Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral

The antinociceptive effect of sarpogrelate, a new selective 5-hydroxytriptamine (5-HT)(2A) receptor antagonist, in the formalin test was examined in rats. Sarpogrelate was administered intraperitoneally, locally (subcutaneously at the formalin test site) or intrathecally 10 min before formalin injection. Intraperitoneal (1-100 mg/kg) and local (0.01-1 mg) administration of sarpogrelate suppressed flinching behavior in both phases 1 (0-9 min) and 2 (10-60 min) in a dose-dependent manner. Intraperitoneal (100 mg/kg) and local (1 mg) injection 7 min after formalin injection reduced phase 2 flinches to the same degree as with the pre-treatment. Intrathecal administration (1-100 microg) showed no antinociceptive action, and facilitated phase 2 flinches at 10 microg. The plasma concentration of sarpogrelate after local administration of 1 mg was lower than after intraperitoneal administration of 10 mg/kg, although local administration produced more potent antinociception. The data imply that the antinociceptive effect of sarpogrelate results mainly from an action at peripheral sites.     

Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats

The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.     

Proglumide enhances the antinociceptive effect of cyclooxygenase inhibitors in diabetic rats in the formalin test

The purpose of this study was to assess the effect of the non-selective cholecystokinin receptor antagonist proglumide on the antinociceptive activity of ketorolac and meloxicam in non-diabetic and diabetic rats. Streptozotocin (60 mg/kg) injection caused hyperglycemia which was maintained for 2 weeks. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Local peripheral ipsilateral, but not contralateral, administration of ketorolac and meloxicam produced antinociception in non-diabetic and diabetic rats. However, the antinociceptive effect of both drugs was significantly reduced in diabetic animals. Proglumide was ineffective by itself and it did not affect the antinociception induced by the cyclooxygenase inhibitors in non-diabetic rats. Contrariwise, proglumide reduced formalin-induced nociception and it increased ketorolac- or meloxicam-induced antinociception in diabetic rats. These results suggest that peripheral cholecystokinin plays an important role in diabetes-induced sensitization as well as in the reduction of the antinociceptive effects of ketorolac and meloxicam in diabetic rats. The combination of cholecystokinin receptor antagonists and ketorolac or meloxicam may be a useful strategy to reduce nociception in diabetic patients.     

Pyritinol reduces nociception and oxidative stress in diabetic rats

The purpose of this study was to assess the antinociceptive and antiallodynic effect of pyritinol as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral acute administration of pyritinol (50-200 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. Moreover, prolonged administration of pyritinol (12.5-50 mg/kg, every 2 days for 2 weeks) reduced formalin-induced nociception. 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) or indomethacin (a non-selective cycloxygenase inhibitor, 5 mg/kg, i.p.), blocked the pyritinol-induced antinociception in diabetic rats. Given alone ODQ, naltrexone or indomethacin did not modify formalin-induced nociception in diabetic rats. Oral acute (200 mg/kg) or prolonged (25 mg/kg, every 2 days for 2 weeks) administration of pyritinol significantly reduced streptozotocin-induced changes in free carbonyls, dityrosine, malondialdehyde and advanced oxidative protein products. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of pyritinol (50-200 mg/kg) reduced tactile allodynia in diabetic rats. Results indicate that pyritinol is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that activation of guanylyl cyclase and the scavenger properties of pyritinol, but not improvement in glucose levels, play an important role in these effects.     

Nociceptive and inflammatory responses induced by formalin in the orofacial region of rats: effect of anti-TNFalpha strategies

