Kappa-opioids produce significantly greater analgesia in women than in men.

Sex differences in human responses to nociceptive stimuli and painful pathological conditions have generally indicated that women report higher pain levels or exhibit less tolerance than men for given stimulus intensities (reviewed in ref. 1 and 2). However, studies have not evaluated sex differences in analgesic responses. We recently reported that the opioid agonist-antagonist pentazocine, which acts predominantly at kappa-receptors, produced significantly better postoperative analgesia in females than in males in patients who underwent surgery for the removal of their third molars (wisdom teeth). In the current study, we evaluated the hypothesis that this sex difference is a characteristic of kappa-opioid agonism. In order to determine whether there are sex differences associated with kappa-opioid agonism, the analgesic efficacy of two other predominantly kappa-opioid analgesics, nalbuphine and butorphanol; was compared in males and females who underwent surgery for the removal of third molar teeth. We found that both nalbuphine and butorphanol produced significantly greater analgesia in females as compared with males. Considering our earlier findings, we conclude that kappa-opioid analgesia is greater in females than in males, probably reflecting a difference in kappa-opioid-activated endogenous pain modulating circuits.

Benzodiazepine mediated antagonism of opioid analgesia.

Activation of supraspinal gamma-aminobutyric acid-A (GABAA) receptors is known to result in antagonism of opioid analgesia. Since benzodiazepines enhance the action of GABA at GABAA receptors, we hypothesized that administration of these agents for preoperative sedation might antagonize the analgesic effects of opioids administered postoperatively. If so, then administration of the benzodiazepine antagonist flumazenil should enhance postoperative morphine analgesia. In a double-blind, placebo-controlled study of patients who received a preoperatively administered benzodiazepine (diazepam) for sedation and a postoperatively administered opioid (morphine) for analgesia, we investigated opioid-benzodiazepine interactions affecting postoperative dental pain. We found that flumazenil significantly enhanced morphine analgesia consistent with the hypothesis that the preoperatively administered benzodiazepine exerts an ongoing antianalgesic effect. In addition, we followed these patients over the first and second postoperative days to determine if there were differences between the drug groups in post-discharge pain, analgesic consumption, or side-effects. Participants receiving flumazenil reported significantly less post-discharge nausea and used significantly less ibuprofen. Since post-discharge pain levels were not significantly different, these results suggest that the patients receiving flumazenil required less analgesic medication to achieve a comparable level of pain control. In summary, our results indicate that the benzodiazepine antagonist flumazenil enhances morphine analgesia and decreases post-discharge side-effects as well as post-discharge need for analgesic medication.

The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain.

Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.

Neurogenic and non-neurogenic mechanisms of plasma extravasation in the rat.

We describe two distinct mechanisms for the enhancement of plasma extravasation in the knee joint of the rat. One is activated by bradykinin and is neurogenic; the other is activated by platelet-activating factor and is non-neurogenic. Bradykinin-induced synovial plasma extravasation is known to be dependent on the sympathetic postganglionic neuron terminal, and to involve prostaglandins, ATP, adenosine A2 receptor action, and the attraction and activation of neutrophils. In this study we found that bradykinin-induced plasma extravasation also involves endothelium-derived relaxing factor; specifically we found that bradykinin-induced plasma extravasation was antagonized stereospecifically by the inhibitor of endothelium-derived relaxing factor synthesis, NG-monomethyl-L-arginine. Perfused alone, platelet-activating factor produced an increase in synovial plasma extravasation which was markedly reduced by the platelet-activating factor receptor antagonists BN 52021 and WEB 2086 (these antagonists did not affect bradykinin-induced plasma extravasation). Platelet-activating factor-induced plasma extravasation was not affected by NG-monomethyl-L-arginine, indomethacin (a prostaglandin synthesis inhibitor), phenol 3-(5H-thiozolo[2,3b]quinazolin) (an A2 receptor adenosine antagonist), dextran sulfate (an inhibitor of leukocyte rolling), hydroxyurea (a depletor of leukocytes), chronic sympathectomy or the depletion of unmyelinated afferent fibers. Of note, the magnitude of platelet-activating factor-induced plasma extravasation was increased by co-perfusion with prostaglandin E2 and attenuated by co-perfusion with L-arginine; that is, two of the mediators involved in neurogenic bradykinin-induced plasma extravasation exerted an influence on non-neurogenic plasma extravasation. Separate mechanisms for bradykinin and platelet-activating factor plasma extravasation were further demonstrated in the streptozotocin-treated diabetic rat, in which there is a peripheral neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Mediation of serotonin hyperalgesia by the cAMP second messenger system.

