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Achillea biebersteinii is a perennial aromatic herb that grows in the Mediterranean area. The leaves of this plant are used in foods as bittering and appetizing agents. In folk medicine, it is used for the treatment of stomachache and abdominal pain. In this study, the analgesic effect of A. biebersteinii methanolic flower extract was tested in three pain models, namely: writhing, tail-flick and paw-licking (formalin) tests. A. biebersteinii extract inhibited abdominal cramps produced by acetic acid. The effect of A. biebersteinii was better than that of 70 mg/kg indomethacin. In tail flick, A. biebersteinii extract increased latency at 30 min and was as effective as 100 mg/kg diclofenac sodium. In formalin test, A. biebersteinii extracts decreased paw-licking and flinching response in early and late phases. Atropine blocked the action of A. biebersteinii extract (300 mg/kg) in the late phase of formalin test as well as in writhing and tail-flick tests. GC-MS analysis revealed that ascaridole and iso-ascaridole were the main constituents of A. biebersteinii flower extract. In conclusion, this study shows for the first time that the antinociceptive effect of A. biebersteinii is mediated by the cholinergic receptor.

Background: The aim of this study was to evaluate the effect of vitamin E co-administration with celecoxib in thermal and inflammatory pain in two model of pain assessment including thermal tail flick test of acute pain and formalin induced inflammatory model in adult male rats., Methods: Seventy two male Wistar rats were divided into a vehicle received intraperitoneally olive oil, indomethacin (20 mg/kg), vitamin E (100, 200 and 400 mg/kg), celecoxib (3, 10, 30 and 60 mg/kg) groups, and combination groups received the combination of vitamin E (100 and 200 mg/kg) and celecoxib (3, 10 and 30 mg/kg). All drugs were dissolved in olive oil. Antinociceptive effect in tail-flick was measured using Area Under Curve (AUC) of responses and Maximum Possible Effect (%MPE) and pain score was used for antinociceptive response in formalin test., Results: Vitamin E and celecoxib changed time course of pain scores in a dose related manner in formalin test but not in tail-flick test. Vitamin E (200 mg/kg) had no effect and merely 60 mg/kg of celecoxib increased %MPE and AUC in tail-flick. The combination of vitamin E (100 or 200 mg/kg) with celecoxib (3 or 10 mg/kg) decreased pain scores compared to vehicle in both phases of formalin test, while in chronic phase (II) the pain scores of combination groups were also decreased compared to vitamin E and celecoxib. However, in tail-flick test the combination of ineffective doses of vitamin E (200 mg/kg) and celecoxib (10 and 30 mg/kg) increased %MPE and AUC compared to vehicle but not compared to celecoxib or vitamin E., Conclusions: Vitamin E and celecoxib showed a dose related antinociceptive effect in inflammatory but not in thermal model of acute pain. However the co-administration of vitamin E with celecoxib caused a significant increase in the antinociceptive effect which was similar to indomethacin, as a standard anti-inflammatory drug. So we suggest the concomitant use of vitamin E with celecoxib and other NSAIDs for potentiation of both anti- inflammatory and analgesic response, as well as the reduction of cardiovascular side effects of celecoxib., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Despite the impact of pain in cognitive dysfunctions and affective disorders has been largely studied, the research that examines pain dimensions in cognitive impairment or dementia is still scarce. In patients with Alzheimer's disease (AD) and related dementias, management of pain is challenging. While the sensory-discriminative dimension of pain is preserved, the cognitive-evaluative and the affective-motivational pain dimensions are affected. Due to the complexity of the disease and the poor self-reports, pain is underdiagnosed and undertreated. In confluence with an impaired thermoregulatory behavior, the patients' ability to confront environmental stressors such as cold temperature can put them at risk of fatal accidental hypothermia. Here, 3xTg-AD mice demonstrate that the sensorial-discriminative threshold to a noxious cold stimulus, as measured by the latency of tail-flicking, was preserved at early and advances stages of disease (7 and 11 month-old, respectively) as compared to age-matched (adulthood and middle aged, respectively) non-transgenic mice (NTg). In both genotypes, the sensory deterioration and poor thermoregulatory behavior associated to age was observed as an increase of tail-flick response and poor sensorimotor performance. At both stages studied, 3xTg-AD mice exhibited BPSD (Behavioral and Psychological Symptoms of Dementia)-like alterations in the corner, open-field, dark-light box and the T-maze tests. In the adult NTg mice, this nociceptive withdrawal response was correlated with copying with stress-related behaviors. This integrative behavioral profile was lost in both groups of 3xTg-AD mice and middle aged controls, suggesting derangements in their subjacent networks and the complex interplay between the pain dimensions in the elderly with dementia., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