This study evaluated the effects of different anti-TNFalpha strategies on the nociceptive and inflammatory responses triggered by formalin in the rat orofacial region. Formalin injection (2.5%) into the right upper lip caused a nociceptive response that was biphasic, with the first phase observed between 0 and 3 min and the second phase between 12 and 30 min. Plasma extravasation induced by formalin was time-related and reached the peak at 360 min. The monoclonal antibody anti-TNFalpha (25 and 50 pg/lip) significantly inhibited the second phase of formalin-induced nociceptive behavior, while the first phase remained unaltered. The systemic treatment with the chimeric anti-TNFalpha antibody infliximab also caused a significant inhibition of the second phase. Interestingly, the local administration of infliximab (50 pg/lip) produced a significant reduction of both phases of formalin-induced nociception. In addition, the systemic pretreatment with the preferential inhibitor of TNFalpha synthesis thalidomide (25 and 50 mg/kg, p.o) promoted a marked reduction of the first and second phases of formalin-evoked nociception. The local administration of the monoclonal antibody anti-TNFalpha (25 and 50 pg/lip) or infliximab (50 pg/lip) markedly reduced the plasma extravasation induced by formalin. Otherwise, formalin-elicited plasma extravasation was not significantly affected by the systemic administration of either infliximab (1 mg/kg; s.c) or thalidomide (50 mg/kg, p.o). Present data suggest that blocking TNFalpha effects, through different pharmacological tools, could represent a good alternative to control orofacial inflammatory pain that is refractory to other drugs.     

Involvement of cholinergic system in suppression of formalin-induced inflammatory pain by cobratoxin

Aim:

To investigate the analgesic effect of cobratoxin (CTX), a long-chain α-neurotoxin from Thailand cobra venom, in a rat model of formalin-induced inflammatory pain.

Methods:

Inflammatory pain was induced in SD rats via injecting 5% formalin (50 μL) into the plantar surface of their right hind paw. CTX and other agents were ip administered before formalin injection. The time that the animals spent for licking the injected paw was counted every 5 min for 1 h.

Results:

CTX (25, 34, and 45 μg/kg) exhibited a dose-dependent analgesic effect during the phase 1 (0–15 min) and phase 2 (20–60 min) response induced by formalin. Pretreatment with naloxone (0.5 or 2.5 mg/kg) did not block the analgesic effect of CTX. Pretreatment with atropine at 5 mg/kg, but not at 2.5 mg/kg, antagonized the analgesic effect of CTX. Treatment with the nonselective nAChR antagonist mecamylamine (3 mg/kg) inhibited the analgesic effects of CTX in Phase 1 and Phase 2 responses, while with the selective α7-nAChR antagonist methyllycaconitine (3 mg/kg) antagonized the effect of CTX only in the Phase 1 response. Treatment with the α7-nAChR agonist PNU282987 (3 mg/kg) significantly reduced the formalin-induced phase 2 pain response, but only slightly reduced the Phase 1 pain response.

Conclusion:

The results suggest that CTX exerts an antinociceptive effect in formalin-induced inflammatory pain, which appears to be mediated by mAChR and α7-nAChR.     

The antinociceptive effect of intrathecal escin in the rat formalin test

This study investigated the antinociceptive effect of intrathecal escin and examined its effect on the formalin-induced activation of c-Fos and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) in the rat spinal cord. Rats were chronically implanted with lumbar intrathecal catheters, and the ability of intrathecal escin to alter nociceptive behaviours in the rat formalin test was examined. The expression of c-Fos and p-p38 MAPK in the dorsal horn of the spinal cord was detected in the control and escin (40μg) groups using immunohistochemical techniques. Intrathecal escin produced a dose-dependent reduction in formalin-evoked flinching behaviour in rats during the second phase; however, no effect was observed in the first phase. In addition, immunohistochemical experiments showed that the expression of c-Fos and p-p38 MAPK in the spinal cord dorsal horn increased after an injection of formalin into the paw. Interestingly, the 40μg dose of intrathecal escin, which was the larger of the two doses that blocked formalin-induced hyperalgaesia, attenuated the formalin-induced increases in c-Fos and p-p38 MAPK in the dorsal horn of the spinal cord. The decrease in pain-related behaviours and c-Fos expression indicated that escin produced antinociceptive effects in the rat formalin test. Although the specific mechanisms of these effects were not investigated, the reduction in p-p38 MAPK in the dorsal horn of the spinal cord may be involved.     

Influence of doxepin used in preemptive analgesia on the nociception in the perioperative period. Experimental and clinical study.

