Ultralow dose fentanyl prevents development of chronic neuropathic pain in rats.

BACKGROUND: Opioids may cause progressive enhancement of pain sensitivity (opioid-induced hyperalgesia [OIH]) and thus, exacerbate existing pain. Animal studies also demonstrate paradoxical OIH with an ultralow dose (ULD, subanalgesic) of opioid; eg, the µ-opioid, morphine. Repeated administration of ULD-morphine resulted in tolerance to ULD-OIH. Prior exposure to ULD-morphine prolonged subsequent morphine antinociception in intact rats (delay of tolerance) and blocked neuropathic pain in nerve-injured rats (no hyperalgesia). Hence, pre-emptive desensitization of the excitatory function of opioid receptors may reduce further activation of a pain facilitatory system exerted by opioid or nerve injury. OBJECTIVE: We determined if ULD-fentanyl (µ-opioid) and U50488H (κ-opioid) also affect post-nerve-injury neuropathy (a rat model of chronic constriction nerve injury [CCI]). DESIGN: Fentanyl (0.5-500 ng/kg) was administered acutely in noninjured rats. Chronic fentanyl (5 ng/kg/day) was initiated either immediately after CCI (day 1-28) or when neuropathy was established (day 7-14) in nerve-injured rats. U50488H (25 µg/kg/day) was given on day 1-28 post-CCI. Saline served as control. Responsiveness was assessed using tail-flick and paw-pressure tests, respectively, in intact and CCI Sprague-Dawley rats of both sexes. RESULTS: ULD-fentanyl evoked pain sensitization in noninjured rats. ULD-OIH was related to dose (inversely), gender (female > male), and was reversed by ketamine. Neuropathy developed after CCI in control (saline) rats. This was not observed in rats of either sex exposed to ULD-fentanyl on day 1-28 post-CCI. Rats treated with ULD-fentanyl from day 7 after CCI exhibited hyperalgesia similar to control rats. U50488H did not block post-CCI neuropathy (regardless of gender). CONCLUSIONS: Pre-emptive use of ULD µ-opioid (not κ-opiod) blocked initiation (not maintenance) of neuropathic pain after CCI in rats. These data may suggest a novel treatment approach in situations when the potential development of neuropathy can be anticipated.

Opioid-induced hyperalgesia and burn pain.

The treatment of pain produced during the management of burn injury has been an ongoing problem for physicians caring for these patients. The main therapeutic option for analgesia has been the repeated and prolonged use of opioids. The adverse effects of opioids are well known but the long term use of opioids which produces tolerance with accompanying dose escalation and dependence is most problematic. Another potentially important consequence of opioid exposure that sometimes masks as tolerance is that of opioid induced hyperalgesia. This syndrome is manifest as enhanced pain, sensitivity and loss of analgesic efficacy in patients treated with opioids who actually become sensitized to painful stimuli. This article focuses on the treatment of burn pain and how current analgesic therapies with opioids may cause hyperalgesia and affect the adequacy of treatment for burn pain. This article also provides possible modalities to help therapeutically manage these patients and considers future analgesic strategies which may help to improve pain management in this complicated patient population.

Novel small molecule α9α10 nicotinic receptor antagonist prevents and reverses chemotherapy-evoked neuropathic pain in rats.

