ketazocine has been researched along with Pain* in 8 studies
8 other study(ies) available for ketazocine and Pain
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Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.
This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist. Topics: Acetic Acid; Animals; Benzomorphans; Brain; Dose-Response Relationship, Drug; Ethylketocyclazocine; Guinea Pigs; In Vitro Techniques; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Morphinans; Morphine; Narcotic Antagonists; Pain; Pain Measurement; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu | 2000 |
Reversal by naloxone of spinal antinociceptive effects of fentanyl, ketocyclazocine and midazolam.
Experiments using measurement of electrical-current threshold as a nociceptive test in the skin of the tail and neck in rats demonstrated that fentanyl, ketocyclazocine and midazolam caused spinally mediated antinociception when the drugs were administered intrathecally via chronically implanted lumbar subarachnoid catheters. The benzodiazepine antagonist flumazenil selectively suppressed the midazolam response, indicating that this benzodiazepine exerted its segmental antinociceptive effect via spinal-cord benzodiazepine receptors. Naloxone blocked the responses to both opioids and also midazolam. The dose of naloxone which suppressed the midazolam response was similar to that required to suppress the response to the kappa-opioid agonist. We suggest that the segmental antinociceptive effects of fentanyl and midazolam are mediated via different pathways; the benzodiazepine exerts its antinociceptive action via a spinal-cord opioid pathway which does not involve mu-receptors. Topics: Analgesia, Epidural; Animals; Catheters, Indwelling; Dose-Response Relationship, Drug; Drug Tolerance; Electric Stimulation; Ethylketocyclazocine; Fentanyl; Flumazenil; Injections, Spinal; Lumbar Vertebrae; Male; Midazolam; Naloxone; Nociceptors; Pain; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, Opioid; Sensory Thresholds | 1991 |
On the mechanism by which midazolam causes spinally mediated analgesia.
The electrical current thresholds for pain (ECTP) in the skin of the neck and tail were measured in rats with chronically implanted lumbar subarachnoid catheters. The effects of a benzodiazepine antagonist and a gamma-aminobutyric acid (GABA) antagonist on the analgesic effects of equivalent doses of midazolam, fentanyl, and ketocyclazocine were studied. These were the minimum doses producing maximal segmental analgesia when given intrathecally (i.e., they all caused a significant and maximum increase in ECTP in the tail, which was similar for all three drugs, but no significant change in the ECTP in the neck). Flumazenil (Ro 15-1788) administration caused a parallel shift to the right of the dose-response curve for midazolam spinal analgesia. Segmental analgesia following midazolam was also significantly attenuated (P less than 0.05) when the selective GABA antagonist bicuculline was given intrathecally at the same time as midazolam. The highest dose of bicuculline used (50 pmol) caused no significant attenuation of the segmental analgesic effects of either ketocyclazocine or fentanyl. The authors concluded that the segmental analgesia produced by intrathecal midazolam is mediated by the benzodiazepine-GABA receptor complex that is involved in other benzodiazepine actions. Topics: Analgesia, Epidural; Animals; Bicuculline; Cyclazocine; Dose-Response Relationship, Drug; Electric Stimulation; Ethylketocyclazocine; Fentanyl; Flumazenil; Male; Midazolam; Pain; Rats; Rats, Inbred Strains; Receptors, GABA-A; Sensory Thresholds | 1990 |
Effects of neonatal spinal cord serotonin depletion on opiate-induced analgesia in tests of thermal and mechanical pain.
There is considerable evidence that serotonin (5-HT) is involved in the analgesic actions of various opiates. However, it is less clear which opioid receptor types interact with these descending systems and whether the various monoaminergic pathways are specific for different types of nociceptive signals. In the present study we lesioned the spinal cord serotonin pathways by neonatal spinal injections of 5,7-dihydroxytryptamine (5,7-DHT) and tested the analgesic effects of morphine and ketocyclazocine one and two weeks later using both mechanical and thermal noxious stimuli. The treatment depleted spinal cord serotonin by more than 90% while not affecting norepinephrine levels. The effects of morphine were greatly attenuated in the depleted animals when the thermal noxious stimulus was applied. The analgesic actions of morphine were only slightly affected when the mechanical stimulus was applied. The effects of ketocyclazocine were not reduced by the treatment. The results further buttress the conclusion that at least part of morphine's analgesic effects are mediated by descending serotonin systems and that these systems are primarily effective against a thermal stimulus. The data suggest that non-5-HT brainstem system(s) are involved in morphine-induced analgesia to a mechanical noxious stimulus. Topics: 5,7-Dihydroxytryptamine; Analgesia; Animals; Animals, Newborn; Cyclazocine; Desipramine; Dihydroxytryptamines; Ethylketocyclazocine; Hot Temperature; Morphine; Pain; Physical Stimulation; Rats; Serotonin; Spinal Cord | 1988 |
Morphine- and ketocyclazocine-induced analgesia in the developing rat: differences due to type of noxious stimulus and body topography.