The aim of the present research was to assess in experimental and clinical study the influence of doxepin administered intraperitoneally (ip) as preemptive analgesia on the nociception in the perioperative period. The pain thresholds for mechanical stimuli were measured in rats. The objective of clinical investigation was to assess the influence of preemptive administration of doxepin on postoperative pain intensity, analgesic requirement in the early postoperative period as well as an assessment of the quality of postoperative analgesia by the patient. Doxepin injected ip (3-30 mg/kg) dose-dependently increased the pain threshold for mechanical stimuli measured in paw pressure test in rats. Doxepin injected 30 min before formalin significantly increased the nociceptive threshold in the paw pressure test. In contrast, doxepin injected 240 min before formalin or 10 min after formalin did not change the nociceptive threshold. Morphine administered subcutaneously (sc) at a dose of 1 mg/kg increased the pain threshold measured in the paw pressure test 55 min after formalin treatment. Injection of 10 mg/kg of doxepin 30 min before formalin further enhanced the response after morphine administration. The results of the clinical study demonstrated that the patients who were administered doxepin preemptively showed significantly lower pethidine requirement in order to achieve a similar level of postoperative analgesia. The results of the research under discussion confirm the theoretical assumptions that there is a possibility to modify the nociception process in the perioperative period through preemptive analgesia using a drug that modifies the activity of the descending antinociceptive system.     

Involvement of serotoninergic mechanism in analgesia by castration and flutamide, a testosterone antagonist, in the rat formalin test

Several studies have suggested that testosterone has a role in nociception. Recently, we have shown that castration and flutamide, a testosterone antagonist, induce analgesia in the late phase of formalin test, which is related to increase of 5-HT levels in the dorsal horn of the lumbar spinal cord. The aim of the present study was to investigate the effect of fluoxetine, a selective serotonin reuptake inhibitor, on castration and flutamide-induced analgesia in order to further explore the role of 5-HT systems in such analgesia. Four weeks after castration, there was an analgesia in the late phase of formalin test, and this was potentiated by acute (0.32 mg kg(-1) ip) treatment of fluoxetine. Furthermore, coadministration of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) produced more antinociceptive effect than those animals receiving fluoxetine and flutamide alone. The analgesic effect of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) was abolished by pretreatment with 5,7-DHT (100 microg/rat it) and naloxone (2 mg kg(-1) ip). In summary, our data suggest that fluoxetine and flutamide have antinociceptive effects in tonic inflammatory pain through functional alteration of serotonergic systems, and their effects are potentiated by coadministration. The possible role of opioidergic system in their antinociceptive effect cannot be neglected.     

Peripheral participation of cholecystokinin in the morphine-induced peripheral antinociceptive effect in non-diabetic and diabetic rats

The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.     

Benfotiamine relieves inflammatory and neuropathic pain in rats

Benfotiamine has shown therapeutic efficacy in the treatment of painful diabetic neuropathy in human beings. However, so far there is no evidence about the efficacy of this drug in preclinical models of pain. The purpose of this study was to assess the possible antinociceptive and antiallodynic effect of benfotiamine in inflammatory and neuropathic pain models in the rat. Inflammatory pain was induced by injection of formalin in non-diabetic and diabetic (2 weeks) rats. Reduction of flinching behavior was considered as antinociception. Neuropathic pain was induced by either ligation of left L5/L6 spinal nerves or administration of streptozotocin (50 mg/kg, i.p.) in Wistar rats. Benfotiamine significantly reduced inflammatory (10-300 mg/kg) and neuropathic (75-300 mg/kg) nociception in non-diabetic and diabetic rats. Results indicate that oral administration of benfotiamine is able to reduce tactile allodynia from different origin in the rat and they suggest the use of this drug to reduce inflammatory and neuropathic pain in humans.     

Effect of topical administration of L-arginine on formalin-induced nociception in the mouse: a dual role of peripherally formed NO in pain modulation.

