Desipramine enhances opiate postoperative analgesia

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid-mediated analgesia systems.     

Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy

Fenfluramine is an indirect agonist of 5-hydroxytryptamine (5-HT) receptors that acts by evoking 5-HT release and blocking 5-HT reuptake in neuronal cells. The current study compared the antinociceptive properties of fenfluramine with those of the tricyclic antidepressants amitriptyline and desipramine in rat models of acute, persistent, and neuropathic pain. In a rat model of neuropathic pain produced by tight ligation of the L(5)/L(6) spinal nerves, i.v. bolus injection of fenfluramine resulted in a dose-dependent and long-lasting (>4 h) blockade of mechanical allodynia (ED(50) = 3.5 mg/kg; 95% confidence interval, 2.2-5.4 mg/kg) and cold allodynia (ED(50) = 2.4 mg/kg; 95% confidence range, 1.2-4.6 mg/kg). Fenfluramine also prevented tonic pain evoked by the s.c. injection of dilute (5%) formaldehyde solution (formalin), into the dorsal hindpaw. The i.v. administration of amitriptyline (4.7 mg/kg) or desipramine (13.5 mg/kg) at maximum tolerated doses did not block either allodynia in rats with spinal nerve ligation-induced painful neuropathy or tonic pain in the formalin test. Fenfluramine had differential effects on acute behavioral responses to noxious thermal (heat), chemical (5% formaldehyde solution), and mechanical stimuli; it completely inhibited nociceptive behavior in the acute phase of the formaldehyde solution test and partially inhibited licking and jumping responses in the hot-plate test but did not alter nociceptive thresholds in either the paw pressure test or the tail immersion test. Intracerebroventricular bolus injection of 240 microg of fenfluramine significantly increased mechanical allodynia thresholds; however, the same dose administered spinally by intrathecal bolus injection was ineffective. The inhibitory effects of fenfluramine on mechanical allodynia (and tonic pain behavior in the formaldehyde solution test) were prevented by pretreatment with 10 mg/kg metergoline, a selective antagonist of 5-HT receptors, but not with the mu-opioid receptor antagonist naloxone. These results suggest that fenfluramine produces analgesia in the formaldehyde solution test and the spinal nerve ligation model of neuropathic pain by potentiating, at least in part, supraspinal 5-HT mediated processes.     

Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats

The present study was performed to evaluate the effects of the tricyclic antidepressant amitriptyline on morphine tolerance in rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters with or without a microdialysis probe, then received a continuous i.t. infusion of saline (control) or morphine (15 microg/h) and/or amitriptyline (15 microg/h) for 5 days. The results showed that amitriptyline alone did not produce an antinociceptive effect, while morphine alone induced antinociceptive tolerance and down-regulation of spinal glutamate transporters (GLAST, GLT-1, and EAAC1) in the rat spinal cord dorsal horn. Co-administration of amitriptyline with morphine attenuated morphine tolerance and up-regulated GLAST and GLT-1 expression. On day 5, morphine challenge (10 microg/10 microl) resulted in a significant increase in levels of the excitatory amino acids (EAAs), aspartate and glutamate, in CSF dialysates in morphine-tolerant rats. Amitriptyline co-infusion not only markedly suppressed this morphine-evoked EAA release, but also preserved the antinociceptive effect of acute morphine challenge at the end of infusion. Glial cells activation and increased cytokine expression (TNFalpha, IL-1beta, and IL-6) in the rat spinal cord were induced by the 5-day morphine infusion and these neuroimmune responses were also prevented by amitriptyline co-infusion. These results show that amitriptyline not only attenuates morphine tolerance, but also preserves its antinociceptive effect. The mechanisms involved may include: (a) inhibition of pro-inflammatory cytokine expression, (b) prevention of glutamate transporter down-regulation, and even up-regulation of glial GTs GLAST and GLT-1 expression, with (c) attenuation of morphine-evoked EAA release following continuous long-term morphine infusion.     