In this study we have evaluated the second messenger system that might couple 5-HT1A receptor activation to produce peripheral hyperalgesia. The intradermal injection of the serotonin (5-hydroxytryptamine; 5-HT) receptor agonist for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH DPAT) produces a dose-dependent hyperalgesia which was attenuated by a cAMP kinase inhibitor (the R-isomer of cyclic adenosine-3'-5'-monophosphate), but prolonged by the inhibition of endogenous phosphodiesterase by rolipram, supporting a role for the cAMP second messenger system. The 5-HT1A receptor agonist, 8-OH-DPAT, and the adenyl cyclase activator, forskolin administered together, produced an additive hyperalgesia, suggesting that the 5-HT1A receptor in peripheral terminals of the primary afferent neurons is positively coupled to the cAMP second messenger system in producing hyperalgesia. The inability of pertussis toxin to inhibit 8-OH DPAT-induced hyperalgesia further supports this hypothesis. The coupling of the 5-HT1A receptor to the cAMP second messenger system appears to be through guanine regulatory proteins since guanosine 5'-O-(3-thiotriphosphate) and cholera toxin both markedly enhanced 8-OH DPAT hyperalgesia. In further support of the role of guanine nucleotide regulatory proteins, guanosine 5'-O-(2-thiodiphosphate), as well as activators of inhibitory guanine regulatory proteins (the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, and the adenosine A1 agonist, N6-cyclopentyladenosine, significantly attenuated 8-OH DPAT hyperalgesia.

Further substantiation of a significant role for the sympathetic nervous system in inflammation.

This study provides significant new evidence substantiating a role of the postganglionic sympathetic neuron in plasma extravasation in the knee-joint of the rat. Increased plasma extravasation produced by the potent inflammatory mediator bradykinin was mimicked by 6-hydroxydopamine, a selective stimulator of sympathetic fibers. Various treatments (chemical sympathectomy, co-perfusion with the local anesthetic lidocaine, or co-perfusion with depolarizing concentrations of potassium) similarly modulated plasma extravasation induced by both bradykinin and 6-hydroxydopamine, but not that produced by platelet activating factor. We also showed that bradykinin is able to release norepinephrine in the knee-joint, indicating action on the sympathetic postganglionic neuron. In summary, these experiments provide substantial additional evidence supporting a significant contribution of the sympathetic post-ganglionic neuron terminal to inflammatory plasma extravasation.

Characterization of distinct phospholipases mediating bradykinin and noradrenaline hyperalgesia.

