Non-opioid Mechanisms Research Articles

Effects of naltrexone and histamine antagonists on the antinociceptive activity of the cimetidine analog SKF92374 in rats

A recent study showed that SKF92374, a structural analog of the histamine H 2 receptor antagonist cimetidine, induces antinociception after intraventricular (i.v.t.) administration in the rat. SKF92374 lacked significant activity on H 1 or H 2 receptors, but had weak activity on H 3 receptors. To test the hypothesis that SKF92374-induced antinociception is mediated by an action on H 3 receptors, the effects of the H 3 agonist R- α-methylhistamine (RAMH) and the H 3 antagonist thioperamide (both by i.v.t. administration) were investigated on SKF92374 antinociception. SKF92374-induced antinociception was slightly enhanced by thioperamide (30 μg), but unaffected by a range of doses of RAMH (up to 2 μg). Furthermore, SKF92374-induced antinociception was not reduced by large doses of systemically-administered antagonists of H 1 (pyrilamine), H 2 (zolantidine), H 3 (GT-2016), or opioid (naltrexone) receptors. These findings show that the novel compound SKF92374 induces antinociception by a non-opioid mechanism that does not utilize brain H 1, H 2 or H 3 receptors.

P-86 - Forced walking stress-induced antinociception through a non-opioid mechanism in mice

P-86 - Forced walking stress-induced antinociception through a non-opioid mechanism in mice

The NMDA Receptor Antagonist, NPC 12626, Reduces the Pronociceptive Effects of Orphanin FQ and Kappa Opiate Antinociception in the Land Snail, Cepaea nemoralis

KAVALIERS, M., E. CHOLERIS AND D. M. SAUCIER.The NMDA receptor antagonist, NPC 12626, reduces the pronociceptive effects of orphanin FQ, and kappa opiate antinociception in the land snail, Cepaea nemoralis. PEPTIDES 18(7) 943–947, 1997.—The heptadecapeptide, orphanin FQ or nociceptin (Phe-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln), originally isolated from rat brain has been identified as an endogenous ligand for the orphan opioid-like receptor. Although orphanin FQ shares some sequence and structural homology with kappa-opioid peptides, it has been speculated to exert its effects through novel nonopioid mechanisms. Kappa opioids have also been suggested to have nonopioid actions in rodents involving the N-methyl-D-aspartate (NMDA) receptor. The present study examined the effects of the competitive NMDA antagonist, NPC 12626, on the antinociceptive effects of the specific kappa-opiate receptor agonist, U69,593, and the pronociceptive effects of orphanin FQ in an invertebrate system, the land snail, Cepaea nemoralis. NPC 12626 had no effect on the basal nociceptive sensitivity of snails, as measured by the latency of response to a thermal (40°C) surface. As reported for rodents, NPC 12626 dose-dependently reduced U69,593-induced antinociception in a manner comparable to that produced by the specific kappa-opiate antagonist, nor-binaltorphimine, while slightly enhancing the antinociceptive effects of the predominately mu-opiate agonist, morphine. Similarly, NPC 12626 dose-dependently reduced the pronociceptive effects of orphanin FQ. These findings with the snail, Cepaea, indicate that NMDA systems/receptors are associated with the mediation of the nociceptive effects of both kappa opioids and orphanin FQ. They suggest an early evolutionary development and phylogenetic continuity of NMDA opioid and related neuropeptide interactions in the mediation of nociception.

Emerging Neuropsychiatric Toxicities of Opioids

Pain is a common complication of cancer. As a result of educational efforts, there has been an appropriate increase in the use of opioids. The increase has resulted in a greater detection of a spectrum of neuro-psychiatric adverse effects that include cognitive failure, hallucinations, delirium, severe sedation, generalized myoclonus, hyperalgesia, allodynia and seizures. Various putative mechanisms have been postulated including the neuro-sensitizing effects of opioid metabolites. Numerous metabolites including morphine-3-glu-curonide, morphine-6-glucuronide, hydromorphone 3-glucuronide, and normeperidine have been implicated. Morphine-3-glucuronide appears to cause hyperexcitability via non-opioid receptor mechanisms which are not yet well defined. Renal impairment, high opioid doses, prolonged opioid administration, borderline cognition, dehydration, neuropathic pain and the presence of other psycho-active drugs have consistently been reported to be correlates of opioid associated CNS irritability. Var...

