Morphine hyperalgesic effects on developmental changes in thermal nociception and respiration in domestic fowl (Gallus gallus).

Domestic fowl tested at 3, 5, and 7 days posthatch jumped from a heated grid more rapidly than animals tested at 14 days posthatch. Morphine (2.5 mg/kg) decreased jump latency in 14-day-old chicks but did not significantly affect jump latency in younger chicks. Respiration was lower in 3-day-old chicks than in the older groups but morphine depressed respiration at each age. In a second experiment morphine significantly decreased jump response latency in 5-day-old chicks when thermal stimulus intensity was lowered and morphine dose increased (5 mg/kg). Posttest respiration rate was depressed by morphine. Morphine hyperalgesia and respiratory depression were reversed by naloxone (5 mg/kg). However, naloxone alone increased jump response latency. Young domestic fowl are more sensitive and/or reactive to a noxious thermal stimulus and are less sensitive to morphine than 14-day-old chicks but morphine hyperalgesia was evident in both 5- and 14-day-old chicks. These hyperalgesic chicks may be tolerant at birth to morphine hypoalgesic effects on nociception.     

Time-dependent codeine hypoalgesia and hyperalgesia in domestic fowl.

Recent research demonstrated that codeine produced hypoalgesia and morphine produced hyperalgesia against a noxious thermal stimulus in young domestic fowl. The bidirectional effects of these opiate agonists on nociception are inconsistent with the notion that codeine's algesic effects result through in vivo demethylation of codeine to yield morphine. In Experiment 1, the temporal pattern (15,30,60 and 120 min) of codeine (30 mg/kg) effects on thermal nociception and respiration were examined in 15-day-old cockerels. Codeine produced a time-dependent biphasic response: hypoalgesia at 15 min and hyperalgesia at 60 and 120 min. Respiration was depressed by codeine at all test intervals. To assess for opioid specificity, Experiment 2 examined the action of naloxone (5 mg/kg) on the temporal pattern (15 and 60 min) of codeine effects (30 mg/kg) on thermal nociception and respiration. Bidirectional codeine algesic effects were observed at the 15- and 60-min test intervals. Naloxone increased the codeine jump latency scores at the 15-min interval and decreased codeine jump latency scores at the 60-min interval. These results suggest that codeine engages opposed nonopioid-mediated hypoalgesic and opioid-mediated hyperalgesic nociceptive systems in this animal model. Codeine depressed respiration at both the 15- and 60-min test intervals and this respiratory depression was reversed by naloxone. These findings support the notion that codeine respiratory effects are mediated by opioid system activity.     

Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance,cross-tolerance,and blockade by naloxone

Rationale Morphine and buprenorphine have analgesic and anxiolytic-like properties. While their analgesic effects have been well characterized, their anxiolytic-like properties have not. Objectives Effects of acute morphine and buprenorphine on the expression of acoustic fear-potentiated startle (FPS) and naloxone pretreatment were assessed. Effects of chronic morphine and buprenorphine on tolerance, cross-tolerance, and withdrawal were also examined. Materials and methods Fear-conditioned rats were given subcutaneous drug treatment immediately before testing for FPS. Experiment 1, rats were administered morphine (0.03, 0.25, 0.63, 2.5, or 10 mg/kg) or buprenorphine (0.004, 0.0075, 0.015, 0.03, or 0.25 mg/kg). Experiment 2, rats were given saline or naloxone (0.5 mg/kg) and 5min later given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg). Experiment 3, rats received once-daily injections of saline, morphine (10 mg/kg), or buprenorphine (0.25 mg/kg) for 7 days. Immediately before testing, saline-treated rats were given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg), morphine-treated rats were given morphine (2.5 mg/kg) or buprenorphine (0.03 mg/kg), and buprenorphine-treated rats were given buprenorphine (0.03 mg/kg) or morphine (2.5 mg/kg). Tolerance and cross-tolerance in analgesia were assessed via the tail-flick test, as were naloxone-precipitated withdrawal. Results Morphine and buprenorphine had parallel dose–response curves in blocking FPS, with buprenorphine 40 times more potent than morphine. Naloxone reversed these effects. Morphine and buprenorphine showed tolerance and cross-tolerance in their anxiolytic-like and analgesic effects. Chronic buprenorphine produced less withdrawal than chronic morphine. Conclusions Cross-tolerance between morphine and buprenorphine suggests a common receptor mediating their anxiolytic-like and analgesic effects.     