Specific prostaglandins have been identified that mediate the sympathetic postganglionic neuron-terminal dependent hyperalgesia induced by bradykinin and norepinephrine, prostaglandin E2 and prostacyclin, respectively. In this study we evaluated the hypothesis that bradykinin and norepinephrine stimulate prostaglandin production in the rat, via distinct phospholipases. We found that, in normal skin, bradykinin hyperalgesia is inhibited by the phospholipase A2 inhibitor, mepacrine, but not by the phospholipase C inhibitor, neomycin and is mimicked by phospholipase A2. In chloroform-treated skin or when co-injected with A23187, bradykinin-induced hyperalgesia was found to consist of two components, one resulting from prostaglandin E2 synthesis (phospholipase A2-dependent) and one resulting from prostacyclin synthesis (phospholipase C-dependent). This latter component is blocked by Quin 2 and verapamil and also inhibited by yohimbine, an alpha 2 receptor antagonist. Arachidonic acid induces a dose-dependent hyperalgesia that was found to be like bradykinin-hyperalgesia in untreated skin (prostaglandin E2-mediated and phospholipase A2-dependent). In chloroform-treated skin or in the presence of A23187, arachidonic acid like bradykinin led to the production of prostacyclin as well as prostaglandin E2. Norepinephrine does not produce hyperalgesia in untreated skin, but in chloroform pretreated skin or in the presence of the calcium ionophore A23187, norepinephrine produces a potent dose-dependent hyperalgesia. This hyperalgesia is prevented by sympathectomy and suppressed by the calcium antagonists Quin 2 and verapamil. It is also suppressed by indomethacin and neomycin but not by SC19220 and mepacrine and is mimicked by phospholipase C.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of morphine analgesia by the GABAB agonist baclofen.

Opioid-GABAergic interactions for the treatment of post-operative pain were investigated in two double-blind, placebo-controlled experiments. We first studied the effect of pre-operatively administered baclofen, a GABAB receptor agonist, on the analgesia produced by intravenously administered morphine, a predominantly mu-opioid analgesic. In a separate trial, we studied the effect of baclofen on the analgesia produced by pentazocine, a predominantly kappa-opioid analgesic. While baclofen alone did not affect the level of post-operative pain, morphine analgesia was significantly enhanced by baclofen compared to placebo. In contrast, baclofen did not affect the level of pentazocine analgesia: however, females receiving pentazocine showed significantly greater analgesia than males.

Enhancement of morphine analgesia by the alpha 2-adrenergic antagonist yohimbine.

Although interactions between opioids and adrenergic agonists in the treatment of pain have been demonstrated in humans, the contribution of specific adrenergic receptors in this interaction remains to be clarified. In a double-blind, placebo-controlled study in male patients with postoperative dental pain, we investigated the effect of preoperative administration of the alpha 2-adrenergic antagonist, yohimbine, on analgesia produced by postoperative intravenous morphine. Although yohimbine by itself did not affect the pain, the overall analgesic effect of morphine was significantly enhanced in the presence of yohimbine. This report is the first to demonstrate that an alpha 2-adrenergic antagonist enhances opiate analgesia in humans.

Chronically administered nicotine attenuates bradykinin-induced plasma extravasation and aggravates arthritis-induced joint injury in the rat.

We recently showed that acute administration of nicotine in the rat decreases bradykinin-induced plasma extravasation and that adrenal medullary-derived epinephrine, acting at a beta 2-adrenergic receptor, mediates the nicotine effect. Since agents which decrease bradykinin-induced plasma extravasation have been associated with increased joint injury in a rat model of chronic inflammation (experimental arthritis induced by subcutaneous injection of Mycobacterium butyricum) we examined the effect of chronic nicotine on both plasma extravasation and the severity of joint injury. In normal rats, bradykinin-induced plasma extravasation was decreased after nicotine administered both by repeated injection (10(-2) mg/kg, s.c., once per h for 4 h) and by continuous long-term infusion (subcutaneous mini-osmotic pump; 1.5 x 10(-3) mg/kg per h for 30 days). Nicotine-induced inhibition of bradykinin-induced plasma extravasation did not show tachyphylaxis. In rats with arthritis, chronic administration of nicotine also produced a decrease in bradykinin-induced plasma extravasation. This effect of chronic nicotine in the arthritic rats was antagonized by co-administration of hexamethonium (a nicotinic receptor antagonist), by surgical removal of the adrenal medulla, or by co-administration of ICI-118,551 (a beta 2-adrenoceptor antagonist). Chronic administration of nicotine decreased the latency to the onset of arthritis and, in a dose-dependent manner, led to an increase in the radiographic joint injury score.(ABSTRACT TRUNCATED AT 250 WORDS)

Mu-opioid agonist enhancement of prostaglandin-induced hyperalgesia in the rat: a G-protein beta gamma subunit-mediated effect?