Acute amitriptyline treatment produces non-opioid-mediated analgesia in the formalin and bee venom tests

Tricyclic antidepressants are often effective for the management of persistent pain, and several neurochemical mechanisms have been proposed. The purpose of the present study was to examine the effect of amitriptyline (AMI) in two animal models of inflammatory pain, the formalin test and the bee venom test, and to ascertain the effect of naloxone on amitriptyline analgesia. A single dose of AMI (20 mg/kg) was found to significantly decrease both phases of formalin pain responses and the initial 10 min of bee venom pain responses. However, naloxone (3 mg/kg) had no effect on AMI analgesia in either test. The results show that single doses of AMI can decrease pain behavior in tests of tonic pain and suggest that non-opioid mechanisms may play a role in addition to opioid mechanisms demonstrated in earlier studies.

The antinociceptive effect of fluvoxamine

The authors conducted a study in order to evaluate the antinociceptive effects of the serotonin-selective reuptake inhibitor (SSRI) antidepressant fluvoxamine and its interaction with various opioid receptor subtypes. Male ICR mice were tested with a hotplate analgesia meter. Fluvoxamine elicited antinociceptive effect in a dose-dependent manner following i.p., i.t. and i.c.v. injection. Naloxone 10 mg/kg s.c. did not abolish the fluvoxamine antinociceptive effect. At the next stage fluvoxamine was administered together with various agonists of opioid receptors. When administered together with opiates, fluvoxamine significantly potentiated analgesia at the K j-opioid receptor subtype ( P<.005) and to a lesser extent, at the μ-, δ-, and K 1-opioid receptors. We conclude that fluvoxamine alone induces an antinociceptive effect. This effect is mediated by a non-opioid mechanism of action. These results suggest a potential role for fluvoxamine in the management of pain when co-administered with opioids at low doses.

A novel approach to the pharmacology of analgesics

To date in the United States when a patient has presented with a complaint of pain requiring some form of pharmacologic relief, the physician has had the choice of two broad classes of drugs: peripherally acting (i.e., NSAID) or centrally acting (i.e., opioid) analgesics. The antidepressant monoamine reuptake inhibitors, particularly when combined with an opioid analgesic, have also proven efficacious in treating certain types of pain conditions. A new approach, available for almost 20 years in Europe and recently approved for use in the United States, is the centrally acting synthetic analgesic tramadol HCl. Preclinical evidence suggests that tramadol produces its antinociceptive effect in animals and analgesic effect in humans through a complementary dual mechanism of action. One mechanism relates to its weak affinity for μ-opioid receptors (6,000-fold less than morphine, 100-fold less than d-propoxyphene, 10-fold less than codeine, and equivalent to dextromethorphan). A metabolite ( O-desmethyltramadol; M1) binds to opioid receptors with a greater affinity than the parent compound and could contribute to this component. However, in most animal tests and human clinical trials, the analgesic effect of tramadol is only partially blocked by the opioid antagonist naloxone, suggesting an important monopioid mechanism. This nonopioid mechanism possibly relates to an increase in central neuronal synaptic levels of two neurotransmitters, 5-hydroxytryptamine (5-HT; serotonin) and norepinephrine. The opioid and nonopioid mechanisms appear to combine in a supra-additive manner in several tests of antinociception, but only in an additive or even counteracting manner in measures of adverse-effect liability. In sum, the apparent dual mechanism of action of tramadol suggests a possible new approach to pain relief. Am J Med. 1996;101(suppl 1A):40S–46S.