In vivo characterization of MMP-2200, a mixed δ/μ opioid agonist, in mice

We have previously reported the chemistry and antinociceptive properties of a series of glycosylated enkephalin analogs (glycopeptides) exhibiting approximately equal affinity and efficacy at δ opioid receptors (DORs) and μ opioid receptors (MORs). More detailed pharmacology of the lead glycopeptide MMP-2200 [H?N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-β-D-lactose)-CONH?] is presented. MMP-2200 produced dose-related antinociception in the 55°C tail-flick assay after various routes of administration. The antinociceptive effects of MMP-2200 were blocked by pretreatment with the general opioid antagonist naloxone and partially blocked by the MOR-selective antagonist β-funaltrexamine and the DOR-selective antagonist naltrindole. The κ opioid receptor antagonist nor-binaltorphimine and the peripherally active opioid antagonist naloxone-methiodide were ineffective in blocking the antinociceptive effects of MMP-2200. At equi-antinociceptive doses, MMP-2200 produced significantly less stimulation of locomotor activity compared with morphine. Repeated administration of equivalent doses of morphine and MMP-2200 (twice daily for 3 days) produced antinociceptive tolerance (~13- and 5-fold rightward shifts, respectively). In acute and chronic physical dependence assays, naloxone precipitated a more severe withdrawal in mice receiving morphine compared with equivalent doses of the glycopeptide. Both morphine and MMP-2200 inhibited respiration and gastrointestinal transit. In summary, MMP-2200 acts as a mixed DOR/MOR agonist in vivo, which may in part account for its high antinociceptive potency after systemic administration, as well as its decreased propensity to produce locomotor stimulation, tolerance, and physical dependence in mice, compared with the MOR-selective agonist morphine. For other measures (e.g., gastrointestinal transit and respiration), the significant MOR component may not allow differentiation from morphine.     

Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat.

Amitriptyline, a non-selective noradrenaline (NA) and 5-hydroxytryptamine (5-HT) reuptake inhibitor, has recently been demonstrated to produce a peripheral antinociceptive action in an inflammatory (formalin test) and a neuropathic pain model (spinal nerve ligation). In the present study, we determined whether desipramine, a selective NA reuptake inhibitor, and fluoxetine, a selective 5-HT reuptake inhibitor, could produce peripheral antinociceptive actions in these same tests. Effects on paw volume also were determined. In the 2.5% formalin test, desipramine and fluoxetine 10-300 nmol produced a dose-related reduction in phase 2 (16-60 min) flinching and biting/licking behaviours when coadministered with the formalin. Phase 1 flinch behaviours (0-12 min) were significantly reduced at the highest dose. These actions are peripherally mediated, as they were not seen when desipramine or fluoxetine (100, 300 nmol) were injected into the contralateral hindpaw. The peripheral action of desipramine and fluoxetine was not altered by coadministration of caffeine 1500 nmol. In the spinal nerve ligation model, desipramine 100 nmol, but not fluoxetine 100 nmol, produced a peripheral anti-hyperalgesic action in the hindpaw corresponding to the ligated side when thresholds were determined using a thermal paw stimulator. In paw volume experiments, desipramine, at doses which are maximally effective in behavioural tests, produced only a slight increase in paw volume, but fluoxetine (10-300 nmol) produced a robust and sustained dose-related increase in paw volume. Amitriptyline also produced minimal effects on paw volume. When coinjected with formalin, no agent significantly altered the degree of paw swelling produced by formalin. The increase in paw volume produced by fluoxetine was inhibited by ketanserin (5-HT2 receptor antagonist), mepyramine (histamine H1 receptor antagonist) and phentolamine (alpha-adrenergic receptor antagonist), but not by the other selective 5-HT receptor antagonists tested or caffeine. The pronounced peripheral pain alleviating actions in the absence of marked changes in paw volume produced by desipramine and amitriptyline, but not fluoxetine, in the formalin test and the spinal nerve ligation model suggest that these agents could be developed as cream or gel formulations to recruit a peripheral antinociceptive action in inflammatory and neuropathic pain states. Such a formulation might permit the attainment of higher and more efficacious concentrations in the region of the sensory nerve terminal, with limited systemic side effects.     

A comparative study of monoaminergic involvement in the antinociceptive action of E-2078, morphine and U-50,488E.

