Decreased Pain Response Research Articles

Nocebo expectations rather than placebo expectations affect topical pain relief: A randomized clinical trial

Patients' expectations and beliefs regarding the potential benefits and harms of medical interventions may induce placebo and nocebo effects, and affect the response to pain therapies. In a randomized clinical trial, we examined the effect of placebo and nocebo expectations on pain relief and adverse events (AEs) in association with a topical treatment among 65 cancer survivors experiencing chronic musculoskeletal pain. Participants received either a 1% camphor-based topical pain patch or a placebo treatment for 14 days. We measured pain severity with the worst pain item of the Brief Pain Inventory (BPI) at baseline and 14 days and treatment expectations at baseline with validated expectation questionnaires. We found that high vs. low nocebo expectations decreased pain severity improvements by 2.5 points (95% confidence interval [CI] −3.8 to −1.2; p<0.001) on a 0–10 numeric rating scale of the BPI and pain response rate by 42.7% (95% CI 0.2–0.6; p<0.001) at day 14, irrespective of placebo expectation status or treatment arms. Patients with high vs. low nocebo expectations in the true arm reported 22.4% more unwanted AEs. High nocebo expectations were associated with increased AEs by 39.5% (odds ratio: 12.0, 95% CI 1.2, 145.5; p=0.029) and decreased pain response in the true arm vs. placebo. Our study demonstrated that nocebo expectations, rather than placebo expectations, elevate the risk of AEs and compromise the effect of topical pain interventions. The findings raise the possibility that nocebo expectations may worsen somatic symptoms through heightening central pain amplification and should be further investigated.

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 ...

Anti-nociceptive Activity of L-citrulline in Mice Using Formalin and Hot Plate Tests: Possible Mechanism of Action

Background: Peripheral pain regulation is a very complex phenomenon due to the numerous neural pathways responsible for it. Objectives: The current study aimed to determine the anti-nociceptive activity of L-citrulline and the possible role of opioidergic, nitric oxide (NO), and serotoninergic systems in mice using the formalin and hot plate tests. Methods: In this study, 300 male NMRI mice were divided into 2 groups: 150 mice were used for the formalin test and 150 for the hot plate test (tests 1-6) with 4 sub-groups in each (n=50). The formalin test determined pain caused by the injection of formalin in the hind paw, and the hot plate test recorded pain reactions caused by heat stimulation as response latency time. Further, time mice capable of staying on the rotarod bar were determined. Results: Morphine reduced licking and biting time and latency time in the hot plate (P&lt;0.05), while L-citrulline (50 and 100 mg/kg) decreased pain response and increased latency time compared to the control (P&lt;0.05). Further, pre-treatment with naloxone following L-citrulline increased licking and biting time in the formalin test and decreased latency time in the hot plate test (P&lt;0.05). In addition, pretreatment with L-NAME following L-citrulline diminished licking and biting time in the formalin test and increased latency time in the hot plate test (P&lt;0.05). Likewise, ad pre-treatment with ritanserin following L-citrulline reduced licking and biting time and latency time compared to control mice (P&lt;0.05). Similarly, licking and biting time and latency time were decreased by pre-treatment with ondansetron following L-citrulline. Finally, no significant disturbance was observed in motor coordination by L-citrulline (25, 50, and 100 mg/kg) at P&gt;0.05. Conclusion: It seems that L-citrulline has anti-nociceptive effects, and its role is mediated by opioidergic, NO systems, as well as 5-HT2 and 5-HT3 receptors. Further, L-citrulline did not disturb motor coordination.

Evaluation of Antiarthritic and Antinociceptive Effects of Cedrol in a Rat Model of Arthritis.

Pharmacological studies revealed that cedrol, a natural sesquiterpene, has antioxidant, anti-inflammatory, and analgesic properties. This study is aimed at evaluating the potential antiarthritic activity of cedrol in a rat experimental model of arthritis induced by using complete Freund's adjuvant (CFA). Arthritis was induced in Wistar rats by CFA (0.1 ml) injection. Cedrol (10 and 20 mg/kg) and indomethacin (5 mg/kg) were orally administered from day one and continued for 21 days. The antiarthritic activity was assessed through mechanical allodynia and thermal hyperalgesia responses, paw edema assessment, and arthritis scores. Serum TNF-α and IL-1β levels were measured for the evaluation of inflammation. Furthermore, serum oxidative stress markers, including malondialdehyde (MDA) and thiol levels, as well as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, were also assessed. Oral administration of cedrol and indomethacin significantly decreased paw edema and arthritis score. Besides, cedrol and indomethacin significantly decreased pain responses. In the serum of the CFA group, TNF-α, IL-1β, and MDA were higher, while thiol and SOD and GPx were lower than the control group. Treatment by cedrol and indomethacin corrected the biochemical parameters in the serum. In this study, cedrol offers potential antiarthritic properties through its anti-inflammatory and antioxidant effects.

