Effects of mexiletine on algogenic mediator-induced nociceptive responses in mice.

To clarify the possible mechanism of the antinociceptive effect of mexiletine, the effects of the agent on formalin- and algogenic mediator-induced nociceptive responses were examined as compared to lidocaine. Subcutaneous (s.c.) injection of 0.5% formalin into the hindpaw caused an acute nociceptive response that lasted about 5 min (first phase). This response then disappeared completely for about 5 min and then recurred lasting about 20 min (second phase). Intraperitoneal (i.p.) administration of mexiletine (10 and 30 mg/kg) significantly and dose-dependently reduced the durations of the first and second phases of formalin-induced nociceptive response. On the other hand, although i.p. administration of lidocaine (10 and 30 mg/kg) had no significant effect on the first phase of formalin-induced nociceptive response, the duration of the second phase response was significantly and dose-dependently reduced. Pretreatment with mexiletine resulted in a significant and dose-dependent inhibition of the nociceptive response produced by intrathecal (i.t.) injection of substance P (0.1 nM), somatostatin (1.0 nM), bradykinin (1 microgram/mouse) and prostaglandin (PG) F2 alpha (1 microgram/mouse). Although lidocaine had no significant effect on the substance P- or somatostatin-induced nociceptive response, bradykinin- and PGF2 alpha-induced nociceptive responses were inhibited. These results suggest that the antinociceptive effect of mexiletine involves the inhibition of substance P-, somatostatin-, bradykinin- and PGF2 alpha-mediated nociceptive transmission in the spinal cord. Furthermore, it is possible that the weaker antinociceptive effect of lidocaine as compared with that of mexiletine may be due to the lack of its inhibitory effect on substance P- and somatostatin-mediated nociceptive transmission in the spinal cord.     

Effects of the putative 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice

The ability of 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to alter nociceptive sensitivity in mice was studied using the tail-flick, hot-plate and formalin tests. Subcutaneous (SC) administration of 8-OH-DPAT (0.63-1.0 mg/kg) dose-dependently increased the temperature at which hindpaw lick occurred in a hot-plate test using slowly rising temperature and increased the latencies to hindpaw lick, but reduced the latencies to jump in a conventional hot-plate test. Intracerebroventricular (ICV) injections (0.25-1.0 microgram) produced similar results in the conventional hot plate test. Following intrathecal (ITH) injections (0.25-1.0 microgram), however, the latencies to hindpaw lick were elevated without any change in jump latencies. In the formalin test a low systemic dose of 8-OH-DPAT (0.063 mg/kg) elicited hyperalgesia, while hypoalgesia was found after a high dose (1.0 mg/kg). ICV injection of 1.0 microgram produced hypoalgesia in the formalin test while the same dose injected ITH was without effect. 8-OH-DPAT did not alter tail-flick latencies, either by SC, ICV or ITH administration. Previous studies have shown that 8-OH-DPAT stimulates central serotonergic receptors, and shows selectivity for the 5-HT1A recognition site. The present findings indicate an involvement of 5-HT1A receptors in the processing of nociceptive information both at spinal and supraspinal sites. However, stimulation of 5-HT1A receptors does not seem to affect spinal, nociceptive reflexes.     

Evaluation of the formalin test to assess the analgesic activity of diflunisal in the rat

The formalin test was evaluated to assess the analgesic activity of diflunisal in the rat. Fifty microliters of a 5% formalin solution was injected into the hindpaw of rats and two distinct nociceptive behaviors, i.e. flinching/shaking and licking/biting of the injected paw, were recorded over 120 min. The effect of factors such as age of the animal, time of injection (morning vs. afternoon), site of injection (right vs. left hind paw) were evaluated. Both nociceptive behaviors exhibited a biphasic time course. Rats weighing 210–220 grams showed a more intense response compared to older rats weighing 240–250 or 270–280 grams. The nociceptive behavior response was affected by the time of formalin injection and was more pronounced in the morning. Diflunisal (100 mg/kg, i.v. infusion over 3 min) caused a significant delay in the flinching/shaking response vs. time curve, whereas the licking/biting response was significantly inhibited. When carried out under carefully controlled conditions, the formalin test may be useful to study the analgesic effect of diflunisal in the rat. It seems to be less sensitive, however, than other commonly used nociceptive tests.     