BACKGROUND: Peripheral neuropathy is a common dose-limiting side effect of chemotherapy. There are no clinically proven analgesics for the treatment of this condition. Drugs from different classes have been tested with mixed results. Identification of novel molecular targets for analgesic(s) is important. Antagonism of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype (absent in brain) is thought to underlie analgesic efficacy of peptide α-conotoxins. We found novel nonpeptide small molecule analogs from a family of tetrakis-, tris-, and bis-azaaromatic quaternary ammonium salts (high potency with selectivity as antagonists at the α9α10 nAChRs) to produce dose-related analgesia in rat models of nerve injury-evoked neuropathy and persistent inflammatory pain. No tests were done in a model of neuropathy induced by drug administration (ie, chemotherapy). METHODS: In this study, a lead bis-analog, ZZ1-61c, was characterized in a rat model of vincristine-evoked neuropathy. Male Sprague-Dawley rats were repeatedly dosed with the vinca-alkaloid, vincristine (100 µg/kg/day IP, days 1 to 5 and 8 to 12). ZZ1-61c (100 µg/kg/day IP) was given either along with or after completion of vincristine (commencing by day 15 when neuropathy was maximum). Responsiveness was assessed with von Frey hairs and the paw-pressure test. The effects of ZZ1-61c on motor function (rotarod) and muscle strength (grip test) were characterized in naïve rats. RESULTS: The development of neuropathy was demonstrated with repeated dosing of vincristine (pain hypersensitivity in response to mechanical stimulation). ZZ1-61c showed both preventive and restorative effects on this condition: (1) vincristine-evoked sensitivity to pressure was reduced by coadministration of ZZ1-61c; (2) established neuropathy was diminished by ZZ1-61c after cessation of chemotherapy. ZZ1-61c did not cause motor dysfunction (rotarod) or muscular weakness (the grip test). CONCLUSIONS: This study suggests that ZZ1-61c, a novel compound with a unique mechanism of antagonistic action at the α9α10 nAChR, may be a potential drug candidate for prevention and attenuation of neuropathic pain resulting from chemotherapy. Such a strategy may provide effective treatment that circumvents toxicity of centrally acting agonists at nAChR.

Effect of prior treatment with ultra-low-dose morphine on opioid- and nerve injury-induced hyperalgesia in rats.

BACKGROUND: In addition to producing analgesia, opioids can increase sensitivity to pain (opioid-induced hyperalgesia [OIH]) in humans and rodents. Tolerance/OIH is likely mediated by similar mechanisms that lead to development of hyperalgesia after nerve injury (neuropathic pain). OIH may be a reason for loss of opioid efficacy and/or a worsening of pain. Ultra-low-dose (ULD) opioid evokes hyperalgesia independently of analgesia. Tolerance to ULD-OIH develops with repeated dosing in rats. OBJECTIVE: The effects of ULD opioids were characterized in two distinct situations where hyperalgesia is expected to occur: following acute opioid treatment and after nerve injury. DESIGN: First, ULD morphine was repeatedly administered (2x day for 5 days) by intrathecal (i.t., 0.01 microg) or intraperitoneal (i.p., 20 microg/kg) routes in rats. Second, morphine (0.01 microg i.t.; 20 microg/kg i.p.) was administered (2x day for 5 days) prior to acute morphine (30 microg i.t.; 10 mg/kg i.p). Third, ULD morphine (20 microg/kg/2x day, i.p.) was given either immediately after nerve injury (days 1-28) or when hyperalgesia was manifested (days 7-14). The tail-flick and paw-pressure tests were used in noninjured and nerve-injured rats, respectively. RESULTS: Tolerance was developed to OIH with repeated ULD morphine by the i.p. route but not the i.t. route. Prior exposure to ULD morphine (i.p.) caused prolongation of morphine analgesia in intact rats and inhibition of the development (but not reversal) of hyperalgesia in nerve-injured rats. Abolishment of OIH (pain desensitization) may diminish activation of pain facilitatory systems due to nerve injury and opioid treatment. CONCLUSIONS: Although the translational aspect of this preclinical study has limitations, the present data may suggest a new strategy for the pre-emptive use of ULD opioids to prevent the development of neuropathic pain with certain procedures or disease states.

The novel small molecule α9α10 nicotinic acetylcholine receptor antagonist ZZ-204G is analgesic.