Effects of mother-sung lullabies on vaccination-induced infant pain and maternal anxiety: A randomized controlled trial

PurposeThis study aimed to investigate the effects of mother-sung lullabies during vaccination on vaccine-induced pain in infants and anxiety in mothers. Design and methodsOur team conducted a randomized controlled trial with two parallel groups between March 4, 2020 and August 28, 2020, at two family health centers in Turkey. This study included 60 healthy-term infants (lullaby group: 30, control group: 30) aged two months, who received the Bacillus Calmette–Guérin (BCG) vaccine, and their mothers. We used the Information Form, the Neonatal Infant Pain Scale, the Intervention Follow-Up Form (including heart rate, oxygen saturation, and crying duration), and the State Anxiety Inventory as data collection tools. ResultsInfants in the lullaby group had significantly decreased pain responses than those in the control group (p < .05). Further, singing a lullaby resulted in significantly reduced maternal anxiety in the lullaby group compared to the control group (p < .05). ConclusionsThe lullaby singing method was effective for reducing infants' pain response and mothers' anxiety during vaccination. Practice implicationsThe lullaby method can be used to reduce pain during potentially painful procedures performed in infants and reduce anxiety in mothers.The study is registered under the ClinicalTrials.gov identifier NCT04692584.

Anti-nociceptive effect of gabapentin in mouse models of acute and chronic pain

Purpose: To investigate the anti-nociceptive effect of gabapentin in acute and chronic pain models.&#x0D; Methods: Four mouse models of pain were used in this study. These comprised thermal tests (hot plate and tail immersion tests), and chemical tests (formalin and acetic acid-induced writhing tests). A total of seventy-two (72) albino mice weighing 25 - 40 g (mean weight = 32.5 ± 5.1 g) were used. In each test, the mice were randomly assigned to three sets of 6 mice each: control group, celecoxib group and drug treatment group. Each test was performed at intervals of 30, 60 and 90 min.&#x0D; Results: During the acute phase, there was no significant decrease in foot raising (FR) or licking and biting (L &amp; B) episodes among the groups (p &gt; 0.05). However, these episodes were significantly (p &lt; 0.05) decreased in the second delayed phase, in the celecoxib and drug-treated groups, when compared with normal control group. Gabapentin significantly (p &lt; 0.05) decreased pain response throughout the course of the thermal tests. The number of writhes within 30 min were significantly reduced in celecoxib and gabapentin-treated animals, compared with negative control group (p &lt; 0.05). Gabapentin produced approximately 60 % protection of writhing, similar to that produced by celecoxib, the standard non-steroidal anti-inflammatory drug (NSAID) used (61 %).&#x0D; Conclusion: The results demonstrate that the gabapentin is effective against chronic inflammatory pain in mice and therefore can be potentially developed as an effective anti-inflammatory agent for humans.

Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats.

Fatty acid amide hydrolase inhibition may be used to control bladder function and pain by modulating endocannabinoid levels in cystitis. We studied the effect of the peripherally restricted fatty acid amide hydrolase inhibitor URB937 in bladder reflex activity and bladder pain using the lipopolysaccharide model of cystitis. We also correlated the URB937's effects with tissue levels of the endocannabinoids anandamide and palmitoylethanolamine. URB937 did not change the reflex activity of normal bladders. In inflamed bladders, URB937 had a U-shaped dose-response curve; following an initial cannabinoid receptor type 1-mediated reduction in pain responses and normalisation of bladder reflex activity, URB937 gradually increased both pain responses and bladder reflex activity through the transient receptor potential ion channel subfamily V member 1. Chronic cystitis increased the tissue levels of anandamide and decreased those of palmitoylethanolamine. At the dose that normalised bladder reflex activity and decreased pain responses, URB937 normalised the levels of anandamide and palmitoylethanolamine in the bladder. At high doses that induced excitatory effects, URB937 apparently did not change anandamide and palmitoylethanolamine levels, which therefore were in the range of the inflamed bladder. Fatty acid amide hydrolase inhibition results in complex changes in bladder endocannabinoid levels. The therapeutic effect of fatty acid amide hydrolase inhibitors is not related to increase in anandamide levels but rather a normalisation of the anandamide and palmitoylethanolamine level ratio.

