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

Main methods: The 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 findings: Local peripheral ipisilateral, but not contralateral, administration of HD (10-100 μg/paw) produced a dose-dependent antinociceptive effect in rats. The CB 1 and CB 2 receptor antagonists AM281 (0.3-30 μg/paw) and SR144528 (0.3-30 μg/paw), respectively, reduced the antinociceptive effect of HD (100 μg/paw). In addition, methiothepin (0.03-0.3 μg/paw) and naloxone (5-50 μg/paw) significantly reduced HD-induced antinociception (100 μg/paw). In vitro, HD reduced only to a minor extent the hydrolysis of anandamide catalyzed by FAAH. Significance: HD local administration produces antinociception that probably results from an indirect activation of peripheral CB 1 and CB 2 cannabinoid receptors. Data suggest that 5-HT 1 and opioid receptors also participate in the antinociceptive effect of this compound. HD may have potential as analgesic drug

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effect of Diclofenac in the Rat 1

ABSTRACT The relationship between the pharmacokinetics and the antinociceptive effect of diclofenac was evaluated using the paininduced functional impairment model in the rat. Male Wistar rats were injected with uric acid in the knee joint of the right hind limb, which induced its dysfunction. Once the dysfunction was complete, animals received a p.o. dose of 0.56, 1, 1.8, 3.2, 5.6 or 10 mg/kg of sodium diclofenac, and the antinociceptive effect and drug blood concentration were simultaneously evaluated at selected times for a period of 6 h. Diclofenac produced a dose-dependent antinociceptive effect, measured as a recovery of the functionality of the injured limb. However, the onset of the antinociceptive effect was delayed with respect to blood concentrations. Moreover, the effect lasted longer than expected from pharmacokinetic data. Therefore, when functionality index was plotted against diclofenac blood concentration, an anticlockwise hysteresis loop was observed for all doses. Hysteresis collapse was achieved using the effect-compartment model, and the plot of functionality index against diclofenac concentration in the effect-compartment data was well fitted by the sigmoidal E max model. Our data suggest slow equilibrium kinetics between diclofenac concentration in blood and at its site of action, which leads to a delayed onset of the antinociceptive effect as well as a longer duration of the response resulting from drug accumulation in synovial fluid. Diclofenac is an NSAID that has been shown to be effective for relieving pain in rheumatic and nonrheumatic diseases On the other hand, it has been established that the relationship between pharmacokinetic properties and pharmacologic effect is the basis for a more rational drug regimen design, because it allows prediction of the time course of the intensity of the effect There are reports wherein the anti-inflammatory and antinociceptive effect of diclofenac cannot be directly explained by circulating concentrations in animals Materials and Methods Animals. Male Wistar rats (weighing, 180-220 g) from our own breeding facilities [Crl:(WI)BR], were used in this study. Animals were housed in a room with controlled temperature (22 Ϯ 1°C) for at least 2 days before the study. Food was withheld for 12 h before the Received for publication May 10, 1996. 1 This work is supported by CONACYT, grant 0250-M. ABBREVIATIONS: AUC, area under the blood concentration-time curve; AUC E , area under the functionality index-time curve; C, blood concentration; C max , maximal concentration; E max , maximal effect; E max obs , maximal observed effect; Ke0, transference rate constant from site effect; PIFIR, pain-induced functional impairment model in the rat; PE, polyethylene; NSAID, nonsteroidal anti-inflammatory drug; FI, functionality index

Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55

Background: Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB1 and CB2) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB1/CB2 receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors. Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors. According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration.Methods: This article reviews select relevant information about the potential role of GPR18 and GPR55 in the pathophysiology of pain.Results: This work summarized novel data supporting that, besides cannabinoid CB1 and CB2 receptors, GPR18 and GPR55 may be useful for pain treatment.Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55

Peripheral and Central Antinociceptive Action of Na\u3csup\u3e+\u3c/sup\u3e–K\u3csup\u3e+\u3c/sup\u3e–2Cl\u3csup\u3e−\u3c/sup\u3e Cotransporter Blockers on Formalin-Induced Nociception in Rats