Cardiovascular and respiratory actions of U50,488H in the unanaesthetized ovine foetus

In an effort to evaluate the feasibility of κ-opioid receptor agonists for use in pregnancy, we have investigated the actions of U50,488H ( trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide) on cardiovascular and respiratory control in the unanaesthetized ovine foetus. Intravenous administration of U50,488H (1.0 mg/kg) to the foetus resulted in an immediate increase in foetal blood pressure ( P < 0.0001) and heart rate ( P < 0.0001) which lasted 15 min, followed by a prolonged loss of heart rate variability for up to 3 h. There was also a significant suppression of foetal breathing movements for 2–3 h ( P < 0.008). Pretreatment with naloxone (12 mg/h) completely blocked the hypertensive and tachycardiac response to U50,488H, but was unable to prevent the loss of variation in heart rate or respiratory depression. These data suggest that U50,488H can exert direct cardiovascular and respiratory actions in the ovine foetus via both opioid and non-opioid mechanisms. The naloxone-insensitive suppression of foetal breathing would severely limit the use of U50,488H as an obstetrical analgesic.

Possible Nonopioid‐Mediated Analgesia Produced by Methotrimeprazine in Rats

BACKGROUND: Several reports in the 1960s demonstrated that methotrimeprazine (MTMZ), a phenothiazine derivative, is effective for treating acute and chronic pain. Although MTMZ has received little attention in recent decades, the fact that it derives from a class of drugs usually associated with cognitive and emotional processes, rather than the traditional analgesics, makes it interesting as a potential source of information about the mechanisms of analgesia.OBJECTIVE: To explore the analgesic properties of MTMZ in a dose‐related design in the formalin test, and to examine whether the lowest dose of MTMZ that produces analgesia will activate endogenous opioid systems.METHODS: The analgesic properties of three doses of MTMZ, compared with a saline control, were explored in male Sprague‐Dawley rats using the formalin test. Sedative effects were studied by using the line‐crossing test concomitantly with the formalin test.RESULTS: MTMZ had no effect during the first phase of formalin responding. During the second phase of the formalin test, MTMZ doses of 5.0 and 10.0 mg/kg produced a significant decrease in formalin responses. Sedative effects were observed at all doses, even though the dose of 2.5 mg/kg did not significantly decrease formalin responses compared with controls. Statistical analyses revealed no significant correlation between the degree of sedation and the degree of analgesia at any dose of MTMZ. The nonspecific opioid antagonist naloxone did not alter the analgesic effect of 5.0 mg/kg MTMZ, indicating that the mechanism of action is independent of endogenous opioid systems.CONCLUSION: MTMZ decreased responses in the formalin pain test in rats. Although the drug′s sedative effects were apparent in the line crossing test, they were not significantly correlated with pain responses. These results suggest that the decrease in formalin responses might be due, in part at least, to the analgesic properties of MTMZ. The fact that MTMZ belongs to a class of drugs that is relatively unexplored in relation to pain and analgesia indicates a potential source for the development of new pharmacological agents for treating persistent pain. Furthermore, the nonopioid mechanism of action suggests that this agent may be useful when opioid medications are contraindicated.

Naloxone evokes a nutritionally dependent LH response in post partum beef cows but not in mid-luteal phase maiden heifers