Phytohormone abscisic acid elicits antinociceptive effects in rats through the activation of opioid and peroxisome proliferator-activated receptors β/δ

The phytohormone abscisic acid exists in animal tissues particularly in the brain. However, its neurophysiological effects have not yet been fully clarified. This study was designed to evaluate the possible antinociceptive effects of abscisic acid on animal models of pain and determine its possible signaling mechanism.Tail-flick, hot-plate and formalin tests were used to assess the nociceptive threshold. All experiments were carried out on male Wistar rats. To determine the role of Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and opioid receptors on the induction of abscisic acid antinociception, specific antagonists were injected 15 min before abscisic acid.The data showed that abscisic acid (5, 10 and 15 µg/rat, i.c.v.) significantly decreased pain responses in formalin test. In addition, it could also produce dose-dependent antinociceptive effect in tail-flick and hot-plate tests. Administration of PPARβ/δ antagonist (GSK0660, 80 nM, i.c.v.) significantly attenuated the antinociceptive effect of abscisic acid in all tests. The antinociceptive effects of abscisic acid were completely inhibited by naloxone (6 µg, i.c.v.) during the time course of tail-flick and hot-plate tests.The results indicated that the central injection of abscisic acid has potent pain-relieving property which is mediated partly via the PPAR β/δ and opioid signaling.

EIF4E phosphorylation regulates ongoing pain, independently of inflammation, and hyperalgesic priming in the mouse CFA model

Mitogen activated protein kinase-interacting kinase (MNK)-mediated phosphorylation of the mRNA cap binding protein eIF4E controls the translation of a subset of mRNAs that are involved in neuronal and immune plasticity. MNK-eIF4E signaling plays a crucial role in the response of nociceptors to injury and/or inflammatory mediators. This signaling pathway controls changes in excitability that drive acute pain sensitization as well as the translation of mRNAs, such as brain-derived neurotrophic factor (BDNF), that enhance plasticity between dorsal root ganglion (DRG) nociceptors and second order neurons in the spinal dorsal horn. However, since MNK-eIF4E signaling also regulates immune responses, we sought to assess whether decreased pain responses are coupled to decreased inflammatory responses in mice lacking MNK-eIF4E signaling. Our results show that while inflammation resolves more quickly in mice lacking MNK-eIF4E signaling, peak inflammatory responses measured with infrared imaging are not altered in the absence of this signaling pathway even though pain responses are significantly decreased. We also find that inflammation fails to produce hyperalgesic priming, a model for the transition to a chronic pain state, in mice lacking MNK-eIF4E signaling. We conclude that MNK-eIF4E signaling is a critical signaling pathway for the generation of nociceptive plasticity leading to acute pain responses to inflammation and the development of hyperalgesic priming.

Development of an experimental rat model of hyperammonemic encephalopathy and evaluation of the effects of rifaximin

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatic dysfunction. However, the precise mechanism of HE is unclear. To elucidate the mechanism, we developed a new rat model of HE with coma using a combination of subcutaneous splenic transposition, partial hepatectomy and portal vein stenosis. In this model, blood ammonia levels increase in the postcaval vein over time and markedly increase in the cerebrospinal fluid (CSF). The distribution of ammonia in the various blood vessels in the HE model suggests that the origin of peripheral blood and CSF ammonia is the mesenteric veins that drain blood from the gastrointestinal tract. Behavioral analysis revealed decreased pain response, increased passivity, and decreased pinna and corneal reflexes, followed by the development of coma. The development of coma in this model was frequent and reproducible. Increased S100 calcium-binding protein B (S100B: a biomarker for brain injury) in venous blood, as well as damaged brain tissue, increased intracranial pressure and cerebral edema were observed in rats with coma. A very high correlation was observed between the blood ammonia concentration in the postcaval vein and the onset of coma. Rifaximin, a poorly absorbed antibiotic that targets gut flora, significantly improved symptoms of HE. Based on these results, our rat model appears to reflect the pathological state of HE associated with acute liver failure and may be a useful model for analysis of hyperammonemic encephalopathy.