1. We investigated the effects of intraplantar (i.pl.) administration of L-arginine and NG-nitro-L-arginine methyl ester (L-NAME) on formalin-induced behavioural nociception in the mouse. 2. L- but not D-arginine, at 0.1-1 microgram per paw, coadministered with i.pl. formalin, enhanced the second-but not the first-phase nociceptive responses, whereas it was without significant effects at 3 micrograms per paw, and conversely, produced antinociception at 10 micrograms per paw, resulting in a bell-shaped dose-response curve. 3. L-NAME at 0.1-1 microgram per paw, when administered i.pl., exhibited antinociceptive activity in the second phase in a dose-dependent manner, although its D-enantiomer produced no effect. 4. An antinociceptive dose (1 microgram per paw) of L-NAME (i.pl.) considerably reduced the increase in second-phase nociception elicited by low doses (1 microgram per paw) of i.pl. L-arginine. The second-phase nociception decrease induced by a large dose (10 micrograms per paw) of i.pl. L-arginine was markedly reversed by i.pl. L-NAME at 0.1 micrograms per paw, raising it to a level above that of the control (formalin only). 5. These results suggest that peripheral NO plays a dual role in nociceptive modulation, depending on the tissue level, inducing either nociceptive or antinociceptive responses.     

Antinociceptive effects of the ORL1 receptor agonist nociceptin/orphanin FQ in diabetic mice.

The antinociceptive potency of nociceptin/orphanin FQ, an opioid-like orphan receptor agonist, was examined using the tail-flick test and the formalin-induced nociception test in diabetic mice. Nociceptin/orphanin FQ, at doses of 0.1 to 10 nmol, intrathecal (i.t.), produced a marked and dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice. The antinociceptive effect of nociceptin/orphanin FQ in the tail-flick test in diabetic mice was greater than that in non-diabetic mice. The antinociceptive effect of nociceptin/orphanin FQ was not antagonized by pretreatment with either beta-funaltrexamine, a selective mu-opioid receptor antagonist, naltrindole, a selective delta-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist. The antinociceptive effects of nociceptin/orphanin FQ in diabetic, but not in non-diabetic mice, were abolished when mice were pretreated with capsaicin i.t. 24 h before testing. In the formalin test, nociceptin/orphanin FQ also produced a marked and dose-dependent antinociceptive effect on the first-phase response, but not the second phase-response, in both diabetic and non-diabetic mice. Furthermore, nociceptin/orphanin FQ significantly and dose-dependently reduced the flinching responses to i.t.-administered substance P in diabetic mice, but not in non-diabetic mice. The results of the present experiments clearly indicate that the antinociceptive potency of nociceptin/orphanin FQ is significantly greater in diabetic mice than in non-diabetic mice. Furthermore, the results of this study suggest that the reduction of substance P-mediated nociceptive transmission in the spinal cord may be responsible for the antinociceptive effect of nociceptin/orphanin FQ.     

Pramipexole inhibits formalin-induce acute and long-lasting mechanical hypersensitivity via NF-kB pathway in rats

Pain is one of the most frequent causes for patients to seek medical care. It interferes with daily functioning and affects the quality of life of the patient. There is a clear need to investigate nonopioid or non-nonsteroidal anti-inflammatory drug alternatives for the treatment of pain. In this study, we determined the effect of acute pre- and posttreatment with pramipexole (PPX), a dopamine D2/D3 selective agonist, on formalin 1%-induced acute and long-lasting nociceptive behavior sensitivity in rats. Moreover, we sought to investigate whether the antiallodynic and antihyperalgesic effect induced by PPX was mediated through the nuclear factor-κB (NF-kB) signaling pathway. Moreover, acute systemic pretreatment with PPX (1 and 3 mg/kg, ip) suppressed the formalin-induced nociceptive behavior during both phases of the formalin test and the development of formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. Acute systemic posttreatment with PPX (3 mg/kg, ip) reverted the formalin-induced long-lasting secondary mechanical allodynia and hyperalgesia. Furthermore, PPX inhibits the protein expression of NF-κB–p65 and the levels of tumor necrosis factor-α and interleukin-1β in the spinal cord of animals with secondary mechanical allodynia and hyperalgesia induced by formalin. These data suggest that PPX has a potential role in producing anti-inflammatory activity. Moreover, the antiallodynic and antihyperalgesic effects induced by PPX can be mediated through the NF-kB signaling pathway.     

