuropathic pain. Ginkgolide B contributes to the suppression of NLRP3 inflammasome activation to prevent hypoxic-ischemic brain injury. However, the role of ginkgolide B on neuropathic pain has not been reported yet. We have shown that administration of ginkgolide B lowered pain threshold measured by paw-withdrawal threshold and paw-withdrawal latency in rats subjected to chronic constriction injury. Nerve fibers in rats postchronic constriction injury were swollen, and the fibrous structure was disordered. Treatment with ginkgolide B attenuated the nerve fiber swelling and reduced the disordered fibrous structure. Ginkgolide B dosage dependently attenuated chronic constriction injury-induced increase of proinflammatory cytokines. Protein expression of NLRP3 and its downstream targets (caspase 1 and IL-1β) were increased by chronic constriction injury and reduced by ginkgolide B. Lastly, ginkgolide B counteracted with the promotive effects of chronic constriction injury on protein expression of TLR4 and p-NF-κB. In conclusion, ginkgolide B demonstrated anti-inflammatory and antinociceptive effects in rats' model with neuropathic pain by suppression of TLR4-NF-κB-mediated NLRP3 inflammasome activation.

Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats

The use of Δ9-tetrahydrocannabinol (THC) by inhalation using e-cigarette technology grows increasingly popular for medical and recreational purposes. This has led to development of e-cigarette based techniques to study the delivery of THC by inhalation in laboratory rodents. Inhaled THC reliably produces hypothermic and antinociceptive effects in rats, similar to effects of parenteral injection of THC. This study was conducted to determine the extent to which the hypothermic response depends on interactions with the CB1 receptor, using pharmacological antagonist (SR141716, AM-251) approaches. Groups of rats were implanted with radiotelemetry devices capable of reporting activity and body temperature, which were assessed after THC inhalation or injection. SR141716 (4 mg/kg, i.p.) blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. SR141716 was unable to block the initial hypothermia caused by THC inhalation, but temperature was restored to normal more quickly. Alterations in antagonist pre-treatment time, dose and the use of a rat strain with less sensitivity to THC-induced hypothermia did not change this pattern. Pre-treatment with SR141716 (4 mg/kg, i.p.) blocked hypothermia induced by i.v. THC and reversed hypothermia when administered 45 or 90 min after THC (i.p.). SR141716 and AM-251 (4 mg/kg, i.p.) sped recovery from, but did not block, hypothermia caused by vapor THC in female rats made tolerant by prior repeated THC vapor inhalation. The CB2 antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB1 receptor activation.

Антиноцицептивные эффекты внутрибрюшинного введения цитиколина на моделях острой боли у крыс линии Вистар

Цель исследования - изучение дозозависимого эффекта мультимодального препарата цитиколина на моделях острой боли у крыс линии Вистар. Методы. Оценку изменения индивидуальной болевой чувствительности у животных проводили с помощью 2 стандартных тестов: «Tail flick» и «Hot plate». Проведено 2 серии опытов. В 1-й и 2-й сериях опытов определяли пороги болевой чувствительности (ПБЧ) у животных до и через 1 час после внутрибрюшинного введения цитиколина в дозах 500 и 1000 мг/кг. Результаты. Введение цитиколин в дозе 500 мг/кг оказывает антиноцицептивное действие: ПБЧ повышался по тестам Hot рlate и Hot рlate. Увеличение дозы цитиколина до 1000 мг/кг не оказывало более выраженного антиноцицептивного действия. Заключение. Введение цитиколина оказывает антиноцицептивные эффекты у крыс, что может свидетельствовать о холинергической активации, индуцированной цитиколином. The aim was to study the dose-dependent effect of the multimodal drug citicoline on models of acute pain in Wistar rats. Methods. Assessment of changes in individual pain sensitivity was performed using 2 standard tests, Tail Flick and Hot Plate. Two series of experiments were carried out. In the 1st and 2nd series of experiments, pain thresholds (PS) were determined prior to and one hour after intraperitoneal citicoline administration at doses of 500 and 1000 mg/kg. Results. Administration of citicoline 500 mg/kg had an antinociceptive effect: PS increased both in the Tail Flick and in the Hot Plate tests. Increasing the citicoline dose to 1000 mg/kg did not exert a more pronounced antinociceptive effect. Conclusion. Citicoline exerts antinociceptive effects in rats, which may indicate the cholinergic activation induced by citicoline.