The possible local peripheral and spinal (intrathecal) antinociceptive effect of Na+–K+–2Cl− cotransporter (NKCC) inhibitors was investigated in the rat formalin test. Nociceptive flinching behavior induced by formalin (1%) injection in the hind paw was assessed following administration of cotransporter inhibitors. Local peripheral pretreatment in the ipsilateral paw with bumetanide (ED30, 27.1±12.7 μg/paw), piretanide (ED30, 109.2±21.6 μg/paw) or furosemide (ED30, 34.3±5.0 μg/paw), but not vehicle (DMSO 100%), produced dose-dependent antinociception in phase 2 of the test. Local bumetanide had the greatest effect (∼70% antinociception). Bumetanide also inhibited formalin-induced flinching behavior during phase 1 (ED30, 105.6±99.1 μg/paw). Spinal intrathecal pretreatment with bumetanide (ED30, 194.6±97.9 μg), piretanide (ED30, 254.4±104.9 μg) or furosemide (ED30, 32.0±6.9 μg), but not vehicle (DMSO 100%), also produced antinociception in phase 2. In this case, only intrathecal furosemide reduced flinching behavior during phase 1 (ED30, 99.4±51.4 μg) and had the maximal antinociceptive effect in phase 2 (∼65% antinociception). The opioid receptor-antagonist naloxone (2 mg/kg, s.c.) did not reverse antinociception induced by either peripheral or spinal administration of NKCC blockers. Our data suggest that the Na+–K+–2Cl− cotransporter localized in sensory neurons at intraspinal and peripheral sites is involved in formalin-induced nociception

Peripheral and Central Antinociceptive Action of Na\u3csup\u3e+\u3c/sup\u3e–K\u3csup\u3e+\u3c/sup\u3e–2Cl\u3csup\u3e−\u3c/sup\u3e Cotransporter Blockers on Formalin-Induced Nociception in Rats

The possible local peripheral and spinal (intrathecal) antinociceptive effect of Na+–K+–2Cl− cotransporter (NKCC) inhibitors was investigated in the rat formalin test. Nociceptive flinching behavior induced by formalin (1%) injection in the hind paw was assessed following administration of cotransporter inhibitors. Local peripheral pretreatment in the ipsilateral paw with bumetanide (ED30, 27.1±12.7 μg/paw), piretanide (ED30, 109.2±21.6 μg/paw) or furosemide (ED30, 34.3±5.0 μg/paw), but not vehicle (DMSO 100%), produced dose-dependent antinociception in phase 2 of the test. Local bumetanide had the greatest effect (∼70% antinociception). Bumetanide also inhibited formalin-induced flinching behavior during phase 1 (ED30, 105.6±99.1 μg/paw). Spinal intrathecal pretreatment with bumetanide (ED30, 194.6±97.9 μg), piretanide (ED30, 254.4±104.9 μg) or furosemide (ED30, 32.0±6.9 μg), but not vehicle (DMSO 100%), also produced antinociception in phase 2. In this case, only intrathecal furosemide reduced flinching behavior during phase 1 (ED30, 99.4±51.4 μg) and had the maximal antinociceptive effect in phase 2 (∼65% antinociception). The opioid receptor-antagonist naloxone (2 mg/kg, s.c.) did not reverse antinociception induced by either peripheral or spinal administration of NKCC blockers. Our data suggest that the Na+–K+–2Cl− cotransporter localized in sensory neurons at intraspinal and peripheral sites is involved in formalin-induced nociception

Anti-inflammatory and anti-allodynic activities in mice of the essential oil and desmethylisoencecalin from <i>Zinnia grandiflora</i> Nuttall

Zinnia grandiflora (Asteraceae) is used to alleviate several painful disorders. The effects of an essential oil prepared by hydrodistillation from Z. grandiflora (EOZ) and its major compound on neuropathic pain, allodynia, and inflammation in mice were assessed. Headspace-solid phase microextraction analysis of an aqueous extract was also carried out. GC-MS analyses of all volatiles revealed that germacrene D (13.24%) and desmethylisoencecalin (DME) (13.24%) were the most abundant compounds. EOZ was effective in reducing inflammation and allodynia in mice. EOZ (300 mg/paw) reverted tactile allodynia more effectively than gabapentin (100 μg/paw). DME (0.1‒10 µg/paw) responses in the carrageenan model were concentration-dependent; the maximum effect was observed at 10 µg/paw, like that of diclofenac (30 μg/paw). In the spinal nerve ligation model, DME (0.1‒10 μg/paw) exerted a concentration-dependent anti-allodynic action; its effect was better than that of gabapentin. A method to quantify zinagrandinolide E in the crude drug was developed and validated.</p