Synergic antinociceptive interaction between tramadol and gabapentin after local, spinal and systemic administration

The possible interaction between tramadol and gabapentin on formalin-induced nociception in the rat was assessed. Tramadol, gabapentin or a fixed-dose ratio combination of gabapentin and tramadol were administered peripherally, spinally and orally to rats, and the antinociceptive effect was determined in the 1% formalin test. Isobolographic analyses were used to define the nature of the interactions between drugs. Tramadol, gabapentin and tramadol-gabapentin combinations produced a dose-dependent antinociceptive effect when administered locally, spinally or orally. ED30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED30 values for the combination estimated from the isobolograms were 126.8 +/- 11.1 microg/paw, 23.1 +/- 2.6 microg/rat, and 2.23 +/- 0.32 mg/kg for the local, intrathecal and oral routes, respectively. These values were significantly higher than the actually observed ED30 values which were 13.3 +/- 2.1 microg/paw, 8.1 +/- 0.6 microg/rat and 0.71 +/- 0.10 mg/kg, indicating a synergistic interaction. Although efficacy was not improved, local peripheral administration resulted in the highest increase in potency, being about tenfold. Spinal and systemic administration increased potency threefold. Data indicate that low doses of the tramadol-gabapentin combination can interact synergistically to reverse formalin-induced nociception and may represent a therapeutic advantage for clinical treatment of inflammatory pain.     

Antinociceptive effect of amygdalin isolated from Prunus armeniaca on formalin-induced pain in rats

Amygdalin is a plant glucoside isolated from the stones of rosaceous fruits, such as apricots, peaches, almond, cherries, and plums. To investigate the pain-relieving activity of amygdalin, we induced pain in rats through intraplantar injection of formalin, and evaluated the antinociceptive effect of amygdalin at doses of 0.1, 0.5, 1.0, and 10.0 mg/kg-body weight by observing nociceptive behavior such as licking, biting and shaking, the number of Fos-immunoreactive neurons in the spinal cord, and the mRNA expression of inflammatory cytokines in the plantar skin. The intramuscular injection of amygdalin significantly reduced the formalin-induced tonic pain in both early (the initial 10 min after formalin injection) and late phases (10-30 min following the initial formalin injection). During the late phase, amygdalin did reduce the formalin-induced pain in a dose-dependent manner in a dose range less than 1 mg/kg. Molecular analysis targeting c-Fos and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) also showed a significant effect of amygdalin, which matched the results of the behavioral pain analysis. These results suggest that amygdalin is effective at alleviating inflammatory pain and that it can be used as an analgesic with anti-nociceptive and anti-inflammatory activities.     

Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats

Diabetes is often associated with painful neuropathy. The current treatments are symptomatic and ineffective. Cannabinoids have been proposed as promising drugs for chronic pain treatment and its antinociceptive effect has already been related in nerve injury models of neuropathic pain, but little has been investigated in painful diabetic neuropathy models. Thus, the current study aims to investigate the potential antinociceptive effect of drugs that alter endocannabinoid system when injected subcutaneously into the dorsal surface of the ipsilateral hind paw in chemical hyperalgesia induced by formalin in both normoglycemic (Ngl) and streptozotocin-diabetic (Dbt) rats. Diabetic rats exhibited exaggerated flinching behaviors during first and second phases of the formalin test, indicating the presence of hyperalgesia. AM404, an anandamide (AEA) re-uptake inhibitor, AEA (an agonist of CB1/CB2 receptors) or ACEA (a selective CB1 receptor agonist) induced antinociception in both phases of formalin test in Ngl and Dbt rats. In both groups, the antinociceptive effect of ACEA was prevented by AM251, a CB1 inverse agonist while the antinociceptive effect of AEA was prevented by AM251 or AM630, a CB2 receptor antagonist. In Ngl rats, the antinociceptive effect of AM404 was prevented by AM251 or capsazepine only during first phase of the formalin test while in Dbt rats, this effect was blocked by pretreatment with AM251 (both phases) or AM630 (second phase). Taken together, these results demonstrated broad-spectrum antinociceptive properties of cannabinoids in a model of painful diabetic neuropathy. Peripheral activation of both cannabinoid receptors seems to mediate the antinociceptive effect of exogenous or endogenous anandamide.     

Chronic administration of desipramine and zimelidine changes the behavioural response in the formalin test in rats.