It was established that stimulation of the lateral hypothalamus (LH) can induce antinociception. Previous studies showed a role for the ventral tegmental area (VTA) and nucleus accumbens (NAc) in antinociception induced by LH stimulation through the orexinergic system. In this study, we tried to assess the involvement of dopamine D1-like receptors within the VTA and NAc in the LH stimulation-induced antinociception. Male Wistar rats were unilaterally implanted with two separate cannulae into the LH and VTA or NAc. Animals received intra-VTA or intra-accumbal infusion of SCH-23390, as a D1-like dopamine receptor antagonist (0.125, 0.25, 1 and 4 μg/rat), 2 min before intra-LH administration of carbachol (125 nM/rat). The antinociceptive effects of SCH-23390 were measured by using a tail-flick analgesiometer and represented as maximal possible effect (%MPE). Results showed that intra-VTA and/or accumbal administration of SCH-23390 could prevent carbachol-induced antinociception. These findings revealed that D1-like dopamine receptors within the VTA and NAc play an important role in antinociceptive effect induced by chemical stimulation of the LH., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management. [ABSTRACT FROM AUTHOR]

Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the mesolimbic dopaminergic pathway, plays a fundamental role in modulating pain and is differentially influenced by stressful events. Since we previously demonstrated the marked association of intra-NAc dopamine receptors with forced swim stress-evoked analgesia in acute pain state, this research was conducted to consider the contribution of intra-accumbal D1- and D2-like dopamine receptors to modulating effects of exposure to restraint stress in pain-related behaviors during the tail-flick test. Stereotaxic surgery was executed to implant a guide cannula within the NAc in male Wistar rats. On the test day, different concentrations of SCH23390 and Sulpiride as D1- and D2-like dopamine receptor antagonists, respectively, were unilaterally microinjected within the NAc. The vehicle animals received saline or 12 % DMSO (0.5 µl) instead of SCH23390 or Sulpiride into the NAc, respectively. Five minutes following receiving drug or vehicle, animals were restrained for 3 h and then their acute nociceptive threshold was measured for a 60-min period by the tail-flick test. Our data revealed that RS considerably enhanced antinociceptive reaction in acute pain states. The analgesia evoked by RS dramatically declined following blocking either D1- or D2-like dopamine receptors in the NAc, an effect was more noticeable by D1-like dopamine receptor antagonist. These findings indicated that intra-NAc dopamine receptors are considerably mediated in the RS-produced analgesia in acute pain states, suggesting their possible role in psychological stress and disease. • Restraint stress evoked antinociceptive responses in acute pain model. • Blocking intra-NAc D1/D2 dopamine receptors diminished restraint stress-induced analgesia. • The role of D1-like receptor in alteration of SIA was more prominent than that of D2-like receptor. • Intra-NAc SCH23390 or Sulpiride without exposure to stress had no impact on the pain threshold. [ABSTRACT FROM AUTHOR]

The effect of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 (Taphalgin), a synthetic derivative of dermorphine, was evaluated in the tail-flick test in mice after a single subcutaneous (s.c.) injection. Taphalgin significantly prolongs the tail-flick latency when administered in the dose range 0.01 – 5 mg/kg. The analgesic effect of a single s.c. injection of Taphalgin at 1 mg/kg exceeds the effect of morphine hydrochloride at the same dose. The effect of Taphalgin at 0.5 mg/kg is comparable to that of morphine hydrochloride at 1 mg/kg. The magnitude and duration of the analgesic effect grow as the dose of Taphalgin increases from 0.5 to 1.5 and 4.5 mg/kg. The maximum 4-h duration of the analgesic effect is observed at doses of 1.5 and 4.5 mg/kg. [ABSTRACT FROM AUTHOR]