AbstractData from two experiments are reported which test the hypothesis that nutrient and/or dry-matter intake and body condition may interact to modify hypothalamic opioidergic activity and thus influence the pulsatile release of LH during the early post-partum period and during the oestrous cycle. Experiment 1 involved 16 multiparous, twin-suckling beef cows, and was a 2 × 2 × 2 factorial design in which the factors were level of post-partum energy intake (80 v. 130 M) metabolizable energy (ME) per day), the digestible undegradable protein (DUP) content of the post-partum diet (14 v. 31 g/kg dry matter), and treatment with either 200 mg or 400 mg naloxone hydrochloride. Blood samples were collected at 15-min intervals for 4h at weeks 4 and 7 post partum. Naloxone was administered intravenously after the eighth sample. Experiment 2 involved 16 cyclic maiden heifers and was also arranged in a factorial manner, with two levels of body condition at the start of the experimental period (2·50 and 3·16 units) and two levels of energy intake thereafter (40 and 80 MJ ME per day). Seven blood samples were collected at 15-min intervals on 4 days consecutively during the mid-luteal phase of the oestrous cycle. On the first 2 of these 4 days naloxone was administered, whilst on the last 2 days a gonadotropin-releasing hormone agonist (buserelin; GnRH) was administered, both after the fourth sample. Plasma from both experiments was assayed for LH and prolactin (Prl).In experiment 1, cows on 130 MJ ME per day returned to oestrus and ovulated earlier than cows on 80 MJ ME per day (44·5 v. 55·0 days; s.e.d. = 3·93; P &lt; 0·05). At week 4 post partum the proportional increase in plasma LH following naloxone challenge was greater for cows on 130 MJ ME per day than cows on 80 MJ ME per day (1·38 v. 1·12; P &lt; 0·05), but the converse was true at week 7 (1·15 v. 1·68; P &lt; 0·05). Cows on the high DUP diet required a higher dose of naloxone to elicit an LH response. Few heifers in experiment 2 exhibited an LH response to naloxone. In contrast, there were significant dietary treatment effects on the LH response to GnRH (P &lt; 0·01). Relatively thin heifers on 40 MJ ME per day exhibited the lowest proportional increases in plasma LH to GnRH challenge, whereas heifers on 80 MJ ME per day and given the higher dose of GnRH produced the greatest plasma LH responses. Mean Prl concentrations before and after feeding in experiment 2 were respectively 13·2 and 10·2 ng/l (P &lt; 0·01).Suckled cows given a high energy diet during the early post-partum period can overcome the opioid mediated block on LH release and resume oestrous cycles earlier than cows given a low energy diet. LH would appear to be inhibited by a non-opioid mechanism in mid-luteal phase heifers. Total pituitary reserves ofLH may be influenced by the animals nutritional status.

Inhibitory Effects of Dynorphin-A on Norepinephrine Uptake by Cardiac Synaptosomal-Mitochondrial Fractions

The effect of dynorphin A-(1-13) (Dyn A-(1-13)) on [3H]norepinephrine ([3H]NE) uptake was examined in cardiac synaptosomal-mitochondrial fractions of control rats (Wistar, WR; Wistar-Kyoto, WKY) and spontaneously hypertensive rats (SHR). In adult WR, Dyn A-(1-13) caused naloxone-insensitive dose-dependent inhibition of [3H]NE uptake with an IC50 of 4.0 microM. The nonopioid Dyn A fragments Dyn A-(2-13) and Dyn A-(6-10) displayed 89 and 11% of the potency of Dyn A-(1-13), respectively, whereas Dyn A-(1-8), Leu-enkephalin, and the selective opioid agonists [D-Ala2, N-MePhe4, Glyol5]enkephalin (DAGO, mu), [D-Ser2, Thr6]Leu-enkephalin (DSLET, delta), and U-50488H (kappa) were inactive. The relative potency of various analogues and fragments of Dyn A in inhibiting [3H]NE uptake correlated well (r = 0.96) with their potency in inhibiting binding of [3H]Dyn A-(1-13) to nonopioid sites on cardiac membrane preparations. Dyn A-(1-13) showed the same potency in inhibiting [3H]NE uptake in prehypertensive (4-week-old) SHR as in age-matched WR and WKY. However, at ages 8 and 16 weeks Dyn A-(1-13) was twice as potent in SHR as in WR and WKY. The increased inhibitory potency of Dyn A-(1-13) in 8-week-old SHR was accompanied by a 1.3-fold increase in number of cardiac nonopioid [3H]Dyn A-(1-13) binding sites. Dyn A and related peptides inhibit [3H]NE uptake by cardiac synaptosomes by a nonopioid mechanism. The possible involvement of such a mechanism in development of hypertension in SHR is discussed.