E-2078 ([N-methyl-Tyr1, N-alpha-methyl-Arg7, D-Leu8]dynorphin A(1-8) ethylamide) is a systemically active dynorphin analog. We examined monoaminergic involvement in the antinociceptive action of E-2078 compared with morphine and U-50,488E (trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)- benzene-acetamide monohydrochloride). The antinociceptive effect of these drugs was determined using the mouse tail-flick test after depletion of norepinephrine or 5-HT by pretreatment with various neurotoxins. Reserpine (i.p.) depleted both norepinephrine and 5-HT. Selective degeneration of noradrenergic nerves was induced by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, i.p.) or intrathecal (i.t.) 6-hydroxydopamine (6-OHDA), whereas 5-HT was depleted by p-chlorophenylalanine (PCPA, i.p.) or 5,7-dihydroxytryptamine (5,7-DHT, i.t.). The antinociceptive action of E-2078 administered s.c. was significantly attenuated in mice treated with reserpine, DSP-4, 6-OHDA, PCPA or 5,7-DHT compared with that in non-neurotoxin animals. Antinociception induced by intracerebroventricular (i.c.v.) and i.t. injection of E-2078 was reversed by reserpine, DSP-4 or PCPA. The antinociceptive action of morphine (s.c.) was attenuated by reserpine, DSP-4, 6-OHDA and PCPA, but not by 5,7-DHT. Antinociception produced by i.c.v. morphine was antagonized by reserpine, DSP-4 and PCPA. In contrast, morphine given i.t. was not affected by these neurotoxins. U-50,488E (s.c.)-induced antinociception was attenuated by reserpine, DSP-4, 6-OHDA, PCPA and 5,7-DHT. Intracerebroventricular U-50,488E was antagonized by reserpine, DSP-4 and PCPA, whereas i.t. U-50,488E was reversed only by reserpine and PCPA(ABSTRACT TRUNCATED AT 250 WORDS)     

Ketamine analgesia is not related to an opiate action in the periaqueductal gray region of the rat brain

Ketamine is an injectable anesthetic agent that has been shown to interact as an agonist at opiate receptors. In addition, its antinociceptive action in rats is antagonized by the narcotic receptor antagonist naloxone. Thus it was assumed that the anesthetic may activate the pain inhibitory pathway, originating in the periaqueductal gray (PAG) and descending into the spinal cord, in a manner similar to that of narcotics like morphine. In the present study, it was verified that the systemic administration of naloxone (3 mg/kg i.p.) antagonized the elevation in tail-flick latency produced by an anesthetic dose of ketamine (160 mg/kg i.p.), but did not alter the duration of anesthesia (defined as duration of the loss of the righting reflex). However, when naloxone (3 micrograms/0.5 microliter/30 sec) was given by microinjection into the PAG it was found to be ineffective against the ketamine-induced elevation of the tail-flick latency. In contrast, the microinjection of the antagonist significantly attenuated (halved) the elevated latency in response to systemically administered morphine (4 mg/kg s.c.). It was also shown that ketamine was unable to elicit an increase in the latency of the tail-flick reflex when administered directly into the PAG over a wide range (0.10-100 micrograms) of doses. On the other hand, a local anesthetic-like effect of ketamine, known to occur when the drug is used in high concentration, was observed when doses exceeding 0.1 microgram were injected into the PAG. This action interfered with opiate actions in the PAG and made data from the microinjection studies difficult to interpret. The descending, pain inhibitory neuronal system originating in the PAG does not appear to participate in the antinociceptive action of ketamine measured by the tail-flick reflex. Perhaps the drug's effects are associated with alternative opiate mechanisms and/or opiate receptor subtypes not present on the cells of origin of the descending nerves within the PAG.     

Interactions of tricyclic antidepressants and barbiturates in barbiturate-tolerant and nontolerant rats.