Studies have indicated that stress-related symptoms can lead to hormonal and neural changes, affecting the pain threshold and nociceptive behaviors. The precise role of orexin receptors (OX1r and OX2r) in stress-induced analgesia (SIA) remains an inquiry yet to be comprehensively elucidated. The current investigation aimed to assess the impact of acute immobilization restraint stress on pain-related behavioral responses after administering antagonists targeting OX1r and OX2r in a rat model using the tail-flick test. After a period of five to seven days post-stereotaxic surgery in CA1, the baseline tail-flick latency (TFL) was recorded for each animal. Subsequently, rats were unilaterally administered varying doses of the OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), the OX2r antagonist (TCS OX2 29; 1, 3, 10, and 30 nmol), or a vehicle (0.5 μl solution containing 12% DMSO) through an implanted cannula. Following a 5-min interval, the animals were subjected to a restraint stress (RS) lasting for 3 h. The tail-flick test was conducted after the stress exposure, and the TFLs were assessed at 60-min intervals. The findings of this study revealed that RS elicits antinociceptive responses in the tail-flick test. Microinjection of OX1r and OX2r antagonists into the CA1 attenuated RS-induced analgesia during the tail-flick test. Furthermore, the results underscored the preeminent role of OX2 receptors in modulating SIA. In conclusion, the orexin system localized within the hippocampal CA1 region may, in part, contribute to the manifestation of SIA in the context of acute pain. [ABSTRACT FROM AUTHOR]

The complicated relevance between stress and pain has been identified. Neurotransmitters and neuropeptides of various brain areas play a role in this communication. Pain inhibitory response is known as stress-induced analgesia (SIA). The studies demonstrated that the nucleus accumbens (NAc) is critical in modulating pain. As a neuropeptide, orexin is crucially involved in initiating behavioral and physiological responses to threatening and unfeeling stimuli. However, the role of the orexin receptors of the NAc area after exposure to restraint stress (RS) as acute physical stress in the modulation of acute pain is unclear. One hundered twenty adult male albino Wistar rats (230–250 g) were used. Animals were unilaterally implanted with cannulae above the NAc. The SB334867 and TCS OX2 29 were used as antagonists for OX1r and OX2r, respectively. Different doses of the antagonists (1, 3, 10, and 30 nmol/0.5 µl DMSO) were microinjected intra-NAc five minutes before exposure to RS (3 hours). Then, the tail-flick test as a model of acute pain was performed, and the nociceptive threshold (Tail-flick latency; TFL) was measured in 60-minute time set intervals. According to this study's findings, the antinociceptive effects of RS in the tail-flick test were blocked during intra-NAc administration of SB334867 or TCS OX2 29. The RS as acute stress increased TFL and deceased pain-like behavior responses. The 50 % effective dose values of the OX1r and OX2r antagonists were 12.82 and 21.64 nmol, respectively. The result demonstrated contribution of the OX1r into the NAc was more remarkable than that of the OX2r on antinociceptive responses induced by the RS. Besides, in the absence of RS, the TFL was attenuated. The current study's data indicated that OX1r and OX2r into the NAc induced pain modulation responses during RS in acute pain. In conclusion, the findings revealed the involvement of intra-NAc orexin receptors in improving SIA. • Acute stress suppresses antinociceptive effects in the animal model of acute pain. • Blockade of OX1r in the NAc diminished the antinociceptive responses induced by RS. • Blockade of OX2r in the NAc diminished the antinociceptive responses induced by RS. • The contribution of OX1r in the NAc is more prominent than OX2r in modulating SIA. [ABSTRACT FROM AUTHOR]