Synergistic interaction between docosahexaenoic acid and diclofenac on inflammation, nociception, and gastric security models in rats.

Preclinical Research & Development The addition of polyunsaturated fatty acids to nonsteroidal anti-inflammatory drugs can increase their antinociceptive activity and produce a gastroprotective effect. The aim of the present study was to examine the effects of the interaction between docosahexaenoic acid (DHA) and diclofenac on inflammation (fixed ratios 1:1, 1:3, and 3:1), nociception (fixed ratio 1:3), and gastric injury in rats. DHA, diclofenac, or combinations of DHA and diclofenac produced anti-inflammatory and antinociceptive effects in rat. The administration of diclofenac produced significant gastric damage, but this effect was not observed with either DHA or the DHA-diclofenac combinations. Effective dose (ED30 ) values were estimated for each individual drug and analyzed isobolographically. The anti-inflammatory experimental ED30 values were 6.97 mg/kg (1:1 fixed ratio), 1.1 mg/kg (1:3 fixed ratio), and 11.34 mg/kg (3:1 fixed ratio). These values were significantly lower (p < .05) than the theoretical ED30 values: 67.94 mg/kg (1:1), 35.37 mg/kg (1:3), and 100.51 mg/kg (3:1). The antinociceptive experimental value was 1.25 mg/kg (1:3 fixed ratio). This value was lower (p < .05) than the theoretical ED30 , which was predicted to be 15.92 mg/kg. These data indicate that the DHA-diclofenac combinations interact at the systemic level, produce minor gastric damage, and potentially have therapeutic advantages for the clinical treatment of inflammatory pain.

Mechanistic Evaluation of Antinociceptive Effects of Bioactive Guided Fractions of Barleria prionitis

Barleria prionitis Linn.(Acanthaceae) is a prickly shrub and traditionally whole plant is used as anti-inflammatory, expectorant, analgesic, diuretic, antirheumaticand antidiabetic. This study was conducted to investigate the antinociceptive and CNS depressant activity of ethanolic extract and the fractions of B. prionitis in mice. Ethanol extract and its fractions were tested at a dose of 200 and 400 mg/kg. Ethanol, petroleum ether and chloroform fractions demonstrated significant antinociceptive activity at 400 mg/kg and significantly increased the latency in hot plate test and the action was antagonised by naloxone, indicating a potential opioid-like mechanism. In conclusion, the ethanol, pet ether and chloroform fractions of B. prionitis markedly demonstrated the antinociceptive action. The CNS depressant and good protective effect on pain stimuli suggest that the possible mechanisms appear to be due to involvement of opioid and/or peripheral receptors.

The potential effects of Melicope ptelefolia root extract as an anti-nociceptive and anti-inflammatory on animal models

The demand of herbal medicine has been increasing for the purpose of reducing the side effects of modern medicine. Melicope ptelefolia (M. ptelefolia) is a local Malaysian plant claimed to have many benefits for health. This study was performed to evaluate the potential of M. ptelefolia root extract as anti-nociceptive and anti-inflammatory agents in rats. The anti-nociceptive activity of M. ptelefolia root extracts (50 and 100mg/kg) was evaluated using acetic acid-induced writhing and tail immersion test, while the anti-inflammatory activity was studied using carrageenan-induced paw edema test. M. ptelefolia root extract significantly inhibited the pain stimulant in acetic acid-induced writhing test, however it did not exert any significant change in the tail immersion test. Nevertheless, the mean reaction time in tail immersion test of M. ptelefolia root extract increased as the doses of extract increased. Furthermore, M. ptelefolia root extract at both doses showed significant anti-inflammatory activity by reducing paw edema volume (p<0.05). In conclusion, methanol root extract of M. ptelefolia possesses anti-inflammatory effects and anti-nociceptive effects in rats.

