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ABSTRACT: In this study we have demonstrated that noradrenaline increases the levels of prostaglandin E2 and prostaglandin I2 (detected as the stable metabolite 6-keto-prostaglandin F1α) synthesized by homogenates of superior cervical ganglia from the adult rat. This noradrenaline-induced prostaglandin production was further characterized: (a) Selective destruction of adrenergic sympathetic postganglionic neurons in the ganglia using 6-hydroxydopamine abolished both basal and stimulated prostaglandin production, (b) Elimination of preganglionic cholinergic sympathetic nerve terminals in the ganglia had no effect, (c) Mepacrine (a phospholipase inhibitor) and indomethacin (a cyclooxygenase inhibitor) attenuated both basal and stimulated prostaglandin production. (d) Yohimbine, but not prazosin, suppressed the noradrenaline dose-response curve for prostaglandin production. The results of these experiments show that, in vitro, noradrenaline stimulates de novo synthesis of prostaglandin E2 and prostaglandin I2 by sympathetic postganglionic neurons. This stimulation by noradrenaline appears to result from action at an α2-adrenergic receptor.
Journal of Neurochemistry 09/1991; 57(4):1145 - 1150. · 4.06 Impact Factor
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ABSTRACT: Prostaglandin E2 and prostacyclin (prostaglandin 12) produce hyperalgesia in animals and humans. Because there is evidence that prostaglandins contribute to pain maintained by sympathetic nervous system activity, we evaluated whether sympathetic postganglionic neurons synthesize these hyperalgesic prostaglandins, and whether production of prostaglandins by these neurons can contribute to sensitization of primary afferent nociceptors. Intradermal injection of arachidonic acid but not linoleic acid, in the rat hindpaw, produces a decrease in mechanical nociceptive threshold. This hyperalgesic effect is prevented by indomethacin, an inhibitor of prostaglandin synthesis or by prior surgical removal of the lumbar sympathetic chain. To test the hypothesis that sympathetic postganglionic neurons are the source of prostaglandins, we measured production of prostaglandin E2 and 6-keto-prostaglandin Fl (the stable metabolite of prostacyclin) by homogenates of adult rat sympathetic postganglionic neurons from superior cervical ganglia. These homogenates produced significant amounts of prostaglandin E2 and 6-keto-prostaglandin F1, and most of this production is eliminated by neonatal administration of 6-hydroxydopamine which selectively destroys sympathetic postganglionic neurons. These results demonstrate that sympathetic postganglionic neurons produce prostaglandins, and supports further the hypothesis that the release of prostaglandins from sympathetic postganglionic neurons contributes to the hyperalgesia associated with sympathetically maintained pain.
Journal of Neurochemistry 10/1989; 53(5):1595 - 1598. · 4.06 Impact Factor
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ABSTRACT: Hyperalgesia onset latencies of inflammatory mediators were quantified by measuring the threshold of the nociceptive flexion reflex in the rat at 1 min intervals after intradermal injection. Prostaglandin E2 and 8(R), 15(S)-dihydroxyicosa-(5E, 9, 11, 13Z)-tetraenoic acid induced hyperalgesia with short onset latencies, compatible with a direct action on primary afferent nociceptors. Bradykinin, norepinephrine and leukotriene B4 induced hyperalgesia with a significant delay in onset, compatible with their known indirect mechanisms of producing hyperalgesia. We propose that use of this approach, rapid frequent measurement of nociceptive threshold, can be used to determine the hierarchy of action of mediators in hyperalgesic mechanisms.
Brain Research.
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ABSTRACT: In this study we eliminated known indirect hyperalgesic mechanisms by blocking the cyclooxygenase pathway of arachidonic acid metabolism with indomethacin, depleting sympathetic postganglionic neurons with 6-hydroxydopamine and depleting polymorphonuclear leukocytes with hydroxyurea. These treatments did not significantly affect the dose-dependence relationship for prostaglandin E2 (PGE2)- and prostaglandin I2 (PGI2)-induced changes in the mechanical nociceptive threshold in the rat. These data are compatible with the hypothesis that PGE2 and PGI2 act directly on peripheral terminals of nociceptive afferents to produce hyperalgesia.
Brain Research.