Background: Exposure to stressful experiences is often accompanied by suppressing pain perception, referred to as stress‐induced analgesia. The neuropeptides orexins are essential in regulating the mechanism that responds to stressful and painful stimuli. Meanwhile, the ventral tegmental area (VTA), as a part of descending pain inhibitory system, responds to noxious stimuli. This study aimed to investigate the role of intra‐VTA administration of orexin receptor antagonists on stress‐induced antinociceptive responses in the animal model of acute pain. Method: Ninety‐three adult Wistar rats weighing 230–250 g were unilaterally implanted by a cannulae above the VTA. Animals were pretreated with different doses (1, 3, 10 and 30 nM/0.3 μl) of SB334867 as the orexin‐1 receptor antagonist and TCS OX2 29 as the orexin‐2 receptor antagonist into the VTA, just 5 min before 6 min exposure to forced swim stress (FSS). Nociceptive threshold was measured using the tail‐flick test as a model of acute pain. Results: The results showed that exposure to FSS could significantly increase analgesic responses. Moreover, intra‐VTA administration of SB334768 and TCS OX2 29 blocked the antinociceptive effect of FSS in the tail‐flick test. Conclusion: The findings suggest that OX1 and OX2 receptors in the VTA might modulate the antinociceptive behaviours induced by FSS in part. Significance: Acute exposure to physical stress suppresses pain‐related behaviors in the animal model of acute pain. Blockade of the OX1 and OX2 receptors in the VTA attenuates antinociceptive responses induced by FSS. The contribution of the OX2 receptors in the VTA is more predominant than OX1 receptors in stress‐induced analgesia. [ABSTRACT FROM AUTHOR]

Purpose: The nociceptin receptor (NOP) was discovered in 1994 and was designated opioid-like receptor; activation of NOP leads to reduced neuronal excitability. Although suggested by the anatomical localization of NOP in brain or spinal cord, the cardiovascular or nociceptive effects of its endogenous ligand, nociceptin, are equivocal. Taking advantage from intrathecal application of nociceptin to simultaneously activate NOP on sympathetic preganglionic neurons in the intermediolateral column (IML) and superficial laminae of dorsal horn, we investigated whether the nociceptin-induced cardiovascular effects engage the participation of baroreflex, and whether the concurrently elicited changes in blood pressure and pain responses are interrelated.Methods: NOPs in the thoracic spinal cord of ICR or C57BL/6 mice were identified with immunofluorescence staining and were activated through intrathecal administration of nocicetpin. The elicited changes in cardiovascular parameters and tail-flick nociceptive responses were measured.Results: Positive immunoreactivity against NOP colocalized with neurons in the IML and superficial dorsal horn layers of thoracic spinal cord. Intrathecal administration of nociceptin (1, 2, or 5 nmol) elicited a significant and dose-dependent decrease in blood pressure or heart rate that was paralleled by reduced baroreflex-mediated sympathetic vasomotor tone and mirrored by augmented cardiac vagal baroreflex, alongside prolonged tail-flick latency with an efficacy of hypotension <<< antinociception. Coadministration of the specific NOP antagonist, UFP101 (10 nmol), blunted all nociceptin-elicited responses. However, restoring blood pressure to baseline level failed to affect the antinociceptive actions of nociceptin.Conclusion: Activation of thoracic spinal NOP in ICR and C57BL/6 mice induces blood pressure and heart rate by decreasing the sympathetic outflow of both arms of the baroreflex arc to the blood vessels and the heart, and the antinociceptive responses to nociceptin are independent of and disproportional to its cardiovascular actions. [ABSTRACT FROM AUTHOR]

Despite the availability of the current drug arsenal for pain management, there is still a clinical need to identify new, more effective, and safer analgesics. Based on our earlier study, newly synthesized 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 10b and 13b, seem to be promising as potential analgesics. The current study was designed to investigate whether novel derivatives attenuate nociceptive response in animals subjected to thermal or chemical noxious stimulus, and to compare this effect to reference drugs. The antinociceptive effect of novel compounds was studied using the tail-flick and formalin test. Pretreatment with novel compounds at all studied doses increased the latency time in the tail-flick test and decreased the licking time during the early phase of the formalin test. New derivatives given at the medium and high doses also reduced the late phase of the formalin test. The achieved results indicate that new derivatives dose-dependently attenuate nociceptive response in both models of pain and exert a lack of gastrotoxicity. Both studied compounds act more efficiently than indomethacin, but not morphine. Compound 13b at the high dose exerts the greatest antinociceptive effect. It may be due to the reduction of nociceptor sensitization via prostaglandin E2 and myeloperoxidase levels decrease.

The opioid pharmacological profile of cis-(-)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a-d and 6a-d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(-)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(-)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment. [ABSTRACT FROM AUTHOR]

The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a–d and 6a–d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(−)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(−)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.