In studies of the effect on nociception of chronic administration of antidepressants, the stress of the injections may influence the results. In this experiment, desipramine or zimelidine were administered in the drinking water of rats, in a concentration yielding a dose of approximately 8 mg/kg/24 hr. Desipramine, given both for a short time (24 hr) and chronically (14 days), induced antinociception in the increasing temperature hot-plate test; zimelidine did not significantly influence the results of this test. In the tail-flick test, neither short-term nor chronic administration of these antidepressants had any effect on nociception, when correction was made for the changes in the temperature of the tail skin. In the formalin test, nine behavioural categories were scored for 1 hr and the data were treated statistically, using a multivariate analysis. Chronic administration of desipramine increased nociceptive behaviour during the first 10 min of the test. Desipramine and, to a lesser extent, zimelidine, changed the response in the late phase (10-60 min), showing less focussed pain-related behaviour (jerks and shaking, licking and biting of the injected paw) and more non-focussed pain-related behaviour (activity states with elevation or protection of the injected paw). It was concluded that desipramine is antinociceptive in the increasing temperature hot-plate test. Desipramine and zimelidine, administered chronically, modify the late phase of the formalin test towards less focussed pain-related behaviour, suggesting an antinociceptive effect. Multivariate analysis of the data of the formalin test seemed to be of value for the interpretation of the data.     

Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice

Rationale Formalin-induced pain is reduced in sigma-1 (σ₁) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for σ₁ receptors, may modulate formalin-induced pain. Results Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain. Haloperidol (0.03–1 mg/kg, s.c.) and reduced haloperidol (metabolite II, 0.25–8 mg/kg, s.c.) dose-dependently inhibited both phases of formalin-induced pain. Haloperidol metabolite I (4–128 mg/kg, s.c.) also produced dose-dependent antinociception in the second phase of the formalin test, but was less potent and effective against first-phase pain. Haloperidol metabolite III (16 and 128 mg/kg) and (−)sulpiride (200 mg/kg), which have no affinity for σ₁ receptors, did not produce significant antinociception in either phase of the formalin test. The order of potency of the drugs to produce their antinociceptive effect [haloperidol > metabolite II > metabolite I ≫ metabolite III= (−)sulpiride=inactive] correlated with their affinity for σ₁ receptors, but not with their affinity for σ₂ or dopamine D₂ receptors. Naloxone (1 mg/kg, s.c.) did not antagonize the antinociception induced by haloperidol and its metabolites. None of the antinociceptive drugs in the formalin test produced any antinociception in the tail flick test. Conclusion These results suggest that the antinociceptive effect of haloperidol and its metabolites in the formalin test is not due to unspecific/generalised inhibition of nociception or modulation of opioid receptors, and that it may be related, at least partially, to the ability of these drugs to interact with σ₁ receptors.     

Methanol extract from mycelium of endophytic fungus Rhizoctonia sp. induces antinociceptive and anti-inflammatory activities in mice

The present study aimed to elucidate the antinociceptive and anti-inflammatory properties of the methanol extract from the mycelium of the endophytic fungus Rhizoctonia sp. (MEMRh) in mice. The antinociceptive activity was assessed using the abdominal constriction, hot plate, and formalin tests. The anti-inflammatory activity was assessed using a murine model of paw edema. Intraperitoneal administration of MEMRh (0.1, 1, 10 and 100?mg/kg, i.p.) produced an inhibition of acetic acid-induced writhing in mice for at least 8?h. In addition, all doses tested of the methanol extract were able to prevent thermal nociception in the hot-plate test. Furthermore, treatment with MEMRh (10?mg/kg, i.p.) inhibited both the early and late phases of formalin-induced nociception. This antinociceptive effect exhibited by MEMRh in the formalin test was reversed by the systemic administration of naloxone. MEMRh produced inhibition in a carrageenan-induced edema model at a dose of 10?mg/kg. The same extract also displayed significant activity against a histamine- or PGE(2)-induced edema model. The experimental data demonstrated that MEMRh showed remarkable anti-inflammatory and antinociceptive activities. Further studies are warranted to define and isolate the active anti-inflammatory and antinociceptive components from this endophytic fungus, which may yield effective agents for the treatment of inflammatory disorders.