Antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist, MPV-2426, in sheep.
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BACKGROUND: alpha2-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. Clonidine is approved for epidural use in the treatment of neuropathic pain, but its wider application is limited by hemodynamic side effects. This study determined the antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist, MPV-2426, in sheep. METHODS: Forty sheep of mixed Western breeds with indwelling catheters were studied. In separate studies, antinociception to a mechanical stimulus, hemodynamic effects, arterial blood gas tensions, cerebrospinal fluid pharmacokinetics, and spinal cord blood flow was determined after epidural, intrathecal, and intravenous injection of MPV-2426. RESULTS: MPV-2426 produced antinociception with greater potency intrathecally (ED50 = 49 microg) than epidurally (ED50 = 202 microg), whereas intravenous administration had no effect. Intrathecal injection, in doses up to three times the ED95, failed to decrease systemic or central arterial blood pressures or heart rate, whereas larger doses, regardless of route, increased systemic arterial pressure. Bioavailability in cerebrospinal fluid was 7% after epidural administration and 0.17% after intravenous administration. Intrathecal MPV-2426, in an ED95 dose and three times this dose, produced a dose-independent reduction in thoracic and lumbar spinal cord blood flow. CONCLUSIONS: MPV-2426 shares many characteristics of other alpha2-adrenergic agonists examined in sheep, but differs from clonidine and dexmedetomidine by lack of antinociception and minimal reduction in oxygen partial pressure after large intravenous and epidural injections. No hemodynamic depression was observed after intrathecal injection at antinociceptive doses. These results suggest this compound may be an effective spinal analgesic in humans with less hypotension than clonidine, although its relative potency to cause sedation was not tested in this study. (+info)
Sex differences in cholinergic analgesia I: a supplemental nicotinic mechanism in normal females.
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BACKGROUND: Cholinergic agents produce analgesia after systemic and intrathecal administration. A retrospective review showed that intrathecal neostigmine was more potent in women than in men, suggesting a sex difference in this response. The purpose of this study was to determine whether such a sex difference exists in normal rats and to examine the pharmacologic mechanisms that underlie this difference. METHODS: Male and female rats with indwelling intrathecal catheters received injections of neostigmine, bethanechol (muscarinic agonist), or RJR-2403 (neuronal nicotinic agonist) alone or with atropine (muscarinic antagonist), mecamylamine (nicotinic antagonist), or phentolamine alpha-adrenergic antagonist) with antinociception determined to a noxious heat stimulus to the hind paw. Time versus subcutaneous paw temperature relationships were defined for males and females. RESULTS: Neostigmine produced dose-dependent antinociception with five times greater potency in female than in male rats. Neostigmine-induced antinociception was reversed in male rats by atropine and unaffected by mecamylamine, whereas it was partially reduced by each antagonist alone in females and completely reversed after injection of both. RJR-2403 was more potent in females than in males, whereas there was no sex difference to bethanechol. Phentolamine partially reversed antinociception from RJR-2403 in females. Paw temperature increased more rapidly in females than in males for the same lamp intensity. CONCLUSIONS: These data demonstrate a large sex difference in antinociception to intrathecal neostigmine that is primarily the result of a nicotinic component in females. Phentolamine reversal suggests that part of this nicotinic component may rely on spinal norepinephrine release. A better understanding of this sex difference could lead to development of novel pain therapy for women. (+info)
Sex differences in cholinergic analgesia II: differing mechanisms in two models of allodynia.