Effects of selective opiate antagonists on morphine-induced hyperalgesia in domestic fowl.

Although morphine typically produces analgesia in a variety of species, recent research has identified a biological model in which morphine produces a naloxone-reversible, paradoxical hyperalgesic response to a noxious thermal stimulus in young domestic fowl. The present study examined opioid receptor-mediation of this atypical opiate effect. Patterns of morphine hyperalgesia (1.25 to 5.0 mg/kg IM) were examined on a standard hot-plate test following administration (10 micrograms/5 microliters ICV) of the mu antagonist beta-funaltrexamine, the delta antagonist naltrindole, or the kappa antagonist nor-binaltorphimine in 15-day-old White Leghorn cockerels. Respiration measures were also recorded because they are indicative of opiate effects. Morphine produced a dose-dependent decrease in mean jump latencies (i.e., hyperalgesic effect). Mu receptor antagonism attenuated this morphine-induced hyperalgesic effect. Kappa receptor antagonism attenuated morphine-induced hyperalgesia only at the highest morphine dose (i.e., 5.0 mg/kg) and delta receptor antagonism failed to attenuate morphine-induced hyperalgesia. These results suggest that morphine-induced hyperalgesia, like morphine-induced analgesia, is mediated primarily by mu receptor activation.     

The effects of restraint stress on nociceptive responses induced by formalin injected in rat's TMJ

It has been reported that stress can alter nociception from superficial tissues, such as skin and subcutaneous region. However, the influence of stress on an experimental deep nociception model is not understood. In this study, the temporomandibular joint (TMJ) formalin test was used to evaluate the effects of acute and chronic restraint stress on nociceptive responses in rats. Animals were initially submitted to one session of acute restraint stress (1 h) or exposed to chronic stress (40 days-1 h/day). Then, animals were killed immediately to collect blood for hormonal determinations by radioimmunoassay, or submitted to the TMJ formalin test to evaluate nociception. Rats submitted to acute restraint presented a performance similar to unstressed controls in the TMJ formalin test, whereas chronically stressed rats showed an increase in nociceptive responses. After 40 days of restraint, morphine was injected i.p. (1, 5 mg/kg or saline). The stressed rats displayed decreased morphine effects on nociception compared to unstressed controls. These findings suggest that repeated stress can produce hyperalgesia, which is, at least in part, due to alterations in the activity of opioid systems. This model may help elucidate the underlying neural mechanisms that mediate the effects of repeated stress on orofacial pain.     

Differences in morphine-induced antinociception in male and female offspring born of morphine exposed mothers

Objective:

Antinociceptive effect of morphine in offspring born of mothers that received saline or morphine during the gestation period was investigated.

Materials and Methods:

Wistar rats (200-250 g) received saline, morphine 0.5 mg/kg or 5 mg/kg during gestation days 14-16. All pups after weaning were isolated treatment/sex dependently and were allowed to fully mature. The antinociceptive effect of morphine was assessed in formalin test. Morphine (0.5-7.5 mg/kg) or saline (1 ml/kg) was injected intraperitoneally 10 min before formalin (50 μl of 2.5% solution in right hind-paw).

Results:

Male offspring born of saline-treated mothers were less morphine-sensitive than females. On the contrary, male offspring exposed prenatally to morphine (5 mg/kg) were more sensitive to morphine-induced antinociceptive response in formalin test. However, no difference in antinociceptive effect was observed amongst offspring of either sex born of mothers treated with morphine 0.5 mg/kg, identifying a lower dose effect of the opioid.