Guanine nucleotide-binding regulatory protein stimulation of adenylyl cyclase has been shown to be an important second messenger system for many processes, including mechanical hyperalgesia. Recently, interactions between guanine nucleotide-binding regulatory protein subunits and adenylyl cyclase affecting the level of cyclic adenosine 3',5'-monophosphate accumulation have been demonstrated. In this study we evaluated such an interaction by measuring paw-withdrawal thresholds to mechanical stimuli in Sprague-Dawley rats in the presence of two direct-acting hyperalgesic agents, prostaglandin E2 and the adenosine A2-agonist, CGS21680. The effects of two agents expected to liberate inhibitory guanine nucleotide-binding regulatory protein subunits were also studied: [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (a mu-opioid receptor agonist) and N6-cyclopentyladenosine (an A1-adenosine agonist). Injection of [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin immediately before prostaglandin E2 or CGS21680 significantly attenuated the hyperalgesia subsequently induced by these agents, i.e. the sensitivity to these hyperalgesic agents was decreased. On the other hand, injection of [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin 5 min after prostaglandin E2 or CGS21680 significantly enhanced the hyperalgesia observed. Injection of the adenosine A1-agonist N6-cyclopentyladenosine immediately before and 5 min after prostaglandin E2 or CGS21680 had a similar effect to [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin. The decrease in sensitivity to prostaglandin E2- and CGS21680-induced hyperalgesia by preadministration of [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin or N6-cyclopentyladenosine and the enhancement by postadministration were all reversed by pertussis toxin, an inhibitor of inhibitory guanine nucleotide-binding regulatory protein, suggesting the involvement of an inhibitory guanine nucleotide-binding regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic components of the human pupillary light reflex.

To investigate the autonomic components of the pupillary light reflex in humans, we used infrared pupillometry combined with a partial local cholinergic (tropicamide) or alpha-adrenergic (thymoxamine) blockade. The pupillary response curve was analyzed using parameters identical or similar to those employed previously to study the autonomic components of the pupillary light reflex. Tropicamide increased baseline pupil area and affected five of the eight measured parameters. Thymoxamine lowered baseline pupil area but did not affect any of the parameters. We found the expected cholinergic contribution to the constrictive phase of the pupillary light reflex but no evidence for peripheral alpha-adrenergic activity during redilation. We propose that redilation primarily involves parasympathetic relaxation, modulated by cholinergic inhibition of the dilator muscle and central sympathetic inhibition of the Edinger-Westphal nucleus.

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat.

1. In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. 2. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective beta 2-adrenoceptor blocker) (30 micrograms ml-1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg-1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 microgram kg-1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that beta 2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg-1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. 3. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg-1, s.c.), and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg-1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. 4. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg-1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. 5. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone.

Effect of E-type prostaglandins on bradykinin-induced plasma extravasation in the knee joint of the rat.

We studied the effect of different E-type prostaglandins on an experimental model of inflammation in the rat. Plasma extravasation was induced in the knee joint of the rat by continuous perfusion of two potent inflammatory mediators, bradykinin (160 nM) or platelet activating factor. Both prostaglandin E1 and prostaglandin E2 (0.5-500 ng ml-1), when perfused with bradykinin, produced a similar dose-dependent enhancement of plasma extravasation. Prostaglandin E2 (0.5-500 ng ml-1) also dose dependently enhanced plasma extravasation induced by platelet activating factor, while prostaglandin E1 significantly enhanced platelet activating factor-induced plasma extravasation only at concentrations above 5 ng ml-1. In contrast, co-perfusion of bradykinin or platelet activating factor with the prostaglandin E1 analogues, enisoprost and misoprostol (0.5-500 ng ml-1) did not enhance plasma extravasation. In fact, misoprostol attenuated plasma extravasation induced by bradykinin. These results demonstrate that in the rat knee joint, misoprostol and enisoprost have different pharmacological actions compared to their parent compound, prostaglandin E1 and to prostaglandin E2.