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ABSTRACT: The physiological basis of the pain and hyperalgesia observed in patients with Raynaud's phenomenon (RP) is unknown. Since estrogen-induced effects on sympathetic postganglionic neurons (SPGNs) have been implicated in the vasomotor abnormalities in patients with RP, we have studied the effects of estradiol on nociceptive thresholds and noradrenaline sensitivity in a nociceptive flexion reflex in the rat. We report that estradiol induces a catecholamine sensitive hyperalgesia. This hyperalgesia is antagonized by yohimbine (anα2-adrenergic antagonist) but not prazosin (anα1-adrenergic antagonist) as well as by inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism. These data are compatible with the hypothesis that the sensory abnormalities observed in patients with RP may depend on estradiol-induced changes in SPGN, resulting in a sympathetically-dependent production of cyclooxygenase products of arachidonic acid.
Brain Research.
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ABSTRACT: The contribution of the stimulatory guanine nucleotide regulatory protein (Gs) to prostaglandin E2 (PGE2)-induced hyperalgesia was investigated in the hairy skin of the rat hindpaw using the Randall-Selitto paw-withdrawal test. Although without effect alone, guanosine-5′-[γ-thio]triphosphate (GTPγS) and cholera toxin — which activate Gs — both increased, while guanosine-5′-[β-thio] diphosphate (GDPßS) — which prevents the activation of Gs — decresed the hyperalgesia induced by PGE2. These data support the hypothesis that the action of PGE2 on primary afferent nociceptors leading to decreases in paw-withdrawal threshold is Gs-mediated.
Brain Research.
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ABSTRACT: This study evaluated the contribution of supraspinal opioid receptors to the production of antinociception, in the rat. I.c.v. administration of a selective μ-(DAMGO) and a selective δ-(DPDPE), but not a selective κ- (U50,488H) opioid receptor agonist, produced significant dose-dependent increases in mechanical nociceptive thresholds. ICI 174,864, a δ-opioid receptor antagonist, completely blocked the antinociceptive effects produced by DPDPE ([D-Pen2,D-Pen5]enkephalin) at a dose that had no effect on the increases in nociceptive thresholds produced by DAMGO ([D-Ala2,N-MePhe4,Gly5-ol]enkephalin). The simultaneous i.c.v. administration of a low-antinociceptive dose of DAMGO or DPDPE given in combination with sequentially increasing doses of the other cpioid agonist, produced synergy (i.e., a more than additive antinociceptive effect), at the lower doses tested. The results of these experiments provide evidence to support the suggestion that both supraspinal μ- and δ-opioid receptors contribute to the production of antinociception, in the rat.
European Journal of Pharmacology.
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ABSTRACT: The nonsteroidal anti-inflammatory drugs are presumed to produce their analagesic effects by inhibiting the cyclooxygenase catalyzed metabolism of arachidonic acid to hyperalgesic prostanoids. This study examined the hyperalgesic effect of a range of prostaglandins. We found, employing the rat paw-withdrawal test, that while intradermal injection of the known hyperalgesic prostaglandins, E2 and I2, produced hyperalgesia, other primary metabolites of the cyclooxygenation of arachidonic acid (prostaglandin F2α, prostaglandin D2, thromboxane B2 and 12(S) hydroxyheptadecatrienoic acid) did not produce hyperalgesia. We conclude that prostaglandin E2 and prostaglandin I2 are the main hyperalgesic metabolites of the cyclooxygenase pathway of arachidonic acid.
Brain Research.
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ABSTRACT: Interactions between selective opioid agonists acting at spinal μ-, δ-, and κ-opioid receptors were evaluated by co-administering a low-antinociceptive dose of the selective δ-agonist, DPDPE, or the selective κ-agonist, U50,488H, with sequentially increasing doses of the selective β-agonist, DAMGO, intrathecally. Antinociceptive synergy (i.e., a more than additive antinociceptive effect) was observed with both combinations of opioid agonists tested. The demonstration of antinociceptive synergy suggests that the subtypes of spinal opioid receptors can act, at least in part, through a common neural circuit.Since our measure of antinociception, the Randall-Selitto paw-withdrawal test, is dependent on a normally functioning motor system, we also evaluated the effects of these same combinations of opioid peptides on motor coordination using a rotarod treadmill. A low-antinociceptive dose of DPDPE or U50,488H co-administered intrathecally, with sequentially increasing doses of DAMGO, did not worsen the decrement in rotarod performance observed with the same doses of DAMGO administered as a single agent. In fact, the low-antinociceptive dose of DPDPE significantly attenuated the decrease in rotarod performance produced when the same dose of DAMGO was administered as a single agent.The results of this study suggest that intrathecal combinations of selective μ- with both δ- or κ-selective opioid agonists can produce antinociceptive synergy without producing an increase in motor side effects. In addition, the results of a secondary analysis, that compared the antinociceptive data from this study with data from our previous studies of intrathecal combinations of sequentially increasing doses of U50,488H with low doses of DPDPE or DAMGO and sequentially increasing doses of DPDPE with low doses of DAMGO or U50,488H, demonstrate distinct differences in the magnitude of the antinociceptive interactions. The most prominent finding from the secondary analysis was that administration of the μ-opioid agonist, DAMGO, as a component of any combination regimen, resulted in the largest enhancement in antinociceptive effects.