Conclusion:

The exposure to morphine during the developmental period may result in altered development of tolerance to morphine and thus involved in drug abuse.KEY WORDS: Formalin test, gestation, morphine, offspring, pain     

Pharmacological evaluation of morphine and non-opioid analgesic adjuvants in a mouse model of skin cancer pain

Using a mouse model of advanced skin cancer which has mixed nociceptive-neuropathic pain, we evaluated the analgesic effects of morphine and analgesic adjuvants. Morphine hydrochloride (10--30 mg/kg, oral) and mexiletine hydrochloride (10--30 mg/kg, intraperitoneal) dose-dependently inhibited thermal hyperalgesia. Baclofen (10 mg/kg, subcutaneous) suppressed thermal hyperalgesia, without effects at lower doses of 1 and 5 mg/kg. Ketamine hydrochloride (50 mg/kg, oral) was without effect. Analgesic tolerance was observed after 6th administration of morphine, and it was not developed until at least 7th administration of mexiletine and baclofen. This mouse model of skin cancer may be useful for the pharmacological evaluation of the effects of opioids and analgesic adjuvants on mixed nociceptive-neuropathic pain of advanced cancer.     

Interactions between metoclopramide and morphine: enhanced antinociception and motor dysfunction in rats

1. Opioid analgesics and anti-emetics are often used concomitantly to treat pain and nausea and vomiting in people with malignant disease. We investigated interactions between the opioid analgesic morphine and the anti-emetic metoclopramide, a dopamine D2 receptor antagonist, on nociception and gross motor function. 2. To assess for antinociceptive interactions, 11 Sprague-Dawley rats were injected intraperitoneally with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5, 1.5 and 5.0 mg/kg) or saline and, 30 min later, the tail-flick latencies to a noxious thermal stimulus (49 degrees C water) were measured. Immediately thereafter we induced reperfusion hyperalgesia in the rats' tails using a tourniquet cuff and tested nociception again. Because, in addition to its ability to block D2 receptors, metoclopramide is also a weak 5-HT(3) receptor antagonist, we assessed in a further 11 rats whether any antinociceptive interactions occurred between morphine (5.0 mg/kg) and ondansetron (0.2 and 2.0 mg/kg), an anti-emetic that selectively antagonizes 5-HT(3) receptors. To assess for motor interactions, we injected another group of nine rats with morphine (5.0 mg/kg) or saline in combination with metoclopramide (0.5 and 5.0 mg/kg) or saline and tested the ability of the animals to run on an 80 mm diameter rod rotating at 25 r.p.m. for 30 min. 3. Metoclopramide was not inherently analgesic or antihyperalgesic, but the highest dose of metoclopramide (5.0 mg/kg) enhanced the analgesic and antihyperalgesic effects of morphine. Neither dose of ondansetron was analgesic or antihyperalgesic or enhanced the antinociceptive actions of morphine. 4. Only the high dose of metoclopramide compromised running performance when administered with saline. However, coadministering morphine with metoclopramide (both doses) decreased motor performance. 5. Therefore, metoclopramide, possibly through its actions on D2 receptors and not 5-HT(3) receptors, enhances the analgesic and antihyperalgesic effects of morphine, but morphine exacerbates metoclopramide-induced motor dysfunction in rats.     

Sex differences in hyperalgesia during morphine infusion: effect of gonadectomy and estrogen treatment

Morphine treatment can paradoxically increase nociception (i.e. hyperalgesia). Since there are putative sex differences in nociception and morphine sensitivity, we compared nociception in male and female mice using the tail-withdrawal test during continuous infusion of two morphine doses (1.6 and 40.0 mg/kg/24 h). Both doses caused hyperalgesia in both sexes, but onset in females always preceded that of males. Although the larger dose initially evoked analgesia, naltrexone (NTX) pellets implanted prior to morphine infusion abolished analgesia but not hyperalgesia. Distinct sex differences also characterized each morphine dose. Specifically, the lower morphine dose caused hyperalgesia that dissipated after 6 days in males but persisted in females for a minimum of 14 days. Despite this difference, N-methyl-d-aspartate (NMDA) receptor antagonists reversed hyperalgesia in both sexes. In contrast, the higher morphine dose evoked hyperalgesia that resolved concurrently in both sexes, but hyperalgesia was reversed by NMDA receptor antagonists in males only. Ovariectomy (OVX), but not OVX followed by estrogen treatment, abolished both sex differences, and resulted in females exhibiting the male-typical pattern. This study thus demonstrates NTX-insensitive morphine hyperalgesia in females as previously reported for males. However, females utilized hyperalgesic mechanisms which were distinct from those employed by males. Data from females subject to OVX/estrogen replacement further indicate that females possess functional male-typical hyperalgesic mechanisms, but are diverted from their use by ovarian sex steroids. Finally, the finding that each morphine infusion dose was characterized by a unique sex difference provides additional evidence for distinct multiple hyperalgesic systems.     