Antinociceptive Effects of Morphine Were Different Between Experimental and Genetic Diabetes

This study was designed to investigate the effect of morphine on formalin-induced nociceptive responses in streptozotocin (STZ) induced-diabetic mice, noninsulin-dependent genetically diabetic db/db mice and their respective controls (ddY and +/+). In nondiabetic (ddY and +/+) mice, morphine (1–10 mg/kg, PO) dose dependently attenuated the biphasic nociceptive responses induced by SC injection of formalin to the hindpaw, demonstrating equipotency on both the first and second phases. Para-chlorophenylalanine (800 mg/kg × 2, PO) and pindolol (1 mg/kg, IP) reduced the effect of morphine on the first phase, sulpiride (10 mg/kg, IP) abolished the effect on both phases, while ketanserin (1 mg/kg, IP) had no effect. In STZ (200 mg/kg, IP)-diabetic mice, morphine weakly attenuated the nociception in comparison to control ddY mice, whereas it had comparable effects in both the first and second phases of control +/+ mice and db/db mice. The serotonergic agonist, meta-chlorophenylpiperazine (0.32–3.2 mg/kg, PO), dose dependently attenuated the biphasic nociceptive responses to formalin in both phases of diabetic mice; however, FR64822, a dopaminergic compound (0.1–10 mg/kg, PO), had little effect. We speculate that activation of both dopaminergic (DA)- and serotonergic-mediated mechanisms are potentially responsible for the effect of morphine on the first phase, while the DA-mediated effect is involved in the second phase. The DA-mediated mechanism, but not the serotonin-mediated one, appears to be altered in both STZ-diabetic and db/db mice. These results suggest that the attenuated effects of morphine might be due to a dopaminergic dysfunction in STZ mice, and that there might be other mechanisms compensating for this attenuation of dopaminergic function in db/db mice.     

Lack of reciprocity between opioid and 5-HT3 receptors for antinociception in rat spinal cord

We examined the properties of the drug interaction between morphine and 5-HT(3) receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 microl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT(3) receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT(3) receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT(3) receptor and opioid receptors at the spinal level. Thus, the 5-HT(3) receptor antagonist may be useful to manage opioid-induced emesis at the spinal level.     

Effect of chronic and acute administration of fluoxetine and its additive effect with morphine on the behavioural response in the formalin test in rats

Serotonergic systems are involved in the central regulation of nociceptive sensitivity. Fluoxetine, a selective inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT), was administered orally (0.16, 0.32, 0.8 mg kg(-1) daily for 7 days), intraperitoneally (0.04, 0.08, 0.16 mg kg(-1) day(-1) for 7 days and a single dose of 0.32 mg kg(-1)) and intracerebroventricularly (10 microg/rat) to rats and nociceptive sensitivity was evaluated using the formalin test (50 microL of 2.5% formalin injected subcutaneously). The effect of fluoxetine was also studied in the presence of 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT) and after co-administration with morphine. Oral (0.8 mg kg(-1)), intraperitoneal (0.16 and 0.32 mg kg(-1)) and intracerebroventricular (10 microg/rat) fluoxetine induced antinociception in the late phase of the formalin test. Furthermore, intrathecal administration of 5-HT (100 microg/rat) induced an analgesic effect. The analgesic effect of fluoxetine (0.16 and 0.32 mg kg(-1), i.p.) and 5-HT (100 microg/rat, i.t.) was abolished by pre-treatment with 5,7-DHT (100 microg/rat, i.t.). In addition, the analgesic effect of 5-HT (100 microg/rat, i.t.) was decreased by pre-treatment with naloxone (2 mg kg(-1), i.p.). Morphine (5 mg kg(-1), i.p.) induced analgesia that was increased by fluoxetine (0.32 mg kg(-1), i.p.). These results suggest that fluoxetine has an antinociceptive effect in tonic inflammatory pain through functional alteration of the serotonergic system and also potentiates the analgesic effect of morphine.     

Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.     

Nociceptive behavior induced by mustard oil injection into the temporomandibular joint is blocked by a peripheral non-opioid analgesic and a central opioid analgesic

The aim of this study was to improve the mustard oil (MO) induced temporomandibular joint (TMJ) nociception model and to investigate the potential analgesic activity of systemic dipyrone and tramadol on the nociceptive behavioral responses induced by injection of low concentrations of the MO into the rat TMJ region. TMJ injection of 2.5% MO produced a significant nociceptive behavior expressed by head flinching and orofacial rubbing. This activity was related to the MO injection since mineral oil (vehicle) did not elicit response. Local application of the lidocaine N-ethyl bromide quaternary salt, QX-314 (2%) and systemic administration of morphine (4 mg/kg) significantly reduced the MO-induced nociceptive responses, validating the nociceptive character of the behaviors. The pretreatment with systemic dipyrone (19, 57 or 95 mg/kg) as well as tramadol (5, 7.5 or 10 mg/kg) was effective in decreasing the nociceptive behavioral responses induced by the injection of MO into the rat TMJ. In conclusion, TMJ injection of low concentrations of MO in rats produces well defined and quantifiable nociceptive behaviors constituting a reliable behavioral model for studying TMJ pain mechanisms and testing analgesic drugs. The results also suggest that dipyrone and tramadol could be effective analgesic options in the management of TMJ pain.     