The influence of thiamin on the efficacy of pregabalin in rats with spinal nerve ligation (SNL)-induced neuropathic pain

Objective: The thiamin is often used in the treatment of neuropathy, and pregabalin is often used to treat neuropathic pain. Our study examined the influence of thiamin on the efficacy of pregabalin in a rat model of spinal nerve ligation (SNL)-induced neuropathic pain.Methods: Sprague-Dawley male rats were randomly divided into six groups. The neuropathic pain-relieving properties were measured by plantar test, cold plate test, and hot plate test after administration of pregabalin (i.v) and/or thiamin (i.p) in SNL rats 14 days after operation.Results: In the therapy period, pregabalin, or thiamin alone all produced antinociceptive effects in rats with neuropathic pain. And combination treatment of thiamin and pregabalin resulted in an enhanced pain relief compared to the administration of pregabalin or thiamin alone.Conclusion: Combination of thiamin and pregabalin produces an additive antinociceptive effect in neuropathic pain rats, this drug combination may offer a beneficial treatment option for neuropathic pain.

Antinociceptive effects of sinomenine in a rat model of postoperative pain.

This study examined the antinociceptive effects of sinomenine in a rat model of postoperative pain. Male and female rats were subjected to a surgical incision in the right hind paw, and the von Frey filament test was used to measure mechanical hypersensitivity after drug or vehicle treatment (p.o. or i.p.). Rats were treated daily with sinomenine before or after the surgery and the AUCs of the antinociceptive effects measured during a 4h period were calculated to determine the ED50 values of sinomenine. The anti-hyperalgesic effects of different doses of a combination of sinomenine and acetaminophen (paracetamol) were assessed in another group of rats. Dose combinations were determined by using a fixed ratio dose-addition analysis method. Sinomenine (5-80mg·kg(-1) ) produced dose-dependent antinociceptive effects in rats that had been subjected to surgery and this effect lasted for 4h. The potency of sinomenine, given i.p. or p.o., did not differ between male and female rats. However, sinomenine was fourfold more potent when given i.p. than p.o. The GABAA receptor antagonist bicuculline blocked the antinociceptive effects of sinomenine. The antinociceptive effect of a daily treatment with sinomenine remained stable throughout the course of postoperative pain. Pretreatment with sinomenine did not alter the mechanical hypersensitivity post-surgery. The combination of sinomenine with acetaminophen produced an infra-additive interaction. Sinomenine demonstrated significant antinociceptive activity against postoperative pain and may be a useful novel pharmacotherapy for the management of postoperative pain.

Pharmacologically inhibiting GluR2 internalization alleviates neuropathic pain.

Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments, so it is critical to find new drugs for this condition. Recently, the cellsurface trafficking of pain-related receptors has been suggested as an important mechanism underlying persistent neuropathic pain. Here, we used the short peptide GluA2-3y, which specifically inhibits the GluA2-dependent endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and tested its anti-nociceptive effect in the periaqueductal grey (PAG) of intact rats and rats with neuropathic pain. Intra-PAG injection of 0.15, 1.5, 7.5, and 15 pmol of GluA2-3y induced dose-dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats, suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation. Furthermore, GluA2-3y had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation. Interestingly, the intra-PAG injection of 15 pmol GluA2-3y had an analgesic effect similar to 10 μg (35 nmol) morphine in rats with neuropathic pain. Taken together, our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation, and inhibiting GluA2 endocytosis with GluA2-3y has potent analgesic effects in rats with neuropathic pain. These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain.

Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor AIP induced antinociception in rats with mononeuropathy

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine- dependent protein kinase, which has been implicated in pain modulation at different levels of the central nervous system. The present study was performed in rats with mononeuropathy induced by left common sciatic nerve ligation. Unilateral sciatic nerve loose ligation produced decreases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation. Intra-nucleus accumbens (NAc) injection of 3μg, 6μg and 12μg of myristoylated autocamtide-2-inhibitory peptide (AIP), the CaMKII inhibitor, dose-dependently increased the HWL to noxious thermal and mechanical stimulation in rats with mononeuropathy. Furthermore, intra-NAc administration of morphine, the HWL to noxious thermal and mechanical stimulation increased markedly, and there were no significant differences between morphine group and AIP group. Taken together, the results showed that intra-NAc injection of AIP induced significant antinociceptive effects in rats with mononeuropathy, indicating that CaMKII may play an important role in the transmission and/or modulation of nociceptive information in the NAc in rats with mononeuropathy.