Pretreatment of rats with tricyclic antidepressants, imipramine, desipramine, amitriptyline and nortriptyline, at two doses (5 and 25 mg/kg) 20 minutes before administration of barbiturate markedly reduced the latent period of the response to barbital and prolonged the sleeping time induced by pentobarbital (PB) and barbital. The effects were dose-dependent. The prolonged sleeping time produced by PB was associated with decreases in the rates of disappearance of PB from the brain and plasma. The effect of tricyclic antidepressants on PB hypnosis in PB-tolerant and nontolerant rats was apparently not related to change in central nervous system (CNS) sensitivity to PB, since at the time of awakening there were no significant differences in the concentrations of unmetabolized PB in either the plasma or brain of tricyclic antidepressant-treated animals as compared to controls. As barbital is not metabolized, potentiation of barbital hypnosis by tricyclic antidepressants must be attributable to a direct effect on CNS rather than on liver microsomal enzymes. Direct evidence was provided by the findings that amitriptyline accelerated the brain uptake of barbital and that amitriptyline-treated animals lost and recovered the righting reflex at brain barbital levels lower than those of controls. Rats made tolerant to the hypnotic effect of barbital also became tolerant, in varying degrees, to the hyposis-prolonging properties of tricyclic antidepressants. It is concluded that tricyclic antidepressants prolong PB sleeping time in PB-tolerant and nontolerant rats by inhibiting its biotransformation in the liver. The action of tricyclic antidepressants to prolong the hypnotic action of barbital in normal rats is related to their direct effects on CNS sensitivity to barbital, but such effects are makedly diminished after animals become tolerant to barbital.     

Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial

Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.     

The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine

The anesthetic agent, ketamine, has the potential to recruit spinopetal noradrenergic and serotonergic neuronal pathways for its antinociceptive effect. Neurochemically, ketamine has been shown to interact with opiate receptors and thus may increase neuronal activity in the spinopetal monoaminergic (norepinephrine and serotonin) systems in a manner similar to morphine. In addition, ketamine should facilitate the antinociceptive effect of the monoamines at the level of the spinal cord by an action of the drug to prevent the neuronal reuptake of the monoamines. In this study, the analgesic action of both ketamine and morphine, as measured by the tail-flick test in rats, was inhibited by norepinephrine, serotonin and opiate receptor antagonists. Monoaminergic receptor inhibitors were more potent as antagonists of ketamine's analgesia while the opiate receptor antagonist naloxone was more effective against morphine analgesia. The greater sensitivity of the antinociceptive effect of ketamine to monoaminergic antagonist may reflect the importance of the inhibition of norepinephrine and serotonin reuptake in the analgesic action of the drug.Transecting the spinal cord of rats at T4-6 revealed distinct differences between the analgesic mechanisms of ketamine and morphine. For example, the potency of ketamine was increased nearly 9-fold in spinal rats whereas morphine's potency was decreased. This observation suggests that ketamine may activate both analgesic and antanalgesic systems supraspinally, and that its antinociceptive effect in intact animals is a summation of these opposing actions. Partial evidence that supraspinal noradrenergic neurons might be involved in the antanalgesic component of ketamine's action was provided by experiments demonstrating enhanced analgesia in intact animals after depletion of norepinephrine with FLA-63.In spinal animals a significant difference was also observed in the neuronal processes mediating the residual analgesic effects of morphine and ketamine. The analgesic effect of morphine remained primarily sensitive to naloxone but seemed to use a local serotonergic process (sensitive to the serotonergic antagonist methysergide) at higher doses of the opiate. Ketamine's analgesia, on the other hand, was only inhibited by methysergide.In conclusion, although it appears that morphine and ketamine may both activate spinopetal monoaminergic processes through an opiate mechanism, the two drugs differ significantly with regard to some of the components of their antinociceptive actions. The differences may be related to ketamine's ability to alter the metabolism of monoaminergic neurotransmitters involved in pain processing.     