Central monoaminergic changes induced by morphine in hypoalgesic and hyperalgesic strains of domestic fowl.

The present research examined morphine dose-response effects on both the formalin test and on CNS monoamine (MA) levels and the metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in hypoalgesic (76) and hyperalgesic (SN) strains of domestic fowl. Morphine produced a significant hypoalgesic response in the 76 strain at 15-45 mg/kg and a significant hyperalgesic response in the SN strain at 5-10 mg/kg. In subsequent experiments, analyses of whole brain (minus tectum), brainstem, and spinal cord MA, DOPAC, and 5-HIAA via high-performance liquid chromatography with electrochemical detection (HPLC-EC) were performed following morphine administration in both the 76 and SN strains. Morphine produced a significant elevation of brain dopamine (DA) and a significant elevation of brain, brainstem, and spinal cord serotonin (5-HT) in both the 76 and SN strains. Morphine elevated brain norepinephrine (NE) in the 76 strain. However, morphine failed to affect brain NE in the SN strain. This distinct morphine effect on brain NE differentiates strain-dependent hypoalgesia and hyperalgesia in domestic fowl.     

Methylphenidate potentiates morphine-induced antinociception, hyperthermia, and locomotor activity in young adult rats

The goal of this study was to determine if the exaggerated morphine-induced conditioned place preference (CPP) response seen in adult rats after preweanling methylphenidate exposure is unique to reward-mediated behaviors or is indicative of generalized changes in opioid-mediated behaviors. Rats were exposed to saline or methylphenidate (2.0 or 5.0 mg/kg) for 10 consecutive days starting on postnatal (PD) 11 with testing beginning on PD 60. In Experiment 1, morphine-induced (0, 2.5, 5.0 or 10.0 mg/kg) antinociception was assessed using the tail immersion and hot plate tasks. In Experiment 2, morphine-induced (0, 2.5, 5.0, or 10.0 mg/kg) hyperthermia and locomotor activity were measured. Morphine caused an increase in antinociception, with early methylphenidate (5.0 mg/kg) exposure potentiating the effects of 5.0 mg/kg morphine. Rectal temperatures were elevated after morphine, with the greatest increase occurring in male rats. Methylphenidate potentiated the hyperthermic effects of morphine (10.0 mg/kg) but only in males. Moderate doses (2.5 and 5.0 mg/kg) of morphine increased the locomotor activity of adult rats, while a higher dose (10.0 mg/kg) decreased locomotion. Interestingly, methylphenidate-pretreated females showed increased locomotor activity relative to controls. These results suggest that early methylphenidate exposure induces general changes in opioid system functioning that are not specific to reward-mediated behaviors.     

Validation of a simple automated movement detection system for formalin test in rats

Aim: To investigate the validity and sensitivity of an automatic movement detection system developed by our laboratory for the formalin test in rats. Methods:The effects of systemic morphine and local anesthetic lidocaine on the nociceptive behaviors induced by formalin subcutaneously injected into the hindpaw were examined by using an automated movement detection system and manual measuring methods. Results: Formalin subcutaneously injected into the hindpaw produced typical biphasic nociceptive behaviors (agitation). The mean agitation event rate during a 60-min observation period increased linearly following increases in the formalin concentration (0.0%, 0.5%, 1.5%, 2.5%, and 5%, 50 μL). Systemic application of morphine of different doses (1, 2, and 5 mg/kg) 10-min prior to formalin injection depressed the agitation responses induced by formalin injection in a dose-dependent manner, and the antinociceptive effect induced by the largest dose (5 mg/kg) of morphine was significantly antagonized by systemic application of the opioid receptor antagonist naloxone (1.25 mg/kg). Local anesthetic lidocaine (20 mg/kg) injected into the ipsilateral ankle subskin 5-min prior to formalin completely blocked the agitation response to formalin injection. These results were comparable to those obtained from manual measure of the incidence of flinching or the duration time of licking/biting of the injected paw. Conclusion: These data suggest that this automated movement detection system for formalin test is a simple, validated measure with good pharmacological sensitivity suitable for discovering novel analgesics or investigating central pain mechanisms.     

Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and treatment of neuropathic pain remains a challenge. The purpose of the present study was to examine the effect of ethosuximide, an anti-epileptic and relatively selective T-type calcium blocker and morphine, a prototypical opioid in the behavioral responses following the chronic constriction injury (CCI) model of neuropathic pain. Experiments were performed on eight groups (n=8) of male Sprague-Dawley rats (230-280 g). The animals were injected with saline, ethosuximide (100, 200, 300 mg/kg), morphine (4 mg/kg), and a combination of morphine (4 mg/kg) plus ethosuximide (100mg/kg, i.p.). The cold-and mechano-allodynia and thermal hyperalgesia were measured prior to surgery (the day 0) and 3, 5, 7, 14 and 21 days post surgery. Ethosuximide and morphine significantly decreased cold and mechano allodynia and thermal hyperalgesia. However, the co-administration of both drugs seems to be more effective than the ethosuximide or morphine alone on cold and mechano allodynia and thermal hyperalgesia .Our results suggest that ethosuximide block tactile and thermal hypersensitivity after the CCI model, also, ethosuximide potentiates the analgesic effects of morphine in neuropathic pain conditions and behavioral responses.     

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.     

Morphine effects on gentamicin disposition and toxicity in mice

Morphine has been shown to reduce renal and hepatic clearance of several xenobiotics in rodents. After iv administration of gentamicin, 10 to 30 mg/kg, its plasma levels were elevated in mice given morphine, 20 mg/kg sc. Plasma clearance of gentamicin was nearly halved by morphine, due primarily to lowering of the elimination constant of gentamicin from 0.03 to 0.02 min-1 (p less than 0.01). Morphine also significantly reduced urine levels of gentamicin and urine volume. In mice given naloxone, 2 mg/kg sc, morphine did not significantly raise plasma levels of gentamicin nor reduce its elimination into urine. Mice were made tolerant by morphine administration for 9 days at ascending doses to 100 mg/kg twice daily. An acute challenge with morphine, 20 mg/kg, was less effective in raising plasma levels of gentamicin or lowering its urinary elimination in tolerant mice than after chronic saline treatment. Partial tolerance to acutely administered morphine and reversal of morphine effects by naloxone suggest opioid receptor-mediated reduction of glomerular filtration by morphine in mice. Despite marked elevation of plasma gentamicin levels in morphine-treated mice, narcotic administration did not significantly increase the acute toxicity of a single dose of gentamicin. LD50 of acutely administered iv gentamicin was 51.6 mg/kg after saline and 45.3 mg/kg after treatment with morphine, 20 mg/kg sc. However, this dose of morphine enhanced the lethality of intravenously infused gentamicin. Morphine administration significantly reduced the dose of infused gentamicin needed to achieve the critical lethal plasma level.     