Distribution in Rats Internal Organs of Intraperitoneally Given 125I-Labeled Heptapeptide [2-8]-Leucopyrokinin ([2-8]-LPK), a Truncated Analog of Insect Neuropeptide Leucopyrokinin.

It was previously found that synthetic, insect-derived octapeptide leucopyrokinin (LPK) applied directly into the lateral brain ventricle induced asignificant antinociceptive effect in rats. Its synthetic truncated analog heptapeptide[2-8]-leucopyrokinin displayed astronger antinociceptive effect in comparison to native LPK. Moreover it was previously found ahigh accumulation of these both 125I-labeled peptides in adrenals, as well as in hypothalamus and in hippocampus of rats brain. The aim of the present study was to assess the distribution of 125I-labeled[2-8]-leucopyrokinin in rats' internal organs an in several parts of the brain after peripheral -intraperitoneal (i.p.) administration. The study was performed on male Wistar rats. Asynthetic[2-8]-leucopyrokinin ([2-8]-LPK) was iodinated with Na125I. On the day of experiment asolution of 125I-[2-8]-LPK was i.p. injected and the next after 1 and 24 hanimals were sacrificed by decapitation. Radioactivity levels in samples of parts of the brain and of internal organs were determined by counter Gamma Auto Count. Auniform, low accumulation 125I-[2-8]-LPK was found in evaluated samples of the brain and in internal organs. The results of the present study indicate aweak penetration into the brain and internal organs of intraperitoneally applied 125I-[2-8]-LPK in rats and correspond with previously determined weak biological effects of i.p. injected LPK and[2-8]-LPK.

Nicotinic acetylcholine receptor α7 subunit is involved in the cobratoxin-induced antinociception in an animal model of neuropathic pain

In this study we report that cobratoxin (CbTX), a long-chain postsynaptic α-neurotoxin isolated from the Thailand cobra, Naja naja kaouthia, has antinociceptive effect in rats with neuropathic pain. The neuropathic pain model was established in rats with partial sciatic nerve ligature (PSNL) method. The pain response was examined behaviorally with mechanical paw withdrawal and thermal paw withdrawal method. Different doses (0.56, 1.12 and 4.50 μg/kg) of CbTX were injected intrathecally. Injection of CbTX resulted in a significant dose-dependent antinociception as evidenced by increased mechanical withdrawal threshold and thermal withdrawal latency. CbTX also induces a significant dose-dependent inhibition of pain-evoked unit discharges of thalamic parafascicular neurons. Both the behavioral mechanical and thermal antinociception and the inhibition of pain-evoked discharges of neurons in thalamic parafascicular nucleus in PSNL model could be mimicked by PUN282987, selective α7 nicotinic AChR (α7 nAChR) agonist and reversed by methyllycaconitine (MLA) selective α7 nAChR antagonist. In summary, these results suggested that AChR α7 subunit was involved in the antinociceptive action of CbTX for neuropathic pain and might be the candidate target for analgesic drug design.

Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor KN93 induced antinociception in rats with mononeuropathy

The present study was conducted on rats with mononeuropathy induced by left common sciatic nerve ligation. Unilateral sciatic nerve loose ligation produced decreases of the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation. Intra-nucleus accumbens (NAc) injection of 1μg, 3μg and 6μg of KN93, the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor, dose-dependently increased the HWL in mononeuropathic rats. Furthermore, intra-NAc administration of morphine, the HWL to noxious thermal and mechanical stimulation increased markedly, and there were no significant differences between morphine group and KN93 group. The results demonstrated that intra-NAc injection of KN93 induced significant antinociceptive effects in rats with mononeuropathy, indicating CaMKII may play important roles in transmission of nociceptive information in the NAc of mononeuropathic rats.