Opposing effect of apomorphine on antinociceptive activity of morphine: a dose-dependent phenomenon

Apomorphine, when administered intracerebroventricularly (0.05 mg/kg) to rats, increased tail-flick latency (a spinal nociceptive response). However, intraperitoneal administration at doses of 1, 3 and 10 mg/kg had no effect, probably because of a tonic supraspinal inhibitory influence on spinal dopaminergic neurones involved in segmental nociceptive processes. Depending on the doses administered, intraperitoneal administration of apomorphine exhibited opposite effects on antinociceptive activity of morphine. Pretreatment with a low dose of apomorphine (1 mg/kg) attenuated, whereas, a high dose (10 mg/kg) potentiated morphine-induced antinociception. Dopamine antagonists, in doses that preferentially block autoreceptors, i.e., haloperidol (0.1 mg/kg, i.p.) and (-)-sulpiride (5 mg/kg, i.p.), antagonised the attenuation of morphine antinociception by a low dose of apomorphine, while treatment with a high dose of haloperidol (1 mg/kg, i.p.) and pimozide (1.25 mg/kg, i.p.) completely antagonised the potentiating effect of a high dose of apomorphine on the antinociceptive activity of morphine. The attenuation of morphine antinociception thus appears to be due to decreased dopaminergic activity as a result of preferential dopamine autoreceptor stimulation by a low dose of apomorphine, whereas potentiation with a high dose of apomorphine is caused by enhanced dopaminergic activity via postsynaptic receptor stimulation.     

Antinociceptive effects of acute and 'chronic' injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats.

The tricyclic antidepressant drugs (TCAs) are commonly used in the treatment of chronic, especially neuropathic, pain. We evaluated their possible effect on a new model of neuropathic pain-related behaviour induced by ligatures tied loosely around the common sciatic nerve. The effects of 3 TCAs with different monoaminergic spectra (clomipramine, amitriptyline and desipramine) were assessed 2 weeks after surgery, the time of the maximum hyperalgesia, on a 'phasic' test (vocalization threshold to paw pressure) and on a 'tonic' test (score of the spontaneous pain-related behaviour). TCAs were acutely (0.5 and 2 mg/kg, i.v.) and 'chronically' injected (7 injections, once every half-life of the drug: 0.75 and 1.5 mg/kg, s.c., for clomipramine and 1.5 and 3 mg/kg, s.c., for amitriptyline and desipramine). Acutely injected clomipramine and amitriptyline (0.5 mg/kg, i.v.) and desipramine (2 mg/kg, i.v.) showed an antinociceptive naloxone-reversible effect, assessed by an increase in the vocalization threshold to the paw pressure test and, for amitriptyline, by a decrease in tonic pain scores. Chronically injected TCAs induced a significant and progressive increase in the vocalization threshold with a time course parallel to that of their suspected plasma or nerve tissue levels: (i) a regular increase of scores for the first 3-4 injections, (ii) then a plateau until the last injection, and (iii) a progressive decrease with a dose-dependent duration of the effect, longer than that obtained with a corresponding acute dose. This study showed that in this new model of mononeuropathy, acutely and chronically injected TCAs induce an antinociceptive effect and suggested that their analgesic action could be related to the monoaminergic spectrum of the drug in relation to the opiate systems.     

Sertraline versus amitriptyline in the prophylactic therapy of non-depressed chronic tension-type headache patients

Abstract Patients with chronic tension- type headache (CTTH) are the most difficult to treat. Tricyclic antidepressants are the first-line therapeutic agents, but their anticholinergic side effects limit their usage. Selective serotonin reuptake inhibitors (SSRI) with fewer side effects than tricyclic antidepressants have also been used in treatment of CTTH, but the results are conflicting. In this study, prophylactic action of sertraline in treatment of nondepressed patients with CTTH was investigated and compared with amitriptyline in a prospective, randomized, open label, parallel-group study. A 4-week baseline period was followed by a 12-week treatment period with either 50 mg sertraline (n=41 patients) or 25 mg amitriptyline (n=44 patients). Efficacies of treatments were determined by using a headache diary, in which patients recorded the occurrence, number, intensity and duration of headaches in days, analgesic drug consumption and any adverse events. Both drugs reduced headache symptoms and analgesic drug consumption at the first, second and third months of treatment compared to baseline values. There was significant superiority of amitriptyline in the headache symptoms and drug consumption reductions versus sertraline at the second and third months of treatment. Side effects were more favorable in the sertraline-treated patients, but dropouts were similar in both groups. These results suggest that both drugs were effective in the treatment of non-depressed patients with CTTH, but in comparison between groups, amitriptyline was more effective than sertraline.     