Tonically Active α5GABAA Receptors Reduce Motoneuron Excitability and Decrease the Monosynaptic Reflex

Motoneurons, the final common path of the Central Nervous System (CNS), are under a complex control of its excitability in order to precisely translate the interneuronal pattern of activity into skeletal muscle contraction and relaxation. To fulfill this relevant function, motoneurons are provided with a vast repertoire of receptors and channels, including the extrasynaptic GABAA receptors which have been poorly investigated. Here, we confirmed that extrasynaptic α5 subunit-containing GABAA receptors localize with choline acetyltransferase (ChAT) positive cells, suggesting that these receptors are expressed in turtle motoneurons as previously reported in rodents. In these cells, α5GABAA receptors are activated by ambient GABA, producing a tonic shunt that reduces motoneurons’ membrane resistance and affects their action potential firing properties. In addition, α5GABAA receptors shunted the synaptic excitatory inputs depressing the monosynaptic reflex (MSR) induced by activation of primary afferents. Therefore, our results suggest that α5GABAA receptors may play a relevant physiological role in motor control

Dexamethasone Increases the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis

Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to assess the effect of dexamethasone on the success of dental anesthesia in patients with SIP. An information search was performed using PubMed and Google Scholar. The risk of bias of the included studies was evaluated with the Cochrane Collaboration’s risk-of-bias tool. The anesthetic success rate, pain intensity (VAS), and adverse effects were extracted. Data were analyzed using the Mantel–Haenszel test and odds ratio or the inverse variance and standardized mean difference. Dexamethasone increased the anesthetic success in comparison with placebo (n = 502; p n = 302; p n = 302; p n = 302; p < 0.0008; MD = −1.27; 95% CIs: −2.01 to −0.53) when compared with placebo. In conclusion, the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP

Supplementary figures -Supplemental material for ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia

<p>Supplemental material, Supplementary figures for ATF2, but not ATF3, participates in the maintenance of nerve injury-induced tactile allodynia and thermal hyperalgesia by Ana B Salinas-Abarca, Isabel Velazquez-Lagunas, Úrzula Franco-Enzástiga, Jorge E Torres-López, Héctor I Rocha-González and Vinicio Granados-Soto in Molecular Pain</p

The &amp;agr;5 subunit containing GABAA receptors contribute to chronic pain

It has been recently proposed that α5-subunit containing GABAA receptors (α5-GABAA receptors) that mediate tonic inhibition might be involved in pain. The purpose of this study was to investigate the contribution of α5-GABAA receptors in the loss of GABAergic inhibition and in formalin-induced, complete Freund's adjuvant (CFA)-induced and L5 and L6 spinal nerve ligation-induced long-lasting hypersensitivity. Formalin or CFA injection and L5 and L6 spinal nerve ligation produced long-lasting allodynia and hyperalgesia. Moreover, formalin injection impaired the rate-dependent depression of the Hofmann reflex. Peripheral and intrathecal pretreatment or post-treatment with the α5-GABAA receptor antagonist, L-655,708 (0.15-15 nmol), prevented and reversed, respectively, these long-lasting behaviors. Formalin injection increased α5-GABAA receptor mRNA expression in the spinal cord and dorsal root ganglia (DRG) mainly at 3 days. The α5-GABAA receptors were localized in the dorsal spinal cord and DRG colabeling with NeuN, CGRP, and IB4 which suggests their presence in peptidergic and nonpeptidergic neurons. These receptors were found mainly in small and medium sized neurons. Formalin injection enhanced α5-GABAA receptor fluorescence intensity in spinal cord and DRG at 3 and 6 days. Intrathecal administration of L-655,708 (15 nmol) prevented and reversed formalin-induced impairment of rate-dependent depression. These results suggest that α5-GABAA receptors play a role in the loss of GABAergic inhibition and contribute to long-lasting secondary allodynia and hyperalgesia