Pharmacological characterization of capsaicin-induced body movement of neonatal rat.

In neonatal rats, nociceptive responses induced by capsaicin were characterized pharmacologically. Capsaicin, injected subcutaneously (s.c.), induced body movement including scratching and struggling responses, and the responses were quantified by using a device composed of an audio speaker as a detector. The capsaicin-induced body movement was inhibited by a tachykinin NK1-receptor antagonist RP-67580 with an ID50 value of 3.5 mg/kg, s.c. Opioid analgesics, morphine, buprenorphine and pentazocine, also inhibited the body movement with ID50 values of 0.085, 0.0079 and 0.92 (mg/kg, s.c.), respectively. Non-steroidal anti-inflammatory drugs, indomethacin, ibuprofen and acetaminophen, did not exert any effect on the capsaicin-induced body movement. Neither the sedative diazepam nor the sedative chlorpromazine inhibited the body movement. It is concluded that the capsaicin-induced body movement in neonatal rats, which is considered to be nociceptive responses mediated by substance P, is sensitive to centrally acting analgesics with micro-opioid receptor agonist activity.     

In the formalin model of tonic nociceptive pain, 8-OH-DPAT produces 5-HT1A receptor-mediated, behaviorally specific analgesia

The experiments examined antinociceptive and intrinsic behavioral effects induced by the prototypical 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino] tetralin) in rats. 8-OH-DPAT (0.01-2.5 mg/kg, subcutaneous (s.c.)) reduced both the paw licking and paw elevation induced by (2.5%) formalin injection into the plantar surface of the right hindpaw; it also produced forepaw treading. All of these effects were completely blocked by pretreatment with WAY 100635 (N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (0.16 mg/kg, s.c.); prazosin (0.63 mg/kg, s.c.) inhibited forepaw treading, but not 8-OH-DPAT's action on paw elevation and paw licking. Repeated injection of 8-OH-DPAT (0.63 mg/kg, s.c.) twice daily for 4 days, markedly reduced 8-OH-DPAT's ability to produce forepaw treading, but exerted only little and inconsistent effects on its paw licking and paw elevation-inhibiting action. The data indicate that 8-OH-DPAT exerts an analgesic action in the formalin model of tonic nociceptive pain; this action is mediated by 5-HT(1A) receptors, and is not confounded by the productive sign (i.e., forepaw treading) of the 5-HT syndrome which 8-OH-DPAT also induces.     

Effects of morphine on formalin-induced nociception in rats

This study focused on the antinociceptive action of morphine in the formalin test in rats. Formalin-induced behaviour is characterised by two phases relevant to acute and tonic pain. Morphine (1-6 mg/kg) was administered systemically before or after the early phase, and its ability to affect the late phase was investigated. Inhibitory effects of morphine (3 mg/kg) injected immediately after the early phase were significantly stronger (32+/-9%) compared to the preemptive administration (84+/-29%, relative to saline-treated controls, 5% formaldehyde). It appears that some neural and/or behavioural changes during the early phase limit effects of morphine on the late phase. Furthermore, manipulation of stimulation intensity (2% vs. 5% formaldehyde) significantly affected the ability of morphine (3 mg/kg) to suppress early (55+/-7% and 76+/-10%, respectively) but not late phase of formalin-induced behaviours. These results agree with the previous demonstrations on the effects of acute nociceptive stimulation intensity on analgesic potency of opiate drugs. Thus, the present study revealed two factors that affect the potency of morphine in formalin test: administration regimen and formalin concentration.     