The glycine/NMDA receptor antagonist (+)-HA966 enhances the peripheral effect of morphine in neuropathic rats

Systemic opioid dosing until adequate analgesia in neuropathic pain may involve intolerable and untreatable side effects. Peripheral opioid receptor mechanisms may participate in the antinociceptive effect of systemic morphine. We evaluated the effect of peripherally injected morphine alone, and the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex (+)-HA966 to modulate the antinociceptive effect of peripheral morphine in a rat model of neuropathic pain. Mononeuropathy was induced by placing four ligatures around the common sciatic nerve. Experiments were performed 2 weeks after the nerve ligature, when the pain-related behavior reached a stable maximum. Rats received injections of either subcutaneous (+)-HA966 (2.5mg/kg) or saline administered 20 min before morphine (50-150 microg injected into the nerve-injured hindpaw). The antinociceptive effect was tested against mechanical (vocalization threshold to hindpaw pressure) or thermal (struggle latency to hindpaw immersion into a 46 degrees C hot water bath) stimuli. In both tests, morphine alone (100-150 microg) produced antinociception. Pretreatment with (+)-HA966 did not potentiate the analgesic effectiveness of the two highest doses of morphine, but it did produce analgesia when combined with a low dose of morphine (50 microg), which did not produce analgesia by itself. These effects were reversed by intraplantar naloxone methiodide (50 microg injected into the nerve-injured hindpaw) indicating a peripherally opioid-mediated mechanism of action. The present studies suggested that combined administration of glycine/NMDA receptor antagonists, and peripherally acting morphine may be an interesting approach in the treatment of neuropathic pain.     

Serotonergic mediation of descending inhibition from midbrain periaqueductal gray, but not reticular formation, or spinal nociceptive transmission in the cat

Electrical stimulation in the midbrain periaqueductal gray (PAG) and lateral midbrain reticular formation (LRF) strongly suppresses the responses of spinal dorsal horn neurons to noxious heating of the skin. The possible role of serotonin (5-hydroxytryptamine, 5-HT) was investigated by quantitatively comparing certain parameters of descending inhibition from PAG and LRF in normal cats [14,15] and cats whose central 5-HT levels had been reduced by pretreatment with p-chlorophenylalanine (PCPA, 300 or 500 mg/kg i.p., 72 h prior to acute experiment). Single lumbar dorsal horn neuronal responses to noxious radiant heating of glabrous footpad skin(50 degrees C, 10 sec, 1/3 min) were recorded in normal and PCPA-pretreated cats anesthetized with sodium pentobarbital and N2O. Inhibition of neuronal heat-evoked responses during midbrain stimulation (mean frequency 30 Hz, up to 800 microA current intensity) was expressed as percent of the unit's control response in the absence of midbrain stimulation. Inhibition by PAG stimulation of units from cats pretreated with 300 mg/kg PCPA (mean inhibition at 450 microA to 60% of control in 12 units) was not detectably different from that in control (non-pretreated) cats. However, inhibition by PAG stimulation was significantly weaker in units from cats pretreated with 500 mg/kg PCPA (mean to 83.4% of control in 9 units). In the latter group, mean current threshold for inhibition was higher, and slope of current-intensity plots lower, than in the control and 300 mg/kg PCPA pretreatment groups. In contrast, mean inhibition by LRF stimulation was enhanced in the 300 and 500 mg/kg PCPA treatment groups in a dose-related manner. In normal (non-pretreated) cats, systemic administration of the putative 5-HT antagonist methysergide (0.07--1 mg/kg) reduced or abolished inhibition by PAG stimulation in each of 8 units. Low doses of methysergide had little or no effect on inhibition produced by LRF stimulation in 6 units. The results suggest pharmacologically distinct mechanisms of inhibition produced by stimulation in PAG and LRF.     