Highlights: [•] Analgesia is the most common feature shared by the cannabinoid and opioid systems. [•] The role of the cannabinoid system in the morphine-induced analgesia is uncertain. [•] Peripheral and intrathecal morphine analgesia is altered in cnr1KO and cnr2KO mice. [•] This attenuation is neither caused by a MOP malfunction nor by its downregulation. [ABSTRACT FROM AUTHOR]

Valeriana officinalis has been extensively used as a herbal remedy in traditional medicine. However, there is no clear evidence on the antinociceptive effects of this plant. The aim of our study was to evaluate the effect of Valeriana officinalis hydroalcoholic extract on pain modulation and its possible mechanism in mice. Adult male Balb/c mice were randomly divided into nine experimental groups. They received i.p. injections of saline, hydroalcoholic root extract of Valeriana officinalis (800, 200, or 50 mg/kg), and morphine; four groups received Valeriana (800 mg/kg) + antagonists of the systems involved in antinociception effects, naloxone, ondansetron, metoclopramide, or scopolamine. Tail-flick and writhing tests were used for estimation of possible modulation of pain. The tail-flick latencies in the Valeriana 800 and 200 mg/kg, but not 50 mg/kg, morphine, and combined Valeriana 800 + + naloxone, ondansetron, metoclopramide, or scopolamine-treated groups were significantly longer than that in the control group. However, the tail-flick latencies in the Valeriana 800 mg/kg + ondansetronand metoclopramide-treated groups were significantly shorter than that upon single action of the extract (800 mg/kg). The numbers of writhings in the extract-treated groups were smaller than in the control one. The numbers of writhings in the Valeriana (800 mg/kg) + ondansetron- and metoclopramidetreated groups were significantly greater than in the extract (800 mg/kg) group. It is concluded that Valeriana officinalis extract possesses a clear analgesic effect and works through the serotonergic and dopaminergic systems. [ABSTRACT FROM AUTHOR]

Objective(s): The aim of study was to investigate the antinociceptive effect of intracerebroventricular (ICV) microinjection of Origanum vulgare (ORG) extract and possible involvement of opioid receptors. Materials and Methods: Cannula was inserted into left ventricle of male rats. Five days after surgery Tail Flick Latency (TFL) was measured after ICV microinjection of, ORG (1, 3 and 6 μg / rat). Effective dose of ORG was injected ICV in concomitant with morphine (2 mg/kg, IP), naloxone (2 mg / kg, IP) and saline (0.5 μl/rat) and TFL was recorded. Results: The co-administration of ORG extract with morphine showed a significant increase in TFL and naloxone, pretreatment significantly inhibited the antinociceptive activity of ORG and morphine. Conclusion: The aqueous extract of ORG possesses antinociceptive activities in the tail-flick test in a dose dependent manner. ORG - induced antinociception may have been mediated by opioid systems. [ABSTRACT FROM AUTHOR]

Abstract: Angiotensins (Angs) modulate blood pressure, hydro-electrolyte composition, and antinociception. Although Ang (5–8) has generally been considered to be inactive, we show here that Ang (5–8) was the smallest Ang to elicit dose-dependent responses and receptor-mediated antinociception in the rat ventrolateral periaqueductal gray matter (vlPAG). Ang (5–8) antinociception seems to be selective, because it did not alter blood pressure or act on vascular or intestinal smooth muscle cells. The non-selective Ang-receptor (Ang-R) antagonist saralasin blocked Ang (5–8) antinociception, but selective antagonists of Ang-R types I, II, IV, and Mas did not, suggesting that Ang (5–8) may act via an unknown receptor. Endopeptidase EP 24.11 and amastatin-sensitive aminopeptidase from the vlPAG catalyzed the synthesis (from Ang II or Ang III) and inactivation of Ang (5–8), respectively. Selective inhibitors of neuronal-nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and a non-selective opioid receptor (opioid-R) inhibitor blocked Ang (5–8)-induced antinociception. In conclusion, Ang (5–8) is a new member of the Ang family that selectively and strongly modulates antinociception via NO–sGC and endogenous opioid in the vlPAG. [Copyright &y& Elsevier]