5 Newer opioid agonists

Summary We have described the pharmacology of four short-acting μ opioid agonists which are being investigated for possible use in anaesthesia. Most of them are typical opioids which retain all of the effects and side effects of fentanyl. Of the group, pentamorphone and mirfentanil seem least promising for further development. Pentamorphone is more potent than fentanyl but does not differ meaningfully in terms of onset, duration, or side effects. Mirfentanil had more interesting possibilities because it would have been the first partial opioid agonist with a relatively short duration. Unfortunately, the administration of high doses caused severe tachycardia in two human subjects and a grand-mal seizure in another. It is possible (though unlikely) that the drug could still be developed for use in a lower dose range. Trefentanil and remifentanil are both typical opioids, but with significantly more rapid elimination than alfentanil and less tendency to accumulate during long infusions. Trefentanil has pharmacokinetics midway between alfentanil and remifentanil, and at the moment, remifentanil is getting most of the attention. Remifentanil is unique in that its effects are terminated by ester hydrolysis in the tissues and blood. The pharmacokinetics of this agent are similar to those of esmolol, and it seems ideally suited for use by intravenous infusion. The context-dependent half-life of this drug is under 4 minutes after an infusion of 4 hours. Remifentanil clearance does not depend significantly upon the patient's age, weight, gender, or hepatic and renal function. The initial trials of the drug in balanced anaesthesia show that it is effective and well tolerated over a wide range of infusion rates. Recovery occurs extremely rapidly when the drug is discontinued, and the onset of postoperative pain is likely to be rapid as well. There are probably situations where recovery from remifentanil will prove to be too fast. The final drug discussed was tramadol, an analgesic which works by both opioid and non-opioid mechanisms. A part of its effect may be similar to the analgesia produced by tricyclic antidepressants by their actions on descending inhibitory pain pathways in the medulla and pons. Tramadol has had extensive clinical use in Europe and can be administered by almost any route. It is a weaker analgesic than the full agonists, and it seems to be appropriate for mild-to-moderate pain in a wide variety of clinical settings. The chief advantage of this drug is its low incidence of acute and chronic side effects.

Central and systemic kappa-opioid agonists exacerbate neurobehavioral response to brain injury in rats.

The endogenous opioid peptide dynorphin has been implicated in the pathophysiology of secondary tissue injury after central nervous system (CNS) trauma. The detrimental effects of dynorphin appear to be mediated through both opioid receptors (probably kappa-receptors) and nonopioid mechanisms. However, both kappa-opioid agonists and antagonists have been reported to improve outcome in models of CNS trauma. To attempt to clarify this controversy, we examined the effects of centrally or systemically administered kappa-opioid agonists on neurological recovery after experimental fluid-percussion brain injury in the rat. Agonists included dynorphin A-(1-17) [Dyn A-(1-17)], which has actions at both kappa 1- and kappa 2-sites, and the selective kappa 1-agonists U-50,488H and U-69,593. des-Tyr-dynorphin A-(2-17) [Dyn A-(2-17)], which is inactive at opioid receptors, was also used. Microinjection of Dyn A-(1-17), but not Dyn A-(2-17) or U-50,488H, into the lateral ventricle 15 min before brain injury significantly worsened motor deficits over a 2-wk period. However, systemic administration of high doses of the kappa-agonists U-50,488H and U-69,593 also significantly worsened neurological outcome. These results fail to demonstrate any protective actions of kappa 1-agonists in this model of experimental traumatic brain injury and suggest that the opioid-related pathophysiological actions of dynorphin may be mediated by kappa 2-opioid receptors.

The form of the conditioned hypoalgesic response resulting from preexposure to a heat Stressor depends on the pain test used

Preexposure to the heated floor of a hot-plate apparatus resulted in conditioned hypoalgesic responses among rats tested in that apparatus. These responses were unaffected by naloxone or a history of morphine among rats tested on the heated floor, but were reversed by naloxone or a history of morphine in rats tested with formalin on the nonheated floor of the apparatus. The results were taken to mean that apparatus cues paired with the heated floor conditionally activated multiple mechanisms of pain control; the nonopioid mechanisms were engaged by the pain that was provoked by the test exposure to the heated floor and the opioid mechanisms were recruited by the pain that was produced by formalin.