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BACKGROUND: Cholinergic agents reduce allodynia after nerve injury in animals and may be useful in the treatment of neuropathic pain. Intrathecally administered neostigmine and neuronal nicotinic agonists are more potent in female than in male rats against acute thermal noxious stimuli. The purpose of this study was to determine whether there is also a sex difference in the antiallodynic effects of intrathecal cholinomimetic agents in two models of allodynia and to test their pharmacologic mechanisms. METHODS: Male and female rats with indwelling intrathecal catheters received injections of neostigmine, bethanechol (muscarinic agonist), RJR-2403 (neuronal nicotinic agonist) alone or with atropine (muscarinic antagonist), mecamylamine (nicotinic antagonist), phentolamine (alpha-adrenergic antagonist), or saline control. The effect of these agents was determined on mechanical allodynia produced by either intraplantar injection of capsaicin or ligation of spinal nerves. RESULTS: Neostigmine and RJR-2403 but not bethanechol were more potent in female than in male rats in reducing allodynia after nerve injury, and antagonist studies were also consistent with a nicotinic component to explain this sex difference. Phentolamine did not reverse neostigmine's effect. In contrast, for capsaicin-induced allodynia, neostigmine plus mecamylamine but not neostigmine or RJR-2403 was more potent in female than in male rats. CONCLUSIONS: These data demonstrate a sex difference of intrathecal neostigmine after nerve injury-induced allodynia similar to that observed in normal animals that received acute noxious thermal stimulation. However, this sex difference is not universal to all pain models because it was not present after intradermal capsaicin injection, nor is its interaction with spinal noradrenergic mechanisms consistent in all models. (+info)
Preweanling naltrindole administration differentially affects clonidine induced antinociception and plasma adrenaline levels in male and female neonatal rats.
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1. The influence of a chronic treatment with the delta-selective opioid antagonist naltrindole (1 mg kg-1) during the preweanling period (daily injections from birth to postnatal day 19), on the antinociceptive and sympatholytic effects of the alpha2-adrenergic agonist clonidine in male and female rats of 20 and 25 days of age was investigated. 2. Nociception was assessed using the tail immersion test (water at 50 degrees C) and plasma levels of adrenaline were measured by high-performance liquid chromatography. 3. The dose of clonidine (1.5 mg kg-1) and the time point at which nociceptive responses were recorded (30 min after the administration of the drug) were chosen on the basis of dose-response (0.5, 1, 1.5 and 2 mg kg-1) and time-response (5, 10, 15, 30 and 60 min) curves which were previously carried out in naive control neonatal rats. 4. In females, the functional blockade of the delta-receptor by neonatal naltrindole treatment did not modify the sympatholytic effect of clonidine but prevented clonidine induced antinociception. Conversely, in males naltrindole treatment allowed the appearance of clonidine antinociception and the sympatholytic effect of clonidine. 5. The results indicate that the delta-receptor is involved in the modulation of antinociceptive and sympatholytic responses to clonidine in neonatal rats and suggest the existence of sex differences in the interactions between delta-opioid and alpha2-adrenergic receptors. (+info)
Impact of chronic pain on health care seeking, self care, and medication. Results from a population-based Swedish study.
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STUDY OBJECTIVE: To explore individual and social factors that could predict health care utilisation and medication among people with chronic pain in an unselected population. DESIGN: A mailed survey with questions about pain and mental symptoms, disability, self care action, visits to health care providers, and medication. SETTING: General populations in two Swedish primary health care (PHC) districts. Medical care was given in a state health system. PARTICIPANTS: A random sample (from the population register) of 15% of the population aged 25-74 (n = 1806). MAIN RESULTS: Among people reporting chronic pain 45.7% (compared with 29.8 of non-chronic pain persons, p < 0.05) consulted a physician and 7.2% (compared with 1.2%, p < 0.05) a physiotherapist during three months. Primary health care was the most frequent care provider. High pain intensity, aging, depression, ethnicity, and socioeconomic level had the greatest impact on physician consultations. Alternative care, used by 5.9%, was associated with high pain intensity and self care. Use of self care was influenced by high pain intensity, regular physical activity, and ethnicity. Alternative care and self care did not imply lower use of conventional health care. Women reporting chronic pain consumed more analgesics and sedatives than corresponding men. Besides female gender, high pain intensity, insomnia, physician consultation, social network, and self care action helped to explain medication with analgesics. Use of herbal remedies and ointments correlated to self care action, visit to an alternative therapist, high pain intensity, and socioeconomic level. CONCLUSIONS: The presence of chronic pain has an impressive impact on primary health care and medication. Various therapeutic actions are common and are partly overlapping. The use of health care among people with chronic pain depends above all on pain perception and intensity of pain but is also affected by ethnicity, age, socioeconomic level, and depressive symptoms. Among people with chronic pain use of analgesics is common in contrast with other types of pain relief (acupuncture, physiotherapy) suitable for treating chronic pain symptoms. (+info)
Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy.
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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. (+info)
Intracisternal nor-binaltorphimine distinguishes central and peripheral kappa-opioid antinociception in rhesus monkeys.