Contralateral Circling Behaviour Induced by Intranigral Injection of Morphine and Enkephalin Analogue FK 33–824 in Rats

Abstract: Contralateral circling behaviour induced by intranigral injection of morphine or an enkephalin analogue, FK 33–824, was studied in rats. Both morphine(0.625–10.0μg)and FK 33–824(1.25–40.0 ng) evoked the same kind of contralateral circling behaviour when injected into the substantia nigra. FK 33–824 was about 1000 times more potent than morphine and its effect lasted a little longer. Pretreatment with naloxone (5 mg/kg subcutaneously or 1 μg intranigrally) almost completely blocked the circling induced by intranigral morphine or FK 33–824. The lesion of the ipsilateral nigrostriatal dopaminergic pathway with 6-hydroxydopamine significantly antagonized both morphine- and FK 33–824-induced circling. Pretreatment with d-amphetamine (l mg/kg intraperitoneally) significantly increased the intensity of the circling induced by morphine or FK 33–824, and pretreatment with haloperidol (0.5 mg/kg subcutaneously) attenuated this intensity. Pretreatment with pilocarpine (10 mg/kg intraperitoneally) or mecamylamine (2 mg/kg intraperitoneally) inhibited the circling, whereas pretreatment with atropine (10 mg/kg intraperitoneally) or nicotine (0.2 mg/kg subcutaneously) increased morphine- and FK 33–824-induced circling. Pretreatment with muscimol (0.5 mg/kg subcutaneously) did not significantly increase morphine-induced circling but tended to increase FK 33–824-induced circling. Pretreatment with bicuculline (3 mg/kg intraperitoneally) slightly but significantly inhibited both morphine- and FK 33–824-induced circling. Pretreatment with strychnine (0.25 mg/kg intraperitoneally) did not modify the circling induced by morphine or FK 33–824. The results show that the contralateral circling behaviour induced by intranigral injection of morphine and FK 33–824 seems to be mediated by the activation of the dopaminergic nigrostriatal system.     

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.     

Antinociceptive effects of Nigella sativa oil and its major component, thymoquinone, in mice

The antinociceptive effects of Nigella sativa oil and its major component, thymoquinone, were examined in mice. The p.o. administration of N. sativa oil (50-400 mg/kg) dose-dependently suppressed the nociceptive response in the hot-plate test, tail-pinch test, acetic acid-induced writhing test and in the early phase of the formalin test. The systemic administration (2.5-10 mg/kg, p.o. and 1-6 mg/kg, i.p.) and the i.c.v. injection (1-4 microgram/mouse) of thymoquinone attenuated the nociceptive response in not only the early phase but also the late phase of the formalin test. Naloxone injected s.c. (1 mg/kg) significantly blocked N. sativa oil- and thymoquinone-induced antinociception in the early phase of the formalin test. Moreover, the i.c.v. injection of naloxone (10 microgram/mouse), the mu(1)-opioid receptor antagonist, naloxonazine (1-5 microgram/mouse), or the kappa-opioid receptor antagonist, nor-binaltorphimine (1-5 microgram/mouse), significantly reversed thymoquinone-induced antinociception in the early phase but not the late phase of the formalin test, whereas the delta-opioid receptor antagonist, naltrindole (1-5 ng/mouse, i.c.v.), had no effect on either phase. The antinociceptive effect of morphine was significantly reduced in thymoquinone- and N. sativa oil-tolerant mice, but not vice versa. These results suggest that N. sativa oil and thymoquinone produce antinociceptive effects through indirect activation of the supraspinal mu(1)- and kappa-opioid receptor subtypes.     

Changes in nociception after acute and chronic administration of zimelidine: different effects in the formalin test and the substance P behavioural assay

The selective inhibitor of the reuptake of 5-hydroxytryptamine (5-HT), zimelidine, was administered intraperitoneally to mice (10 mg/kg) and nociceptive sensitivity was evaluated using the formalin test (20 microliters of 1% formalin, injected subcutaneously) and the assay for substance P (5 ng administered intrathecally). Zimelidine increased the behavioural response to formalin, but reduced the response to substance P. These effects of zimelidine seemed to be unchanged after chronic treatment (2 X 10 mg/kg for 14 days). It is suggested that zimelidine produces a central antinociceptive effect, but elicits a peripheral hyperalgesia, which predominates in the formalin test.     

The stress of a novel environment reduces formalin pain: possible role of serotonin

Compared to rats that were given three daily sessions of habituation to a laboratory environment, non-habituated rats were behaviourally less reactive when pain was produced by 0.05 ml of 2.5% formalin injected s.c. in one hindpaw. This behavioural analgesia was equivalent to that produced by approximately 2.0 mg/kg morphine and was interpreted as analgesia induced by the stress of exposure to a novel environment. Methysergide (10 mg/kg) or 1-valine (200 mg/kg) alone, or combined with naloxone (0.1 or 2.0 mg/kg), reversed the effect of exposure to a novel environment. Naloxone itself had no significant effect. In habituated rats 1-valine reduced the response to formalin-induced pain whereas methysergide combined with naloxone increased it. It is concluded that analgesia induced by the stress of exposure to a novel environment depends on serotonin.     

Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 µl) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.     