Antinociceptive activity of peptides related to interleukin-1β-(193–195), Lys-Pro-Thr

A series of closely related peptide analogues of Lys-Pro-Thr [(interleukin-1β-(193–195)] have been investigated in two models of antinociception in mice (acetic acid-induced abdominal constrictions and formalin tests) and compared with morphine, aspirin and indomethacin. Formalin-induced nociceptive responses in the mouse showed early (0–5 min) and late (15–30 min) phases of peak activity. Lys- d-Pro, Lys- d-Pro-Thr, Lys- d-Pro-Arg, Lys- d-Pro-Val, morphine and aspirin, were antinociceptive in both phases after intraperitoneal (i.p.) and oral (p.o.) administrations. Lys- d-Pro-Leu inhibited the early phase response only after i.p. injection. Lys- d-Pro-Val-NH 2, Lys- d-Pro-Gln, Lys- d-Pro-Tyr, Lys- d-Pro-Asn, Asp-Lys- d-Pro-Val and indomethacin were active only against the late phase (ED 50 values of 64, 32, 44, 94, 67 and 25 mg/kg i.p., respectively). Several of the peptides showed good bio-availability, e.g. Lys- d-Pro-Asn (ED 50: 10 mg/kg i.p.,; 11.4 mg/kg p.o.) in the abdominal constrictions test, where two modes of action were apparent, non-opioid and opioid; non-opioid (naloxone-insensitive antinociception) mechanisms were illustrated by Lys- d-Pro-Thr and Lys- d-Pro-Asn; opioid (naloxone-sensitive antinociception) mechanisms by Lys- d-Pro-Val and Lys- d-Pro-Leu. These data identify orally active antinociceptive peptides in both antinociceptive tests with varied relative potency profiles to morphine, indomethacin and aspirin in the mouse formalin test.

Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives?

Elevated resting blood pressure is associated with decreased pain sensitivity in both animals and humans. Recent evidence suggests that this relationship may be mediated by endogenous opioid peptides in hypertensives, but the precise mechanism has not been investigated in normotensives. We examined the effect of opioid receptor blockade with naloxone on the relationship between resting blood pressure and pain sensitivity in normotensive humans. Sixteen young adults were given cold pressor and handgrip challenges after treatment with either naloxone or saline in a placebo-controlled, within-subject design. Multiple regression procedures indicated that resting systolic blood pressure was a significant predictor of cold pain ratings even after the effects of naloxone were statistically controlled. The interaction between systolic blood pressure and opioid blockade was non-significant. These data suggest that the relationship between resting blood pressure and pain sensitivity in normotensive humans is mediated, at least in part, by non-opioid mechanisms.

The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABA A receptor complex

Administration of morphine-3-glucuronide (M3G) by the intracerebroventricular (i.c.v.) route in doses of 2–8 μg produced a marked dose-dependent behavioural excitation in adult Sprague-Dawley rats. When LY274614 (1–50 ng i.c.v.) or midazolam maleate (25–50 μg i.c.v.) was administered 20 min prior to a maximal excitatory dose of M3G (7 μg), all excitatory behaviours were reduced. In contrast, when LY274614 (200 ng i.c.v.) was given after M3G (7 μg), it did not reduce all of the excitatory behaviours. Since we have also shown in in vitro binding studies that M3G has very low affinity for the known binding sites on the N-methyl-D-aspartate (NMDA) and the γ-amino-butryic acid (GABA A) receptor complexes (1), the results of this study suggest that the anti-convulsant compounds, LY274614 and midazolam, are functional antagonists of the excitatory effects of M3G. LY274614 (1–50 ng i.c.v.) and midazolam (25–50 μg i.c.v.) did not produce significant behavioural excitation and phenyclidine (PCP)-type effects were not observed. This contrasts with the NMDA receptor antagonists CGS19755 and MK801, where PCP-type effects have been reported to interfere with behavioural assessment. Morphine hydrochloride in a maximal analgesic dose (50 μg i.c.v.), did not reduce the excitation score of a maximal excitatory dose of M3G (7 μg), lending support to the view that M3G's excitatory effects are elicited through a non-opioid mechanism.