Objective: We aimed to investigate the role of Kv7 potassium channels in the morphine- induced antinociception in both acute and neuropathic pain models. Methods: Neuropathic pain was induced by partial ligation of the right sciatic nerve. For intracerebroventricular (i.c.v.) injections, each rat was equipped with a permanent cannula. The response to painful thermal stimuli was assessed by the tail-flick test. In sciatic nerve- ligated rats, thermal hyperalgesia was assessed by paw withdrawal latencies in the plantar test and the mechanical hyperalgesia was determined by rigid von Frey filaments. Results: Rats received morphine (2, 5, 20 µg/10 µl; i.c.v.) or saline (10 µl; i.c.v.) 15 min before the tests. In all tests, morphine produced significant antinociceptive effect. When a Kv7 potassium channel blocker, linopirdine (0.1, 1, 10 µg/10 µl; i.c.v.) was administered 15 min before morphine, the effect of i.c.v. morphine in the tail-flick test and plantar test but not in the test with von Frey filaments were prevented. Conclusions: Kv7 potassium channels contribute to the effect of i.c.v. morphine on acute pain induced by thermal stimulation. In the sciatic nerve-ligated rats, these channels play role in the effect of morphine on thermal hyperalgesia, but not on mechanical hyperalgesia. [ABSTRACT FROM AUTHOR]

Pain is a common debilitating condition in diabetes; however, sensitivity to pain during the estrous cycle varies and the overall pathophysiology remains poorly understood. The aim of the present study was to investigate pain sensitivity during the estrous cycle in diabetic rats. Adult female rats weighing 220-250 g were maintained on 12-h light/dark cycles. Food and water were available ad libitum. Animals were divided into two groups, healthy and diabetic rats. The estrous cycle phases were monitored by vaginal lavage and pain sensitivity was evaluated by tail-flick test, performed over 60 min during each phase. Data were analyzed by t test and the level of significance was considered to be P<0.05. Results showed that the diabetic group had a significantly (P<0.05) higher analgesic index than that of the healthy group. Percentage of pain sensitivity was significantly (P<0.05) higher in metestrus than that of other phases of the estrous cycle. These results showed that the pattern of neuropathy expression in diabetes varied during estrous cycle, which may be due to fluctuations in sex hormone levels. [ABSTRACT FROM AUTHOR]

Abstract: Rolling mouse Nagoya (tg rol ) is a spontaneously occurring P/Q-type voltage-gated Ca2+ channel (VGCC) mutant mouse. A P/Q-type VGCC with the tg rol mutation has lower voltage sensitivity of activation, and mice with a homozygous genotype (tg rol /tg rol ) but not with a heterozygous genotype (tg rol /+) show impaired motor coordination of the hind limbs. To investigate the roles of P/Q-type VGCC in pain sensing mechanisms, behavioral responses of adult tg rol mice to thermal, mechanical and chemical nociceptive stimuli were examined by the plantar, tail-flick, von Frey and formalin tests. The latency of the withdrawal response to thermal stimuli in the plantar or tail-flick tests was significantly longer in tg rol /tg rol mice than in tg rol /+ and wild-type (+/+) mice, and in tg rol /+ mice than in +/+ mice. The withdrawal response to mechanical stimuli in the von Frey test was lower in tg rol /tg rol mice than in +/+ mice. Although the licking time during the first 5 min after the formalin injection was similar among all of the three genotypes, that during 5–60 min was significantly shorter in tg rol /tg rol mice than in tg rol /+ and +/+ mice, and in tg rol /+ mice than in +/+ mice. Artificial inflammation induced by injection of complete Freund''s adjuvant (CFA) into a hind paw significantly enhanced the withdrawal response recorded in the plantar and von Frey tests regardless of the mouse genotype. The CFA-enhanced response in the tg rol /tg rol mice was similar to the response in +/+ mice without the CFA injection. These results suggest that tg rol mutant mice show hypoalgesic responses caused by a lower sensitivity to nociceptive thermal, mechanical and chemical stimuli. It is concluded that the P/Q-type VGCC has a pro-nociceptive role and that the tg rol mutant mouse may be a useful tool to investigate the role of the P/Q-type VGCC in pain sensing mechanisms. [Copyright &y& Elsevier]