Intrathecal morphine and clonidine: antinociceptive tolerance and cross-tolerance and effects on blood pressure

The effects of acute and chronic intrathecal (i.t.) administration of the opioid receptor agonist, morphine, or the alpha-2 adrenoceptor agonist, clonidine, on nociception and blood pressure were examined in rats. In rats lightly anesthetized with pentobarbital, morphine produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 10.0 micrograms) and small, non-dose-related pressor effects. These effects were antagonized by pretreatment with the opioid receptor antagonist naloxone (30.0 micrograms i.t.), whereas the alpha-2 adrenoceptor antagonist yohimbine (30.0 micrograms i.t.) potentiated the pressor effects and did not alter the antinociceptive effects of morphine. Chronic treatment with morphine (32.0 micrograms/day for 7 days) produced tolerance to the antinociceptive effects of morphine in conscious rats, and chronic morphine or chronic clonidine (32.0 micrograms/day for 7 days) reduced the antinociceptive potency of morphine in lightly anesthetized rats. The pressor effects of morphine were attenuated by chronic morphine and were converted to marked, dose-dependent depressor effects by chronic clonidine. Clonidine dose dependently inhibited the tail-flick reflex in lightly anesthetized rats (ED50 = 1.7 micrograms) and produced biphasic effects on blood pressure; lesser doses (0.1-3.2 micrograms) produced depressor effects whereas a greater dose (10.0 micrograms) produced a pressor response. Yohimbine, but not naloxone, antagonized the antinociceptive effects of clonidine, whereas both yohimbine and naloxone altered the dose-response function for the effects of clonidine on blood pressure. Tolerance developed to the antinociceptive effects of clonidine in the hot-plate, but not in the tail-flick, test in conscious rats. In lightly anesthetized rats, the antinociceptive potency of clonidine was reduced by chronic clonidine or chronic morphine, whereas chronic clonidine, but not chronic morphine, shifted the dose-response function for effects of clonidine on blood pressure to the right. These results indicate that the antinociceptive effects of acute i.t. morphine and clonidine are mediated by spinal opioid and alpha-2 adrenergic receptors, respectively. However, tolerance to and cross-tolerance between i.t. morphine and i.t. clonidine suggest that spinal opioid and alpha-2 adrenergic systems interact in producing antinociception. These systems also appear to interact in complex ways to exert effects on blood pressure.     

The competitive N-methyl-D-aspartate receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) potentiates the antinociceptive effects of opioids that vary in efficacy at the mu-opioid receptor

(-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) is a competitive N-methyl-D-aspartate receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. Although administration of LY235959 alone generally does not produce antinociception, LY235959 potentiates the antinociceptive effects of morphine in squirrel monkeys. The present study was designed to determine whether LY235959 would potentiate the acute antinociceptive effects of morphine as well those of the opioid receptor agonists l-methadone, levorphanol, butorphanol, and buprenorphine. A squirrel monkey titration procedure was used in which shock (delivered to the tail) increased in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15-s shock period (fixed ratio 5) produced a 15-s shock-free period after which shock resumed at the next lower intensity. Morphine (0.3-3.0 mg/kg i.m.), l-methadone (0.1-0.56 mg/kg i.m.), levorphanol (0.1-1.0 mg/kg i.m.), butorphanol (1.0-10 mg/kg i.m.), and buprenorphine (0.01-0.03 mg/kg i.m.), but not LY235959 (0.1-1.0 mg/kg i.m.), dose and time dependently increased the intensity below which monkeys maintained shock 50% of the time (median shock level, MSL). LY235959 dose dependently potentiated the effect of each opioid agonist on MSL when concurrently administered to monkeys. Although LY235959 potentiated the antinociceptive effect of each opioid examined in a statistically significant manner, LY235959 seemed more potent and effective when combined with higher efficacy opioids. The present data suggest that the N-methyl-D-aspartate antagonist, LY235959, can potentiate the antinociceptive effects of a range of opioid receptor agonists independently of nonspecific motor effects.     