Low Back Pain Response to Pelvic Tilt Position: An Observational Study of Chiropractic Patients

ObjectiveThe aim of this study was to look for differences between patients with an increased pain response as compared with those with a decreased pain response. MethodsData were collected from consecutive new patients with lumbar or lumbopelvic pain in a chiropractic clinic. A pelvic tilt exercise was included in the initial examination, and pain response was noted. Analysis was made of pain and disability severity, as well as symptom location, chronicity, and other characteristics, before and after a course of chiropractic care. ResultsPatients with an increased pain response to pelvic tilt (n = 12) had higher levels of pain and disability at baseline than patients without (n = 34). There were no between-group differences in other aspects of their complaints; in age, sex, or body mass; or in the types of care they received (eg, manipulation, stretching, exercise instruction). On the average, both groups of patients showed improvement with chiropractic care, and there was no detectable difference in improvement between groups. ConclusionsThis study found that patients experiencing pain in response to a pelvic tilt maneuver may have a poorer precare status than patients with a decreased pain response.

Decreased pain responses of C–C chemokine receptor 5 knockout mice to chemical or inflammatory stimuli

Chemokines are small chemotactic cytokines that elicit many physiological and pathological effects through binding to their corresponding receptors. Recent studies have suggested that C–C chemokine receptor (CCR) 5 interacts with μ-opioid receptor and modifies a nociceptive reaction. We examined effects of CCR5 deficiency on pain responses by employing CCR5 knockout (KO) mice. We found that pain responses of CCR5 KO mice to chemical or inflammation stimuli were milder than those of CCR5 wild type (WT) mice. However, there was no remarkable change in thermal nociception. To prove the involvement of CCR5 deletion in lowered nociception, we examined pain reactions with CCR5 WT mice following treatment of a CCR5 antagonist (D-Ala1-peptide T-NH2, DAPTA). Chemical or inflammatory pain behavior was significantly relieved by intracerebroventricular infusion of the inhibitor. When we assessed expression level of μ-opioid receptor (MOR) in the periaqueductal gray where the receptors are critical for analgesic effects, immunoreactivity of MOR was significantly higher in CCR5 KO mice than WT mice without change in phosphorylation level of the receptor. Reduced nociceptive responses in CCR5 KO mice were moderated by administration of naloxone and d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), MOR antagonists. Our data indicate that CCR5 deficiency is related to up-regulation of MOR without an increase in the receptor desensitization which might result in increased analgesic effects against chemical or inflammatory stimuli. Alternatively, higher amount of opioid ligands in CCR5 mice might be linked to these results. Therefore, CCR5 appears to be a therapeutic target for treatment of pain related diseases such as inflammatory hyperalgesia.

Antagonism of stimulation-produced analgesia by naloxone and N-methyl-D-aspartate: role of opioid and N-methyl-D-aspartate receptors

The present study aims to investigate the influence of electrical stimulation of periaqueductal gray (PAG) following peripheral nerve injury and its modulation by naloxone and N-methyl-D-aspartate (NMDA). Chronic neuropathic pain was induced by chronic constriction injury of the sciatic nerve, and subsequently a cannula was implanted in the PAG area for the purpose of electrical stimulation and intra-PAG drug administration. Intra-PAG administration of morphine, ketamine, and their combination were found to elicit antinociceptive response on hot-plate test. Electrical stimulation of PAG was also observed to demonstrate decreased pain response on hot-plate test, and this effect was reversed by the administration of naloxone, NMDA, and their combination, when injected into the PAG area. These findings suggest that apart from the opioid receptors, probably NMDA receptors also have a role to play in stimulation-produced analgesia.