Discriminative stimulus and response rate-decreasing effects of kappa opioids: Antagonism by naloxone

The present study examined the discriminative stimulus and response rate-decreasing effects of kappa opioids in pigeons trained to discriminate a 0.017 mg/kg dose of bremazocine from saline. Bremazocine, spiradoline, C1977, U69, 593 and U50, 488 substituted completely for the bremazocine stimulus in a dose-dependent and naloxone-reversible manner. Apparent pA 2 values (range, 6.01–6.81) of naloxone against the descriminative stimulus effects of these kappa opioids were smaller than those reported previously in the pigeon for naloxone against the discriminative stimulus effects of various mu opioids. Bremazocine, C1977, soiradoline and U69, 593 also decreased rate of responding in a dose-dependent and naloxone-reversible manner. The apparent pA 2 values (range, 6.25–6.44) for naloxone against the rate-decreasing effects of bremazocine, C1977 and U69, 593 were not different from the apparent pA 2 values for naloxone against their discriminative stimulus effects. An apparent pA 2 for naloxone against the rate-decreasing effects of spiradoline could not be determined due to the shallow slope of the Schild plot. Although the rate-decreasing effects of U50, 488 were antagonized by naloxone, the degree of antagonism was small and not dose-dependent. These findings indicate that the discriminative stimulus and rate-decreasing effects of some kappa opioids are mediated by similar mechanisms and that a non-opioid mechanism may contribute to the rate-decreasing effects of spiradoline and U50, 488.

Epibatidine is a nicotinic analgesic

Epibatidine, an alkaloid isolated from skin of the poison frog, Epipedobates tricolor, has been shown to be a very potent analgesic with a non-opioid mechanism of action. We found that epibatidine was about 120 times more potent and has longer duration than nicotine in analgesia, which could be antagonized by pretreatment with mecamylamine. Furthermore, epibatidine competed with high affinity (ifIC 50 = 70 pM, K i = 43 pM) for [ 3H]cytisine binding in rat brain preparations. These results indicated that the analgesic activity of epibatidine is attributed to its unique property as the most potent nicotinic acetylcholine receptor agonist.

CLONIDINE COMBINED WITH SUFENTANIL AND BUPIVACAINE WITH ADRENALINE FOR OBSTETRIC ANALGESIA

Clonidine produces analgesia via a non-opioid mechanism and it may be used as an interesting adjuvant to local anaesthetics and opioids in obstetric analgesia. To examine the effects of the addition of clonidine to bolus injections of bupivacaine, adrenaline and sufentanil, we enrolled 50 women receiving extradural analgesia for vaginal delivery into a double-blind study. They were allocated randomly to two groups: group A received a 10-ml extradural solution of bupivacaine 12.5 mg combined with adrenaline 25 micrograms and sufentanil 10 micrograms; group B received the same solution with clonidine 30 micrograms. Each patient was allowed two subsequent injections of the chosen solution. Subsequently, if still in the first stage of labour, analgesia was augmented with additional 10-ml injections of bupivacaine 12.5 mg with adrenaline 25 micrograms, without sufentanil or clonidine. The latter solution was used for perineal analgesia in group A; clonidine 30 micrograms was added in group B. During the first and second stages of labour, there was no difference between the two groups in duration of analgesia after the first injection (142 min in group A; 127 min in group B), number of injections (1.8 in group A; 1.9 in group B) and the total bupivacaine requirements (33.9 mg in group A; 34 mg in group B). The quality of analgesia was evaluated as very good in both groups (23/25 in group A; 24/25 in group B). The degree of motor block or the frequency of other side effects were not enhanced by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)