Opioid agonist and antagonist antinociceptive properties of [D-Ala2,Leu5,Cys6]enkephalin: selective actions at the deltanoncomplexed site

The present study used the irreversibly binding enkephalin analog, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) in an effort to determine whether selective agonist and antagonist properties could be demonstrated at hypothesized types of opioid delta receptors previously termed the deltanoncomplexed and the deltacomplexed sites. These putative subtypes of delta receptors have been functionally distinguished on the basis of involvement (i.e., deltacomplexed) in the modulation of mu-mediated effects such as antinociception. Intracerebroventricular administration of DALCE or the reference delta and mu agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and morphine, to mice all produced antinociception in the warm-water tail-flick test in a dose- and time-related manner. Maximal effects with DALCE were seen at +10 min and significant antinociception could be detected for approximately 1 hr; DALCE was 3- and 90-fold more potent than i.c.v. morphine and DPDPE, respectively. The antinociceptive effects of i.c.v. DALCE and DPDPE, but not those of morphine, were antagonized by the selective delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, suggesting that the antinociception associated with the peptides was mediated through a delta receptor. DALCE pretreatment up to 24 hr before testing, a time at which this compound did not produce antinociception, significantly blocked the i.c.v. DPDPE antinociceptive effect as well as that of DALCE itself, but not that of morphine, suggesting long-lasting DALCE antagonism at a delta receptor. Modulation of morphine antinociception was demonstrated with subeffective doses of i.c.v. DPDPE or [Met5]enkephalin, but not with subeffective doses of i.c.v. DALCE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pre-treatment with amantadine on morphine induced antinociception during second phase formalin responses in rats

The clinically available NMDA-receptor antagonist drug, amantadine, has been shown to result in morphine sparing effects in humans after surgery. However, no data are available to describe the exact form of interaction. The present study aims to profile the possible effects of amantadine (0, 12.5, 25 or 50 mgkg(-1) i.p.) pre-treatment on morphine (0, 0.63, 1.25, 2.5 or 5 mgkg(-1) s.c.) induced antinociception in rats. The (automated) formalin test (5% formalin, 50 microl) was used to assess if amantadine enhances the antinociceptive activity of morphine. Possible motor impairment was assessed with a rotarod test. Morphine was measured in serum of amantadine or vehicle treated rats to search for possible pharmacokinetic interactions between amantadine and morphine. Isobolographic analysis provided evidence for a synergistic interaction between amantadine and morphine in the second phase of the formalin test. No evidence was found to indicate that amantadine induced motor impairment at the doses potentiating morphine during the second phase of the formalin test. There was no evidence for a pharmacokinetic interaction between amantadine and morphine. Since, the second phase of the formalin test is dependent on activation of the NMDA receptor system it is concluded that an antagonistic activity of amantadine at the NMDA receptor most likely contributes to the synergistic interaction observed between amantadine and morphine in rats.     

Guanethidine and related agents: III. Antagonism by drugs which inhibit the norepinephrine pump in man

Antagonism of the antihypertensive action of guanethidine by the tricyclic antidepressants, desipramine and protriptyline, has been demonstrated in controlled studies. These antidepressants also prevent the effect of the related ring-substituted guanidinium adrenergic neuron blockers, bethanidine and debrisoquin. That the rise in blood pressure when desipramine is added to guanethidine therapy is not due simply to a pressor action of the two drugs in combination was demonstrated by the lack of an increase in blood pressure when guanethidine was added to desipramine therapy.Investigations were conducted to determine whether antagonism of guanethidine's clinical effect could result from blockade by the tricyclic antidepressants of the norepinephrine pump in the adrenergic neuron membrane, thereby preventing the uptake of guanethidine into the neuron by this pump. Like guanethidine, the indirectly acting pressor amine, tyramine, enters the neuron via the norepinephrine pump. Desipramine, protriptyline, and amitriptyline in clinical doses all were found to block the pressor action of tyramine while potentiating the pressor effect of norepinephrine. The amino acid, methyldopa, does not enter the neuron via the norepinephrine pump, and its antihypertensive action is not altered by concomitant administration of tricyclic antidepressants. It is concluded from the evidence in this investigation together with the results of previous studies in experimental animals that clinical doses of desipramine-like drugs inhibit the norepinephrine pump in the peripheral adrenergic neuron in man and thereby prevent uptake of guanethidine to its site of action.