Behavioral Management of Migraine Headache Triggers: Learning to Cope with Triggers

The literature on migraine triggers is reviewed, including the most common triggers, interactions between triggers, the research evidence related to the capacity of self-reported triggers to precipitate headaches, and the neurobiologic pathways by which triggers induce migraine attacks. An argument is developed against the standard advice to avoid migraine triggers as the best way of preventing attacks, based on conceptual and practical criticisms, and consideration of cognate literatures on chronic pain, stress, and anxiety. A small number of studies suggest that exposure to headache triggers has the same effect as exposure to anxiety-eliciting stimuli, with short exposure associated with increased pain response and prolonged exposure associated with decreased pain response. On the basis of this literature, "learning to cope with triggers" is advocated, where controlled exposure and approach/confront strategies are used to manage migraine triggers, except in cases where such an approach would probably be inappropriate.

L-type calcium channel blockers, morphine and pain: Newer insights

Earlier, we had reported that co-administration of opioids and L-type calcium channel blockers (L-CCBs) like diltiazem could prove useful in the treatment of cancer pain. Much of this report was based upon earlier published work involving animal models of pain exposed to brief periods of noxious radiant heat without any tissue injury. However, pain in clinical situations usually result from tissue injury. Thus, the aim of the current investigation was to study the analgesic effect of this combination of drugs in the rat formalin test which is associated with actual tissue injury. Wistar rats (n=60) received either L-CCB (nifedipine/nimodipine/verapamil/diltiazem i.p.) or morphine (s.c.) or both drugs. The formalin test was done 30 min after morphine or placebo injection. The naloxone reversal test was also done. Administration of L-CCBs alone, particularly diltiazem, increased pain in the formalin test. In contrast, co-administration of these L-CCBs with morphine led to decreased pain response, though statistically significant decrease was noted only with nimodipine + morphine. Naloxone reversed this analgesic effect, indicating that it was primarily an opioid-mediated effect. The results show that administration of L-CCBs alone may prove counterproductive in the therapeutic management of pain (anti-analgesic effect). However, co-administration of both drugs (morphine and nimodipine) in quick succession could lead to adequate pain relief.

Sex Differences in the Relationship Between Maternal Negative Life Events and Children's Laboratory Pain Responsivity

Previous research has demonstrated links between psychosocial factors, including negative life events (NLE) and pain in children. This study examined sex differences in the relationship among mother-reported NLE, child NLE, mother somatization, and children's laboratory pain responses for heat, cold, and pressure pain tasks. We predicted that maternal NLE would be moderately associated with girls' pain responses but would not be associated with boys' pain responses. Participants were 176 nonclinical children (89 boys) aged 8 to 18 years (mean = 12.2, SD = 2.7) and their mothers. Mothers and children completed questionnaires assessing their perceptions of NLE experienced in the previous 12 months. Contrary to predictions, maternal NLE were related to pain responses in both boys and girls, although in opposite directions. Thus, increased maternal stress was associated with increased pain responses in girls but with decreased pain responses in boys. In addition, the impact of maternal NLE was only apparent for heat and pain tasks, indicating differential effects for various types of pain. The current findings underscore the importance of family variables in understanding sex differences in children's pain. Future research is needed to examine the mechanisms within the parent-child relationship that contribute to sex-differentiated pain outcomes, particularly under conditions of exacerbated parental stress.

Oral pregabalin reverses cold allodynia in two distinct models of peripheral neuropathic pain

A major symptom of persistent neuropathic pain, which may develop after peripheral nerve injury, is hypersensitivity (allodynia) to normally innocuous cold stimuli. Although the anticonvulsant pregabalin has been demonstrated to relieve neuropathic pain, both in preclinical models and clinically, the analgesic effect of the drug in animals has not been profiled for cold hypersensitivity. Therefore, we examined the effect of pregabalin (single oral dosing: 30, 100, 300 μmol/kg) on cold allodynia in two models of chronic neuropathic pain, the spared nerve injury (SNI) and the spinal nerve ligation (SNL) models. A significant antiallodynic effect was observed with pregabalin at all doses tested with a maximal effect of 71% (SNI) and 60% (SNL), respectively compared to vehicle. For comparison, only the highest dose tested of pregabalin (300 μmol/kg), significantly decreased pain responses in phase 2 of the rat formalin test (∼ 67% pain inhibition). However, pregabalin at this high dose also affected other centrally mediated behavioural functions, such as motor activity and anxiolytic behaviour in naïve animals, which could potentially interfere with the pain readout. The present study demonstrates that oral administration of pregabalin significantly reduces both cold allodynia induced in the SNI and the SNL models of neuropathic pain as well as formalin-induced nociception, albeit with different sensitivity and potency.