Pain.
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ABSTRACT: This study evaluated the antinociceptive effects produced when different combinations of supraspinal μ- and δ-opioid agonist were co-administered with spinal μ-, δ-, and κ-opioid agonist. Using the Randall-Selitto paw-withdrawal test, in the rat, changes in nociceptive thresholds were measured following co-administration of sequentially increasing i.c.b. doses of either DAMGO or DPDPE with a low-antinociceptive dose of intrathecal DAMGO, DPDPE, or U50,488H. Antinociceptive synergy (i.e. a more than additive antinociceptive effect) was demonstrated with all of the combinations tested except for supraspinal DPDPE co-administered with spinal DAMGO. The results of this study provide support for the suggestion that supraspinal and spinal antinociceptive mechanisms share, in part, common neural circuits. Marked differences in the overall magnitude of the antinociceptive effects produced by the various combinations of opioid agonists were demonstrated through a secondary analysis of the data. When sequentially increasing i.c.v. doses of DAMGO were administered, significantly larger increases in nociceptive thresholds were observed with co-administration of intrathecal injections of low antinociceptive doses of either DAMGO or U50,488H compared to DPDPE. In contrast, when DPDPE was administered supraspinally, the largest increases in nociceptive thresholds were demonstrated with co-administration of DPDPE at the spinal site. The results of the secondary analysis provide support for the hypothesis that descending antinociceptive control systems activated by supraspinal administration of selective μ- and δ-opioid agonists interact, differently, with spinal μ-, δ, and κ-opioidergic mechanisms.
Brain Research.
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ABSTRACT: Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (PAG) including the dorsal raphé, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrations in all areas showed similar time courses: morphine was detected in the first dialysate sample (13–15 min) and maximal concentrations were reached at 45 min after injection. When in vivo recoveries of morphine from the spinal cord and brain areas were taken into account, no significant differences between morphine concentrations in the various areas were found. The relationship between extracellular morphine concentrations and morphine-induced analgesic behavior was investigated by simultaneously measuring morphine in the dialysate and its analgesic effect in the paw-withdrawal and tail-flick tests. In all areas sampled, the extracellular concentrations of morphine at different times after i.p. injection, significantly correlated with the magnitude of behavioral analgesia assessed by either test. The highest correlation was obtained between extracellular concentrations of morphine in the spinal cord and PAG and behavioral analgesia assessed in the paw-withdrawal test. Our data indicate that, after systemic injection, morphine is evenly distributed throughout the spinal cord and brain including potential anatomical sites of morphine's analgesic action. We estimate that the minimal extracellular morphine concentration in spinal cord that is required to produce a significant increase in nociceptive threshold is approximately 100 pg/25 μl, which corresponds to a tissue concentration of about 100 ng/g of morphine.
Brain Research.
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ABSTRACT: An important limitation in behavioral tests of the hyperalgesic and analgesic effects of drugs is the low sensitivity of the measuring technique associated with inter- and intra-subject variability. Since familiarity with the experimental situation and novelty of the stimulus significantly influences an animal's behavior, we have tested the hypothesis that intensive training of rats, in the Randall-Selitto paw-withdrawal test, will increase the sensitivity of this test for detecting hyperalgesic effects of intradermal injections of the inflammatory mediator, bradykinin (BK). Mean baseline of the mechanical nociceptive threshold decreased between the first and second, and stabilized by the third day of training. Although there was no significant difference between the effects of BK or its vehicle (saline) on nociceptive threshold on day 1, on subsequent days BK produced a dose-dependent decrease in nociceptive threshold that could be distinguished from the effect of vehicle. These data demonstrate that training in the experimental paradigm can increase sensitivity for detecting hyperalgesic effects of inflammatory mediators in behavioral tests.