Gender difference in analgesic response to the kappa-opioid pentazocine.

Gender difference in analgesia produced by the kappa-opiate pentazocine was investigated in a model of post-operative dental pain. In a recent study [Gordon et al., Neuroscience, 69 (1995) 345-349.] evaluating interaction between the GABAB agonist baclofen and opiates with respect to postoperative analgesia we found that females receiving pentazocine for the treatment of postoperative pain showed better analgesia than did males receiving similar treatment. To follow-up this result, we evaluated for the effect of gender on analgesia produced by pentazocine administered to participants not receiving another experimental medication. The analgesic response to pentazocine in ten females was compared to that in eight males. All participants were administered pentazocine after undergoing surgery for the removal of impacted third molars. We confirm our previous finding that pentazocine produces significantly greater analgesia in females than in males; no significant difference was observed in analgesia among females in different phases of the menstrual cycle.

Remission maintenance therapy in acute myelogenous leukemia.

Because no conclusive evidence as to the efficacy of maintenance chemotherapy in acute myelogenous leukemia (AML) existed, a study to obtain such information was done. Twenty-six adult patients with AML in whom complete remission had been achieved following induction chemotherapy were randomly assigned to receive either maintenance chemotherapy consisting of cytarabine and 6-thioguanine for two days each month or to receive no maintenance therapy. The data showed a significant difference in remission duration between the two groups, with median remission lengths for the maintained and unmaintained groups being 10.3 and 6.7 months, respectively (p<.05). In 46 percent of the maintained patients there were remissions lasting longer than 11 months, whereas in none of the unmaintained patients was there such a prolonged remission. No significant drug-induced toxicity was observed. That the prolonged exposure to these chemotherapeutic agents, which were also used in our induction program, did not adversely affect the rate of successful reinduction therapy was shown by identical 50 percent complete remission rates for second inductions in both groups. In patients with palpable splenomegaly at the time of diagnosis, there was no prolongation of remission with maintenance therapy. These data indicate the potential utility of maintenance chemotherapy for prolonging remission duration in acute myelogenous leukemia.

Role of vagal afferents and spinal pathways modulating inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine.

1. Nicotine, a major active component of tobacco smoke, has been shown to modulate the inflammatory response via both peripheral and central nervous system pathways. Recently we found that spinal intrathecal administration of nicotine dose-dependently inhibits bradykinin-induced plasma extravasation (BK-induced PE) in the knee joint of the rat and that the dose-response curve for the inhibition of BK-induced PE by intrathecal nicotine is shifted to the left, by six orders of magnitude, after surgical interventions in the abdominal cavity, which might have interrupted visceral afferents to the neuraxis. Therefore we focused, in this study, on the contribution of the vagal afferents to depression of BK-induced PE by intrathecal nicotine. Furthermore, the effect of acute spinalization at the level C6-C8 was investigated. The hypothesis was that impulse activity in vagal afferents has a pronounced inhibitory effect on the modulation of BK-induced PE by intrathecal nicotine and that spinal pathways are important in mediating this effect. 2. Chronic subdiaphragmatic vagotomy and elimination of vagal afferents, by neonatal capsaicin treatment or by application of kainic acid to the nodose ganglia, enhanced the potency of intrathecal nicotine depression of BK-induced PE, by six to seven orders of magnitude when compared with the control. 3. Acute subdiaphragmatic vagotomy enhanced the potency of intrathecal nicotine-induced depression of BK-induced PE (without changing its maximum effect), by about three to four orders of magnitude when compared with the sham-operated (control) animals (with intact vagus nerves).(ABSTRACT TRUNCATED AT 250 WORDS)