Abstract: The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and humans. The aim of this study was to assess the involvement of the dorsal raphe nucleus (DRN) in the post-ictal antinociception. The second aim was to study the role of serotonergic intrinsic mechanisms of the DRN in this hypo-algesic phenomenon. Pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl− influx antagonist, was peripherally used to induce tonic–clonic seizures in Wistar rats. The nociceptive threshold was measured by the tail-flick test. Neurochemical lesions of the DRN, performed with microinjection of ibotenic acid (1.0 μg/0.2 μL), caused a significant decrease of tonic–clonic seizure-induced antinociception, suggesting the involvement of this nucleus in this antinociceptive process. Microinjections of methysergide (1.0 and 5.0 μg/0.2 μL), a non-selective serotonergic receptor antagonist, into DRN caused a significant decrease in the post-ictal antinociception in seizing animals, compared to controls, in all post-ictal periods presently studied. These findings were corroborated by microinjections of ketanserin (at 1.0 and 5.0 μg/0.2 μL) into DRN. Ketanserin is an antagonist with large affinity for 5-HT2A/2C serotonergic receptors, which, in this case, caused a significant decrease in the tail-flick latencies in seizing animals, compared to controls after the first 20 min following tonic–clonic convulsive reactions. These results indicate that serotonergic neurotransmission of the DRN neuronal clusters is involved in the organization of the post-ictal hypo-algesia. The 5-HT2A/2C receptors of DRN neurons seem to be critically involved in the increase of nociceptive thresholds following tonic–clonic seizures. [Copyright &y& Elsevier]

Abstract: Nitric oxide (NO) plays an important role in initiation and maintenance of pain, and NO precursor nitroglycerin is able to activate spinal and brain structures involved in nociception. It is also known that acute and chronic stress induce biochemical changes affecting both pain threshold and behaviour, and that the biological pattern of depression can be mimicked in the laboratory using chronic unavoidable stress paradigms (learned helplessness). We, therefore, evaluated the effects of acute and chronic immobilization stress on pain response to nitroglycerin administration in the rat. Pain perception was expressed as the latency of response to a tail-flick test (hot stimulus). Measures were made 1, 2 and 4h following nitroglycerin (10mg/kg i.p.) or vehicle. Nitroglycerin caused hyperalgesia after 2 and 4h (p &#60;0.05 versus baseline). Acute stress (90min) induced a clear analgesic state (p &#60;0.01 versus non-stressed control animals), and nitroglycerin injection was unable to reverse stress-induced analgesia in this setting. By contrast, exposition to chronic immobilization stress (7 days) caused a significant increase in pain response (p &#60;0.05); in this case, hyperalgesia was shown to be further enhanced by nitroglycerin administration (p &#60;0.05 versus vehicle). These findings support the view that a condition of chronic stress used in the laboratory to reproduce the biological features of depression can enhance hyperalgesia induced by nitroglycerin administration. These observations may be relevant to pain disorders, and particularly to migraine, since nitroglycerin is able to induce spontaneous-like pain attacks in humans, and an unfavourable migraine outcome (transformation into a chronic daily headache) is associated with chronic stress and comorbid depression. [Copyright &y& Elsevier]

The present study was undertaken to clarify how spinal muscarinic receptors can be involved in the antinociceptive effects induced by morphine in thermal stimulation. The morphine-induced antinociceptive effects (26.6μmol/kg, s.c.) was inhibited by an intrathecal (i.t.) injection of the muscarinic antagonist (M) atropine and the M1/M4 antagonist pirenzepine in a dose-dependent manner. In contrast, the M2 antagonist methoctramine and the M3 antagonist 4-DAMP did not inhibit the morphine-induced antinociceptive effects. Injection (i.t.) of the putative M1 agonist McN-A-343 resulted in dose-dependent antinociceptive effects in thermal stimuli. In addition, antinociceptive effects induced by the i.t. injection of morphine were not inhibited by the M1/M4 antagonist pirenzepine, although pirenzepine did inhibit the intracerebroventricular (i.c.v.) injection of morphine-induced antinociceptive effects. These results suggest that the morphine-induced antinociceptive effects in thermal stimuli are regulated by the M1 or M4 receptor in the spinal cord. [Copyright &y& Elsevier]