Chronic pain is inadequately managed with currently available classes of analgesic drugs. Recently, peptide antagonists of the α9α10 nicotinic acetylcholine receptor were shown to be analgesic. The present study was conducted to characterize a novel small molecule, non-peptide antagonist at nicotinic receptors. The tetrakis-quaternary ammonium compound ZZ-204G was evaluated for functional activity on cloned nicotinic receptors expressed in Xenopus oocytes. In-vivo efficacy was assessed in rat models of tonic inflammatory pain (formalin test), neuropathic pain (chronic constriction nerve injury), and thermal nociception (tail flick test). ZZ-204G was an antagonist at nicotinic receptors inhibiting the α9α10 subtype with an IC50 of 0.51 (0.35-0.72) nM. Antagonist activity at other nicotinic subtypes (α1ß1δε, α2ß2, α2ß4, α3ß2, α3ß4, α4ß2, α4ß4, α6/α3ß2ß3, α6/α3ß4 and α7) was 10-1000-fold lower than at the α9α10 subtype. In competition binding assays, the k(i) of ZZ-204G at γ-aminobutyric acid(A), serotonin(3), γ-aminobutyric acid(B), κ- and µ-opioid receptors was 1000- to >10,000-fold lower than at α9α10 nicotinic receptors. Parenteral administration of ZZ-204G dose-dependently decreased nociceptive behaviors (paw flinches) in the formalin test and mechanical hyperalgesia in the chronic constriction nerve injury model of neuropathic pain. ZZ-204G was not antinociceptive in the tail flick assay. Results from the rotarod assay indicated that lower doses of ZZ-204G that were analgesic did not alter motor function. In summary, ZZ-204G represents a prototype small molecule antagonist for α9α10 nicotinic receptors and provides a novel molecular scaffold for analgesic agents with the potential to treat chronic inflammatory or neuropathic pain.

Priapism following a lumbar sympathetic nerve block.

OBJECTIVE: To understand an unusual complication of a common procedure. DESIGN: This article chronicles the side effect of a lumbar sympathetic nerve block (LSNB). SETTING: Loyola University Medical Center Outpatient Chronic Pain Clinic. PATIENTS: One. RESULTS: Our patient had several hours of priapism following a LSNB. CONCLUSIONS: A bilateral lumbar sympathetic nerve block can lead to unopposed parasympathetic penile stimulation and cause priapism.

Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain.

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

Buprenorphine-induced hyperalgesia in the rat.

In addition to analgesia opioids may also enhance pain sensitivity. Opioid-induced hyperalgesia, typically associated with potent mu-opioid agonists (e.g. fentanyl, morphine, and heroin), may be of clinical importance due to the possible counteraction of analgesia and/or paradoxical enhancement of a pre-existing pain condition during opioid therapy. Buprenorphine, a potent opioid analgesic, has a complex pharmacology on mu and kappa receptors. Buprenorphine has a better analgesia/toxicity profile (a ceiling effect for respiratory depression, less potential for abuse) compared to typical mu-opioids. Little is known about buprenorphine-induced hyperalgesia. Potentially, a lack of hyperalgesia with these other characteristics could make buprenorphine a more desirable opioid for management of chronic pain. Responsiveness to high and ultra-low doses of buprenorphine was examined following acute and repeated administration in a rat model of thermal nociception (the tail-flick test). Buprenorphine produced a dose-related antinociception. Loss of efficacy (tolerance) followed by enhanced pain sensitivity occurred with repeated dosing of buprenorphine. Delayed hyperalgesia, seen in association with antinociceptive tolerance, was blocked by the NMDA receptor antagonist, ketamine. Buprenorphine (ultra-low dose) resulted in immediate hyperalgesia, which was also reversed by ketamine, in a dose-related fashion. No tolerance to hyperalgesia was seen with repeated dosing of low-dose buprenorphine. The antinociceptive effect of buprenorphine was diminished in rats, which previously exhibited hyperalgesia with buprenorphine. In summary, bimodal properties of buprenoprhine were separately demonstrated: pronociceptive at ultra-low dose and antinociceptive at higher doses. An NMDA-receptor mechanism was involved in hyperalgesia with buprenorphine.

Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain.