Morphine hyperalgesic effects on the formalin test in domestic fowl (Gallus gallus)

Preliminary research demonstrated that formalin injected into the foot of leghorn cockerels elicited significantly more footlifts of longer duration than physiological saline. The formalin test was subsequently used to examine morphine effects in this species. Previous research demonstrated strain-dependent naloxone-reversible morphine hyperalgesia against thermal nociception in cockerels. In Experiment 1 herein White Leghorn cockerels were given either 0.0, 0.5, 1.5, or 2.5% formalin SC into the foot 30 min after an IM injection of either physiological saline or 2.5 mg/kg morphine sulfate. The frequency and duration of formalin-elicited footlifts increased significantly as a function of formalin concentration. Morphine significantly increased footlift frequency and duration at all but the 0.0% formalin concentration. Morphine inhibited respiration in these animals. In Experiment 2, naloxone (5.0 mg/kg) significantly reversed both the hyperalgesia and the respiratory depression induced by morphine. These results demonstrate that morphine hyperalgesia in leghorn cockerels is neither unique to hot plate test procedures nor peculiar to thermal nociception. Atypical morphine effects in this model may be specific to nociception, however, because hyperalgesia was not accompanied by atypical morphine effects on respiration.     

Mazindol and lidocaine are antinociceptives in the mouse formalin model: involvement of dopamine receptor

The antinociceptive potential of mazindol, an anorectic drug, and lidocaine, an amide-type local anesthetic, were investigated in the mouse formalin test with concurrent motor function assessment. In addition, the role of dopamine and opioid receptors in mediation of the antinociceptive action of these drugs was examined. The i.p. injection of mazindol (1.25–10 mg/kg) and lidocaine (10–30 mg/kg) induced significant antinociceptive responses in both phases of the test. Cocaine (20 mg/kg, i.p.), used as positive control, also inhibited the pain responses caused by formalin. Haloperidol (0.2 mg/kg, i.p.), and sulpiride (5 mg/kg, i.p.), a dopamine D₂ receptor antagonist, reduced the antinociceptive actions of mazindol and cocaine, while SCH 23390, R(+)-7-chloro 8-hydroxy-3methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (0.03 mg/kg, i.p.), a dopamine D₁ receptor antagonist, did not affect these responses. Only the antinociception associated with mazindol was reversed by naloxone (2 mg/kg, i.p.). The same pretreatments failed to modify lidocaine-induced antinociception. The drug conditions used in this study did not reveal any motor impairment in the rotarod test. These observations suggest an involvement of dopaminergic mechanisms, mainly via dopamine D₂ receptors, in the antinociceptive action of mazindol in the formalin test, but the nature of mechanisms involved in the lidocaine responses remains unsolved.     

Locomotor activity in morphine-treated rats: Effects of and comparisons between cocaine,procaine, and lidocaine

The effects of cocaine, procaine, and lidocaine on open field and spontaneous (actophotometer) locomotor activities were assessed and compared in rats (1) treated acutely with morphine (single injection), (2) made dependent on morphine (SC pellets), (3) implanted with morphine and withdrawn at the time of peak dependence, and (4) implanted SC with lactose-containing pellets (sham). Cocaine-induced (10 or 30 mg/kg) open field and spontaneous locomotor activities were significantly greater in each of the four groups than those of the corresponding groups administered saline. Procaine (50 or 100 mg/kg) significantly reduced open field locomotor activity in all morphine-treated rats and spontaneous locomotor activity in acute rats. Lidocaine (30 mg/kg) significantly depressed spontaneous locomotor activity in acute rats. Upon comparison of the activities induced by the three local anesthetics, open field locomotor activity of sham-implanted rats was greater following cocaine (10 or 30 mg/kg) than following procaine (50 or 100 mg/kg). Only morphine withdrawn rats manifested greater activity following cocaine (10 mg/kg) than following either procaine (50 mg/kg) or lidocaine (10 mg/kg); activities were equivalent in dependent and acute rats. In contrast, cocaine-induced (30 mg/kg) open field locomotor activity of all morphine-treated rats was greater than either procaine- (100 mg/kg) or lidocaine- (30 mg/kg) induced activities. Spontaneous locomotor activity of all groups except acute morphine was greater following both doses of cocaine than following both doses of either procaine or lidocaine. In acute rats, only cocaine (10 mg/kg) induced greater activity than the other local anesthetics. Thus, stimulation of locomotor activity following cocaine treatment is a pharmacological property unique to cocaine and not shared by either procaine or lidocaine. Further, the data indicate that the methods selected for assessing locomotor activity may not give comparable results.