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Systemic administration of nor-binaltorphimine (nor-BNI) produces a long-lasting kappa-opioid receptor (kappaOR) antagonism and has kappa(1)-selectivity in nonhuman primates. The aim of this study was to establish the pharmacological basis of central kappaOR antagonism in rhesus monkeys (Macaca mulatta). After intracisternal (i.c.) administration of small doses of nor-BNI, the duration and selectivity of nor-BNI antagonism were evaluated against two kappaOR agonists, (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) and bremazocine. Thermal antinociception was measured in the warm water (50 degrees C) tail-withdrawal assay and sedation was evaluated by observers blind to treatment conditions. Following i.c. pretreatment with 0.32 mg nor-BNI, a 5- to 10-fold rightward shift of the U50,488 baseline dose-effect curve was observed in antinociception. In contrast, this dose of nor-BNI only produced an insignificant 2-fold shift against bremazocine. Pretreatment with a smaller dose (0.032 mg) of nor-BNI produced a 3-fold shift of U50, 488, which lasted for 7 days, but failed to alter the potency of bremazocine. This differential antagonism profile of i.c. nor-BNI also was observed in sedation ratings. In addition, the centrally effective dose of nor-BNI (0.32 mg), when administered s.c. in the back, did not antagonize either U50,488- or bremazocine-induced antinociception and sedation. After i.c. pretreatment with the same dose, nor-BNI also did not antagonize the peripherally mediated effect of U50,488 against capsaicin-induced thermal nociception in the tail. These results indicate that i.c. nor-BNI produces central kappaOR antagonism and support the notion of two functional kappaOR subtypes in the central nervous system. Moreover, it provides a valuable pharmacological basis for further characterizing different sources of kappaOR-mediated effects, namely, from central or peripheral nervous system receptors. (+info)
Adenosine-supplemented blood cardioplegia attenuates postischemic dysfunction after severe regional ischemia.
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BACKGROUND: Various studies have reported that the administration of adenosine (ADO) in cardioplegia reduces myocardial ischemic injury, but this timing may not utilize ADO's potential against myocardial reperfusion injury. This study tested the hypothesis that ADO-supplemented blood cardioplegia (BCP) or ADO administered during reperfusion reduces postischemic dysfunction after severe regional ischemia. METHODS AND RESULTS: After 75 minutes of left anterior descending coronary artery occlusion, total cardiopulmonary bypass was initiated; cold (4 degrees C) antegrade BCP (8:1 blood:crystalloid) was delivered every 20 minutes for the first 3 doses, and 27 degrees C BCP was delivered for the terminal infusion. Dogs (n=6 per group) received unsupplemented BCP, ADO (100 micromol/L/L) supplemented in all infusions of BCP (ADO-CP), or ADO (100 micromol x L(-1) x L(-1)) supplemented only in the terminal infusion of BCP followed by intravenous ADO (140 microg x kg(-1) x min(-1)) infusion for the first 30 minutes of reperfusion (ADO-R). Postischemic regional systolic shortening was significantly greater in the ADO-R group (5+/-2.0%) than in the BCP group (-3+/-1.0%), but not in the ADO-CP group (2+/-0.2%). Postischemic regional diastolic stiffness in the area at risk during end reperfusion was lower with ADO-R (1.8+/-0.3%) than with ADO-CP (2.7+/-0.3%) or BCP (4.4+/-0.5%). Infarct size was reduced in the ADO-CP (29+/-2%) and ADO-R (21+/-2%) groups compared with the BCP group (42+/-4%). Edema in the myocardial area at risk was decreased in the ADO-CP (82+/-0.2%) and ADO-R (80+/-0.4%) groups compared with the BCP group (86+/-0.7%). Adherence of fluorescently labeled neutrophils (PMNs) to postischemic coronary artery endothelium was attenuated by ADO-R (55+/-2 PMNs/mm(2)), but not by ADO-CP (114+/-5 PMNs/mm(2)), compared with BCP (118+/-3 PMNs/mm(2)). CONCLUSIONS: The results show that BCP supplemented with ADO reduces infarct size, preserves postischemic systolic and diastolic regional function but does not attenuate coronary artery endothelial dysfunction unless administered during reperfusion. (+info)