Mu-opioids (i.e. morphine, oxycodone, hydrocodone) are considered to be the primary drugs for treatment of moderate to severe acute, chronic and cancer pain. Despite their analgesic effectiveness they have several clinically significant side-effects (cognitive, motor, respiratory, cardiovascular, gastrointestinal). They also have a limited spectrum of action, being more effective for nociceptive than neuropathic pain. In an effort to identify other opioid analgesics with greater effectiveness in mixed pain states and with a better side-effect profile compared to the classical mu-opioid agonist, morphine, a relatively little-known morphine derivative, morphine-6-O-sulfate, was characterized using a range of well-established rodent pain models. The present data demonstrated that morphine-6-O-sulfate was efficacious after several routes of administration, including neuroaxial (intrathecal), parenteral (intraperitoneal) and oral in the rat. It showed potent, dose-related, analgesic activities against acute nociceptive pain (the tail flick test), neuropathic pain (chronic constriction nerve injury hyperalgesia and allodynia) and inflammatory pain (formalin test). It had a good separation based on dose (at least 10-fold) between side-effects (incoordination, hypolocomotion, inhibition of gastrointestinal motility) and analgesia in all models of pain tested. In addition, morphine-6-O-sulfate had a more favorable potency ratio for delay of gastrointestinal transit and analgesia when compared to morphine. These preclinical findings suggest that morphine-6-O-sulfate is a potential candidate for development as a novel opioid for management of nociceptive, neuropathic and mixed pain states.

The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain.

Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(-)- and R(+)-enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(-)- rather than the R(+)-enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)-enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(-)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(-)-nornicotine (sub-analgesic dose) was combined with a low-dose of the micro-opioid, morphine. These preclinical data suggest that S(-)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, and mixed pain).

The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers.

Abuse of prescription opioids has risen precipitously in the United States. Few controlled comparisons of the abuse liability of the most commonly abused opioids have been conducted. This outpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential and potency of oral oxycodone (10, 20 and 40 mg), hydrocodone (15, 30 and 45 mg), hydromorphone (10, 17.5 and 25mg) and placebo. Healthy adult volunteers (n=9) with sporadic prescription opioid abuse participated in 11 experimental sessions (6.5h in duration) conducted in a hospital setting. All three opioids produced a typical mu opioid agonist profile of subjective (increased ratings of liking, good effects, high and opiate symptoms), observer-rated, and physiological effects (miosis, modest respiratory depression, exophoria and decrements in visual threshold discrimination) that were generally dose-related. Valid relative potency assays revealed that oxycodone was roughly equipotent to or slightly more potent than hydrocodone. Hydromorphone was only modestly more potent (less than two-fold) than either hydrocodone or oxycodone, which is inconsistent with prior estimates arising from analgesic studies. These data suggest that the abuse liability profile and relative potency of these three commonly used opioids do not differ substantially from one another and suggest that analgesic potencies may not accurately reflect relative differences in abuse liability of prescription opioids.

Effects of norketamine enantiomers in rodent models of persistent pain.

NMDA-receptor antagonists are potential drugs for chronic pain treatment, in particular for neuropathic pain involving central sensitization processes. Clinical use of available NMDA antagonists, such as ketamine, is limited for this indication due to its side effects (psychotomimetic, sedative, motor). There is a need for novel NMDA-receptor antagonist(s) with better analgesia/toxicity profile(s). One such potential candidate is norketamine, a primary metabolite of ketamine. S(+) and R(-)norketamine were characterized utilizing rodent models of persistent pain: the chronic constriction nerve injury model of peripheral neuropathy (CCI) and the formalin-injection model of tonic inflammatory pain (formalin test). Side effects (motor coordination, stereotypic behaviors, locomotor activity) were also assessed. (+/-)Ketamine served as a reference NMDA-receptor antagonist in some studies. Norketamine alleviated, in a dose-dependent fashion, mechanical and thermal hyperalgesia (CCI), and blocked formalin-induced flinches (2nd phase). It had less effect on tactile allodynia (CCI). Efficacy was demonstrated after parenteral and oral administration. The antinociceptive properties resided primarily in the S(+) enantiomer. Antinociception was not accompanied by significant side effects. The present findings suggest that norketamine, in particular the S(+) enantiomer, might be a useful NMDA-receptor antagonist for treatment of chronic pain involving central sensitization.

Interaction between morphine and norketamine enantiomers in rodent models of nociception.