Palmitoylethanolamide is a New Possible Pharmacological Treatment for the Inflammation Associated with Trauma

The endogenous fatty acid palmitoylethanolamide (PEA) is one of the members of N-acyl-ethanolamines family. PEA was identified more than five decades ago and was shown to reduce allergic reactions and inflammation in animals along with influenza symptoms in humans. Interest in this compound faded, however, until the discovery that one of its structural analogs, anandamide (arachidonoylethanolamide), serves as an endogenous ligand for cannabinoid receptors, the molecular target of Δ9-tetrahydrocannabinol in marijuana. Since this finding, PEA has been shown to inhibit peripheral inflammation and mast-cell degranulation, as well as to exert neuroprotective and antinociceptive effects in rats and mice. These actions are also mediated by PPAR-α activation and are accompanied by a decrease in nitric oxide production, neutrophil influx, and expression of proinflammatory proteins such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition to the hypothesis that PEA has potent immunoregulatory properties, recent data have demonstrated that PEA may also play a key role in the regulation of complex systems involved in the inflammatory response, pruritus, neurogenic and neuropathic pain. In this review, we discuss briefly the present understanding therapeutic mechanisms of PEA and the novel possible PEA clinical use for the treatment of several inflammatory diseases and trauma.

Palmitoylethanolamide is a New Possible Pharmacological Treatment for the Inflammation Associated with Trauma

The endogenous fatty acid palmitoylethanolamide (PEA) is one of the members of N-acyl-ethanolamines family. PEA was identified more than five decades ago and was shown to reduce allergic reactions and inflammation in animals along with influenza symptoms in humans. Interest in this compound faded, however, until the discovery that one of its structural analogs, anandamide (arachidonoylethanolamide), serves as an endogenous ligand for cannabinoid receptors, the molecular target of Δ9-tetrahydrocannabinol in marijuana. Since this finding, PEA has been shown to inhibit peripheral inflammation and mast-cell degranulation, as well as to exert neuroprotective and antinociceptive effects in rats and mice. These actions are also mediated by PPAR-α activation and are accompanied by a decrease in nitric oxide production, neutrophil influx, and expression of proinflammatory proteins such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition to the hypothesis that PEA has potent immunoregulatory properties, recent data have demonstrated that PEA may also play a key role in the regulation of complex systems involved in the inflammatory response, pruritus, neurogenic and neuropathic pain. In this review, we discuss briefly the present understanding therapeutic mechanisms of PEA and the novel possible PEA clinical use for the treatment of several inflammatory diseases and trauma.

N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception

AimsTo investigate the local antinociceptive effect as well as the possible mechanisms of action of a novel analogue of palmitoylethanolamide (PEA) N-(4-methoxy-2-nitrophenyl)hexadecanamide (HD) in the rat formalin test. Main methodsThe formalin test was used to assess the antinociceptive activity of HD in vivo. The hydrolysis of anandamide catalyzed by fatty acid amide hydrolase (FAAH) was used to determine the action of HD on FAAH activity in vitro. Key findingsLocal peripheral ipisilateral, but not contralateral, administration of HD (10–100μg/paw) produced a dose-dependent antinociceptive effect in rats. The CB1 and CB2 receptor antagonists AM281 (0.3–30μg/paw) and SR144528 (0.3–30μg/paw), respectively, reduced the antinociceptive effect of HD (100μg/paw). In addition, methiothepin (0.03–0.3μg/paw) and naloxone (5–50μg/paw) significantly reduced HD-induced antinociception (100μg/paw). In vitro, HD reduced only to a minor extent the hydrolysis of anandamide catalyzed by FAAH. SignificanceHD local administration produces antinociception that probably results from an indirect activation of peripheral CB1 and CB2 cannabinoid receptors. Data suggest that 5-HT1 and opioid receptors also participate in the antinociceptive effect of this compound. HD may have potential as analgesic drug.

Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats: New concepts in mu opioid receptor pharmacology: From a symposium on new concepts in mu-opioid pharmacology

Herkinorin is the first μ opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of β-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin's antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinociceptive effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states.