Brain Research.
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ABSTRACT: Intrathecal administration of PGE2 and PGF2α and intradermal administration of PGE2 but not PGF2α, in low doses, produce hyperalgesia as measured by the Randall-Selitto paw-withdrawal test. Indomethacin (2 mg/kg, i.p.) prevented intrathecal PGF2α, but not PGE2-induced hyperalgesia. We propose that the central nociceptive effects of PGF2α are mediated, indirectly, by effecting the cyclooxygenation of arachidonic acid in the central nervous system.
Brain Research.
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ABSTRACT: This study compared the antinociceptive and motor effects produced by intrathecal administration of selective μ-, δ-, and κ-opioid receptor agonists in the rat. Changes in nociceptive threshold were measured using the Randall-Selitto paw-withdrawal test and changes in motor coordination were evaluated using the rotarod treadmill test. Each opioid agonist produced statistically significant, dose-dependent increases in mechanical nociceptive thresholds compared to vehicle controls. In the motor coordination studies, DAMGO and DPDPE, but not U50, 488H, produced statistically significant decreases in rotarod performance scores compared to vehicle controls. The results of these studies suggest that motor side-effects produced by opioid agonists need to be considered when interpreting the results of antinociceptive tests that are dependent on a normally functioning motor system.
Brain Research.
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ABSTRACT: Recent evidence suggests that one of the factors that may influence the assessment and management of pain is a person's gender. However, only a limited amount of information exists on gender differences in responses to analgesic medications. Based on a review of the available literature published between 1966 and 1998, we suggest that opioids are better analgesics for women. The information in this paper comes predominantly from several studies on the use of patient-controlled analgesia for the management of postoperative pain. Additional information comes from our recent work that demonstrated a sexual dimorphism in oral surgery patients' responses to three different opioid analgesics that share the property of acting as agonists at the kappa-opioid receptor. The paper concludes with a discussion of the major recommendations for future research regarding the gender biology of pain.
Pain Forum. 8(1):34-44.
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ABSTRACT: This study evaluated the effects of intrathecal administration of a low-analgesic dose of the selective μ-agonist DAMGO co-administered with sequentially increasing doses of either the selective δ-agonist DPDPE or the selective κ-agonist, U50,488H on mechanical nociceptive thresholds in the rat. Potent analgesic synergy was observed with both combinations. Since an elevation in nociceptive threshold can result from motor deficits, as well as true analgesia, we also evaluated the effects of the combination regimens on motor coordination using a rotarod apparatus. The combination regimens produced significantly less motor deficits than those observed when DPDPE and U50,488H were administered as single agents. These findings of enhanced analgesia with decreased motor side-effects associated with administration of fixed μ/δ or μ/κ combinations suggest that co-administration of opiates that act at different receptors may constitute a superior approach to the treatment of pain.
Brain Research.
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ABSTRACT: It has been suggested that bradykinin (BK) and norepinephrine (NE) induce hyperalgesia, indirectly, by stimulating the production of prostaglandin products of the cyclo-oxygenase pathway of arachidonic acid metabolism. However, the specific PGs that mediate the hyperalgesic effects of BK and NE are unknown. Two endogenous PGs, prostaglandin E2 (PGE2) and prostacyclin (PGI2) are known to produce hyperalgesia. Since the hyperalgesic effects of PGE2 and PGI2 can be distinguished by the duration of the hyperalgesia they induce, we have compared the duration of BK and NE hyperalgesia with those of PGE2 and PGI2. To further address the type of PG mediating BK and NE hyperalgesia, we have evaluated the ability of SC19220, a PG-receptor antagonist, to distinguish the hyperalgesia induced by PGE2 and PGI2. BK induces hyperalgesia with duration similar to that of PGE2. NE induces hyperalgesia with duration similar to that of PGI2. SC19220, at low doses, antagonizes PGE2 and BK hyperalgesia but not PGI2 and NE hyperalgesia. These data are compatible with the suggestion that the prostaglandin products mediating BK and NE hyperalgesia differ, BK hyperalgesia being mediated by PGE2 and NE hyperalgesia by PGI2.
Brain Research.