Ketamine, one of a few clinically-available N-Methyl-D-aspartate (NMDA)-receptor antagonists, is known to improve the analgesic efficacy of opioids in humans and rodents. However, the use of ketamine in combination with opioids is mainly restricted to the perioperative setting, due to severe psychotomimetic, sedative and motor side effects. Recent data from our laboratory demonstrated that a major metabolite of ketamine, norketamine, in particular the S(+) enantiomer, had a better antinociception/side effects profile than ketamine in rats. It is unknown if norketamine affects opioid antinociception. In the present study, morphine (a low dose) was combined with S(+)- and R(-)-norketamine (sub-antinociceptive doses) and characterized utilizing rodent models of pain including: thermal nociception (the tail-flick test), peripheral neuropathy (chronic constriction nerve injury) and tonic inflammatory pain (the formalin test). The data showed that: 1) Norketamine enhanced morphine antinociception and blocked tolerance to this effect; 2) Norketamine potentiated morphine effectiveness in the alleviation of symptoms resulting from injury to nerve (mechanical hyperalgesia, tactile allodynia) and peripheral tissue (formalin-induced nociceptive behavior); 3) S(+)-norketamine was more potent than R(-)-norketamine; 4) Antinociception was not confounded by significant side effects. Morphine-S(+)-norketamine combination drug therapy may prove clinically useful for the alleviation of acute and chronic pain of differing etiology.

Characterization of the antinociceptive and pronociceptive effects of methadone in rats.

BACKGROUND: Recently, it has been appreciated that in addition to their antinociceptive properties, opioid analgesics also can enhance pain sensitivity (opioid-induced hyperalgesia [OIH]). OIH may enhance preexisting pain and contribute to dose escalation, tolerance, and misuse/abuse of opioids. Better information is needed to determine which opioid or opioid combinations may be least likely to produce OIH and therefore possibly represent better choices for pain management. Herein the authors have examined the hyperalgesic and antinociceptive properties of racemic methadone and its enantiomers alone and in combination with morphine in rats. Methadone is of particular interest because it possesses both micro-receptor agonist and N-methyl-d-aspartate receptor antagonist activities. METHODS: The antinociceptive and hyperalgesic properties of d,l-methadone, l-methadone, and d-methadone were characterized by dose and sex using the thermal tail-flick test (high and low intensity). The responses to l- and d-methadone combinations with morphine were also determined with this model. RESULTS: Antinociceptive and hyperalgesic effects of d,l-methadone were demonstrated. These effects were related to dose but not to sex. The degree of hyperalgesia was greater with l-methadone compared with d,l-methadone. In contrast, d-methadone (N-methyl-d-aspartate antagonist) did not produce hyperalgesia. Furthermore, d-methadone blocked morphine hyperalgesia, enhanced antinociception, and abolished sex-related differences. This seems to be the result of antagonistic activity of d-methadone at the N-methyl-d-aspartate receptor. CONCLUSION: The current findings with methadone are supportive of previous findings implicating mu-opioid and N-methyl-d-aspartate receptor mechanisms in OIH. Better understanding of OIH may help in choosing the most appropriate opioids for use in the treatment of pain.

Characterization of the antinociceptive effect of oxycodone in male and female rats.

A number of investigators have shown that sex plays an important role in the analgesic effects of opioids. Typically, the antinociceptive responsiveness to mu opioid agonists such as morphine is greater in male than in female rats. The effect of sex on kappa opioid analgesia is less known. The present study was conducted to examine sex-related differences in responsiveness to oxycodone (putative kappa/mu opioid agonist). This information is important since oxycodone is widely used clinically for treatment of pain. The present results indicated that oxycodone had a greater antinociceptive response in female rats compared to male rats. This sex specific responsiveness to oxycodone, however, was lost with chronic administration. The greater antinociception in female rats was even more prominent with U50,488H (selective kappa agonist). Further, low (subanalgesic) doses of oxycodone and U50,488H enhanced the sensitivity to pain (hyperalgesia) to a greater extent in male than in female rats. This is in contrast to the previously shown greater hyperalgesic effect of subanalgesic doses of the mu opioid agonist, morphine, in female than in male rats. The present findings suggest that sexual dimorphism in the effect of opioids is related to the opioid receptors on which they predominately act.

Characterization of morphine-induced hyperalgesia in male and female rats.