Effects of Mepyramine and Famotidine on the Physostigmine-Induced Antinociception in the Formalin Test in Rats

In this study, the effects of mepyramine (H1-receptor antagonist), famotidine (H2-receptor antagonist), physostigmine (a cholinesterase inhibitor) and atropine (muscarinic-receptor antagonist) have investigated on the formalin-induced nociception in rats. The effects of mepyramine and famotidine have also examined on nociceptive changes induced by physostigmine and atropine. Nociception was induced by intraplantar injection of formalin (50 microL, 1%) into the right hind paw and the time spent licking and biting of the injected paw, was taken as a measure of pain. Formalin induced a marked biphasic (first phase: 0-5 min and second phase: 15-45 min) pain response. The used drugs did not change the first phase of formalin-induced pain. Subcutaneous injection of physostigmine significantly (p<0.05) suppressed pain. Subcutaneous injection of atropine alone did not change the intensity of pain, but pretreatment with atropine significantly (p<0.05) prevented physostigmine-induced antinociception. Intraperitoneal injections of mepyramine and famotidine significantly (p<0.05) decreased pain response. Mepyramine did not significantly change, but famotidine significantly (p<0.05) prevented analgesic effect of physostigmine on pain. Atropine did not inhibit the antinociceptive effects of both mepyramine and famotidine on formalin-induced nociception. These results indicate that physostigmine through muscarinic cholinergic receptors suppresses the pain induced by formalin. Both H1 and H2 receptor antagonists produce antinociception. Histamine H2, but no H1 antagonists may be involved in physostigmine-induced antinociception.

Decreased pain response in mice following cortex-specific knockout of the N-methyl-d-aspartate NR1 subunit

Studies have shown that N-methyl-D-aspartate (NMDA) receptors play a critical role in pain processing at different levels of the central nervous system. In this study, we used cortex-specific NR1 knockout mice (C57BL/6 strain) to elucidate the role of cortical NMDA receptors in pain processes. On post-natal day 20, paw withdrawal latency (PWL) to a noxious thermal stimulus was measured in male and female knockout (KO), control (Ctrl), and C57BL/6 (C57) mice. Twenty-four hours later, the same mice were tested in the formalin-pain assay (20 microl of 5% formalin injected into one hind-paw). The results show that KO mice (both male and female) have significantly reduced pain responses during both early and late phases of formalin test, as compared with Ctrl and C57 mice (p<0.01). By contrast, no differences among groups were found in PWL to a noxious thermal stimulus. Taken together, these results demonstrate dissociation in the role of cortical NMDA receptors in mediating different types of pain.

Local administration of N‐acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats

The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) selectively activates group II metabotropic glutamate receptors (mGluRs). Systemic administration of inhibitors of the enzymes that inactivate NAAG results in decreased pain responses in rat models of inflammatory and neuropathic pain. These effects are blocked by a group II mGluR antagonist. This research tested the hypothesis that some analgesic effects of NAAG peptidase inhibition are mediated by NAAG acting on sensory neurite mGluRs at the site of inflammation. Group II mGluR agonists, SLx-3095-1, NAAG and APDC, or NAAG peptidase inhibitors, ZJ-43 and 2-PMPA, injected into the rat footpad reduced pain responses in carrageenan or formalin models. The analgesic effects of SLx-3095-1, APDC, ZJ-43, 2-PMPA and NAAG were blocked by co-injection of LY341495, a selective group II mGluR antagonist. Injection of group II mGluR agonists, NAAG or the peptidase inhibitors into the contralateral rat footpad had no effect on pain perception in the injected paw. At 10-100 microm ZJ-43 and 2-PMPA demonstrated no consistent agonist activity at mGluR2 or mGluR3. Consistent with the conclusion that peripherally administered NAAG peptidase inhibitors increase the activation of mGluR3 by NAAG that is released from peripheral sensory neurites, we found that the tissue average concentration of NAAG in the unstimulated rat hind paw was about 6 microm. These data extend our understanding of the role of this peptide in sensory neurons and reveal the potential for treatment of inflammatory pain via local application of NAAG peptidase inhibitors at doses that may have little or no central nervous system effects.