Platycodin D (PD), one of several triterpene saponins, was isolated from roots of Platycodon grandiflorum. We previously reported that intracerebroventricular (i.c.v.) administration of PD showed an antinociceptive effect as measured by the tail-flick assay. However, its exact role in the regulation of antinociception in the various types of pain models has not yet been characterized. Thus, we attempted to find antinociceptive profiles of PD in various pain models. PD administered intraperitoneally (i.p.), i.c.v. or intrathecally (i.t.) showed antinociceptive effects in dose-dependent manners as measured by the tail-flick, writhing and formalin tests. In the tail-flick test, PD at the low doses reached the peak after 15 minutes and returned to the control level after 60 minutes. However, higher doses of PD showed a strong antinociception at least for 1 hour. PD administered i.t. showed stronger antinociception than that induced by i.c.v. administration PD in both tail-flick and writhing tests. In the formalin test, PD administered i.p., i.c.v. or i.t. showed antinociceptive effects during both the first (direct nociceptive stimulation) and second (late inflammatory) phases. Pretreatment with naltrexone i.p., i.c.v. or i.t. did not affect PD-induced inhibition of the tail-flick response. Our results suggest that PD shows a strong antinociceptive effect on the tail-flick, writhing and formalin tests, acting on central nervous system. However, PD-induced antinociception may not be mediated by the opioid receptors. [ABSTRACT FROM AUTHOR]

Nitroglycerin is a nitric oxide (NO) donor which activates nuclei involved in nociceptive transmission following systemic administration. The effect of nitroglycerin on the nociceptive threshold was studied in rats by means of two experimental tests that explore different modalities of pain: the tail-flick test and the formalin test. Nitroglycerin induced a significant reduction in the latency of the tail flick 2 and 4 h after its administration. Similarly, formalin-induced pain-related behaviour increased significantly 2 and 4 h after nitroglycerin administration. [Copyright &y& Elsevier]

• Blockade of the orexin-1 receptors in the CA1 attenuated the LH stimulation-induced analgesia. • Microinjection of the TCS OX2 29 into the CA1 decreased the LH stimulation-induced analgesia. • Intra-CA1 infusion of SB334867 or TCS OX2 29 has similar impact on analgesic responses in acute pain model. • Solely microinjection of both antagonists fails to change nociceptive behaviors in tail-flick test as acute pain model. • Neither carbachol nor orexin receptor antagonists induced change in locomotion. The lateral hypothalamus (LH) orexinergic neurons project to numerous brain regions implicated in pain perception, including the CA1 part of the hippocampal formation. Moreover, the roles of orexin receptors (OXRs) in the CA1 in anti-analgesic consequences of the LH chemical stimulation by carbachol, muscarinic receptor agonist, in acute pain have not been clarified. The current research showed OXRs antagonist administration's effect in the CA1 on analgesia elicited by the LH chemical stimulation in a tail-flick test as an acute model of pain. The control groups, including vehicle-control groups, were given intra-LH administration of saline (0.5 μL), following intra-CA1 infusion of DMSO (12 %; 0.5 μL), and carbachol-control groups were treated with carbachol (250 nM/0.5 μL saline) into the LH following DMSO in the CA1. Treated groups received SB334867 (1, 3, 10, and 30 nM/0.5 μL DMSO) or TCS OX2 29 (0.1, 1, 10, and 20 nM/0.5 μL DMSO) as OX1R or OX2R antagonist, respectively, in the CA1 prior intra-LH administration of carbachol. After all injections, all rats underwent the tail-flick test over a 60-min time. Infusion of SB334867 or TCS OX2 29 in the CA1 impaired the analgesic consequences following chemical stimulation of the LH in acute pain. Meanwhile suppressive impact of the OX1R or OX2R antagonist on the analgesic impact of LH chemical stimulation was approximately identical. The current investigation provided a new document about the critical involvement of hippocampal orexinergic system in the modulatory role of the LH-CA1 path in pain perception. [ABSTRACT FROM AUTHOR]

Nicotine (0.16-0.50 mg/kg, SC) was found to exert a potent antinociceptive action on thermal stimuli as measured by the tail-flick test. This antinociceptive action of nicotine could be blocked by centrally active nicotinic or muscarinic blockers implicating both classes of cholinergic receptors in this effect. Quaternary blockers, however, failed to prevent nicotine-induced antinociception. This finding, together with the ability of small doses of nicotine (25 μg) to induce potent antinociceptive effects when administered centrally, suggests a central site of action for the antinociceptive action of nicotine. The present results also support the suggestion that nicotine may selectively reduce sensitivity to certain classes of pain stimuli, perhaps through a central releasing action on acetylcholine. [ABSTRACT FROM AUTHOR]