The pain enhancing (hyperalgesic) effect of morphine was characterized in relation to pain stimulus (thermal, mechanical), dose, mode of administration (acute, chronic), sex and mechanism. We found that a low (subanalgesic) dose of morphine enhanced the sensitivity to thermal and mechanical noxious stimuli in a dose- and sex-related manner. Morphine hyperalgesia was inversely related to dose (0.002-0.2mg/kg) and was more pronounced in female than male rats. The N-methyl-d-aspartate receptor antagonist, ketamine, antagonized morphine hyperalgesia. Tolerance developed to hyperalgesia following repeated (chronic) dosing with low dose morphine. Several additional findings were noted in rats tolerant to morphine-induced hyperalgesia. The efficacy of an analgesic dose of morphine was increased (female rats). Sex-related differences in morphine's analgesic action (male>female) were attenuated. Development of tolerance to the analgesic effect of morphine was delayed. The present findings may have an implication for the use of mu opioids in the clinical setting.

Morphine tolerance in male and female rats.

Several studies indicate greater sensitivity to morphine (MOR) analgesia in male compared to female rats under the acute dosing condition. The present study investigated whether the same sex difference in sensitivity persists in MOR-tolerant rats. MOR was administered chronically (7 mg/kg twice daily) until tolerance developed in each rat. Tolerant rats were treated randomly with higher graded doses of MOR (10-25 mg/kg). Analgesia (tail-flick test) and spontaneous motor activity (total locomotion) were measured. The present data confirmed previous studies showing a greater sensitivity to acute MOR in male than in female rats. However, the sex differences seen in MOR sensitivity were abolished in tolerant rats. The rate of acquisition of tolerance was similar in male and female rats. The analgesic response was not affected by motor depression.

Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats.

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan (DEX), ketamine (KET), and MK-801 on morphine (MOR)-induced antinociception has been investigated in male and female rats. DEX (7.5, 15, and 30 mg/kg), KET (0.75, 1.5, and 3 mg/kg), and MK-801 (0.075, 0.15, and 0.3 mg/kg) dose-dependently enhanced MOR-induced (3 mg/kg) analgesia in female rats. DEX and KET enhanced the peak effect, whereas MK-801 increased both magnitude and duration of analgesia. DEX also enhanced MOR-induced analgesia in male rats. However, the interaction was of less magnitude in male compared with female rats. The effects of KET and MK-801 on MOR-induced analgesia were negligible in male rats. A 3-mg/kg dose of MOR given alone produced greater analgesia in male than in female rats, but in the presence of NMDA antagonists, MOR elicited similar analgesic responses in both sexes.

The effects of flumazenil on the antinociceptive actions of morphine in rats.

The 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (Flumazenil)-morphine interaction on analgesia (acute pain model, tail-flick test) was tested after intraperitoneal (IP) and intrathecal (IT) routes of administration in female rats. Analgesia was enhanced by the concurrent administration of Flumazenil with morphine (IP), in a dose-related way. Flumazenil alone (IP) did not produce analgesia. In contrast, morphine analgesia was not enhanced by Flumazenil by the IT route. These data demonstrate that Flumazenil enhances morphine-mediated antinociception by mechanisms that are likely to involve benzodiazepine receptors at sites other than the spinal cord.

Modification of morphine analgesia and tolerance by flumazenil in male and female rats.

This study assessed the effect of the central benzodiazepine receptor antagonist, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (flumazenil), on morphine-induced analgesia, locomotor effects, and development of tolerance in rats. The thermally evoked pain (tail flick) response was determined after acute and chronic intraperitoneal (i.p.) administration of morphine and flumazenil, alone and in combination. In acute studies, flumazenil induced weak analgesia unrelated to dose and sex, whereas morphine-induced analgesia was dependent on both dose and sex (male>female). Flumazenil dose-dependently enhanced the analgesic effect of morphine in female but not in male rats. Isobolographic analysis suggested synergism between flumazenil and morphine in female rats, but antagonism in male rats. Flumazenil-induced locomotor changes (alone and with morphine) were related to sex but not dose. Chronic coadministration of flumazenil with morphine enhanced analgesia and attenuated tolerance development in female rats. The findings suggest a possible role for flumazenil as an adjunct with opioids in acute and chronic pain therapy.