A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80

delta-Opioid receptor agonists have been postulated to induce analgesia without the adverse effects commonly associated with mu-opioids e.g. morphine. In the present study, we evaluated the occurrence of antinociceptive and opioid-like side effects in rats (n=5-7) treated with a single dose of subcutaneous morphine (0.01 to 40 mg/kg) or SNC80 (0.63 to 80 mg/kg). The antinociceptive effects of morphine and SNC80 were compared using a range of nociceptive tests including the tail withdrawal test, the acetic acid-induced abdominal constriction (writhing) assay, the automated formalin test and a model of inflammation-induced thermal hyperalgesia. The adverse effects of both drugs were examined in animal models for gastrointestinal (GI) inhibition (charcoal test; ricinus oil test), respiratory depression (blood-gas analysis), motor disturbances (automated rotarod model) and abuse liability (drug discrimination learning). Morphine displayed significant antinociceptive and adverse effects in all the animal models employed. SNC80 exhibited a significant effect in the writhing test and limited efficacy in a model of inflammation-induced thermal hypersensitivity. A delay in the occurrence of diarrhoea and some limited increases in PCO(2) were observed with the higher doses of SNC80 (> or =40 mg/kg). In conclusion, the delta-opioid agonist SNC80 lacks both the analgesic efficacy and adverse effects of mu-opioids. However, the activity of SNC80 in the inflammatory model suggests delta-opioid agonists may be useful analgesics in the treatment of some forms of inflammatory pain.     

Large-amplitude 5-HT1A receptor activation: a new mechanism of profound,central analgesia

We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.     

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.     

The alpha2A-adrenoceptor subtype is not involved in inflammatory hyperalgesia or morphine-induced antinociception

The purpose of the present study was to investigate the role of the alpha(2A)-adrenoceptor subtype in inflammatory hyperalgesia, and in adrenergic-mu-opioid interactions in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and thermal stimuli were studied in alpha(2A)-adrenoceptor knockout mice and their wild-type controls. Thermal nociception was evaluated as paw withdrawal latencies to radiant heat applied to the hindpaws. Mechanical nociception was measured using von Frey monofilament applications to the hindpaws. Mechanical and thermal hyperalgesia, induced with intraplantar carrageenan (1 mg/40 microl) were compared in alpha(2A)-adrenoceptor knockout and wild-type mice. The effects of the systemically administered mu-opioid receptor agonist morphine (1-10 mg/kg) were evaluated on mechanical withdrawal responses under normal and inflammatory conditions in knockout and wild-type mice. Withdrawal responses to radiant heat and von Frey monofilaments were similar in alpha(2A)-adrenoceptor knockout and wild-type mice before and after the carrageenan-induced hindpaw inflammation. Also, the antinociceptive effects of morphine in mechanical nociceptive tests were similar before and after carrageenan-induced hindpaw inflammation. Our observations indicate that alpha(2A)-adrenoceptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia. In addition, alpha(2A)-adrenoceptors do not appear to play an important role in mu-opioid receptor-mediated antinociception or antihyperalgesia.     

Functional magnetic resonance imaging studies of opioid receptor-mediated modulation of noxious-evoked BOLD contrast in rats

Rationale Functional magnetic resonance imaging (fMRI) in rats can non-invasively identify brain regions activated by physiological stimuli and the effects of pharmacological intervention on these responses. Objectives This study was conducted to investigate the effects of systemic administration of the μ-opioid receptor agonist morphine on whole brain functional signal intensity in anaesthetised rats; to investigate whether pre-treatment with the opioid receptor antagonist naloxone blocks the effects of morphine; to determine whether pre-treatment with morphine attenuates noxious-evoked changes in whole brain functional signal intensity. Methods Continuous whole brain fMRI scanning was used to study brain signal intensity prior to, and following, systemic administration of morphine (5 mg/kg, n=7), systemic administration of naloxone (1 mg/kg) and morphine (n=8). Effects of pre-treatment with saline (n=5) or morphine (5 mg/kg, n=5) on formalin (5%, intraplantar)-evoked changes in signal intensity were determined. Data were processed using SMP99 with fixed-effects analysis (p<0.05). Results Morphine produced significant positive bilateral increases in signal intensity in the cingulate cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05), and these effects were blocked by naloxone. Intraplantar injection of formalin produced a significant positive increase in signal intensity in the cingulate cortex, somatosensory cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05). Morphine attenuated formalin-evoked increases in signal intensity in the PAG, amygdala, hypothalamus and cingulate cortex. Conclusion Our data demonstrate that morphine modulates noxious-evoked changes in signal intensity in discrete brain regions. fMRI studies in rats are able to identify specific brain regions involved in the pharmacological modification of physiologically evoked changes in regional brain activation.