Patterns of morphine- and ketocyclazocine-induced analgesia in limb withdrawal and tail-flick tests of thermal and mechanical nociception were examined in the preweanling rat. In the forepaw test, morphine was more effective than ketocyclazocine with both thermal and mechanical stimuli. Both drugs first induced analgesia between 3 and 5 days of age. In the tail-flick test, ketocyclazocine-induced analgesia preceded morphine's effects against both thermal and mechanical stimuli by several days. Ketocyclazocine produced robust analgesia between 7 and 10 days of age, while the effects of morphine did not peak until day 14. In the hindpaw, morphine was more effective than ketocyclazocine against a higher intensity mechanical stimulus, while ketocyclazocine was more effective against a lower intensity mechanical stimulus. Morphine-induced analgesia was reversed by lower doses of naloxone than was ketocyclazocine-induced analgesia, regardless of body part tested, against all noxious stimuli. These findings demonstrate differences in morphine- and ketocyclazocine-induced analgesia that are dependent upon age, body topography, stimulus type and intensity and imply different physiologic roles of mu- and chi-opioid receptors in analgesia. Topics: Age Factors; Analgesics; Animals; Animals, Suckling; Central Nervous System; Cyclazocine; Ethylketocyclazocine; Morphine; Naloxone; Pain; Pain Measurement; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu | 1987 |
Kappa opioid receptor-mediated analgesia in the developing rat.
The prototypic kappa opiate ketocyclazocine produced robust analgesia in 10-day-old rats in the tail-flick nociceptive test. The kappa-opiate behavioral response coincided with the onset of a rapid rise to adult levels in brain kappa receptor site density. In contrast, morphine (prototypic mu opiate) was without marked effect until 14 days of age. The period of rapid mu receptor increase did not take place until days 14-16, which was after kappa receptor levels had already plateaued. Further, there was no or incomplete cross-tolerance between ketocyclazocine and morphine at 14 days of age. The present study, therefore, establishes a role for the kappa binding site in thermal analgesia in the tail flick test and differentiates its ontogenetic pattern from that of the mu receptor. Topics: Age Factors; Animals; Brain; Cyclazocine; Drug Tolerance; Ethylketocyclazocine; Hot Temperature; Morphine; Pain; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu | 1986 |
Impairment of ketocyclazocine antinociception in rats by perinatal lead exposure.
The development of ketocyclazocine antinociception has been measured in lead-exposed rats as an indirect determinant of kappa-opioid receptor system development. Perinatal lead administration (at 300 and 1000 ppm) in the maternal drinking water from conception to weaning, impaired the antinociceptive activity of ketocyclazocine (using the paw pressure test) in 10-day-old rats. Lead caused a dose-dependent impairment of ketocyclazocine antinociception, the paw pressure threshold for 0.4 mg/kg being reduced from 207 g to 135 g in the 1000 ppm lead dose-group. Ketocyclazocine antinociception was impaired in the high-lead dose-group at 21 days, but unaffected at 30 days. Blood lead levels in 10-day-old animals were below 35 micrograms/100 ml in the low-lead dose-group and below 50 micrograms/100 ml in the high-lead dose-group. It is suggested that lead may disrupt the development of kappa-opioid receptor systems in the central nervous system and that this disruption occurs early in development. Topics: Animals; Animals, Newborn; Animals, Suckling; Cyclazocine; Dose-Response Relationship, Drug; Ethylketocyclazocine; Female; Lead; Lead Poisoning; Pain; Pregnancy; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Sensory Thresholds | 1985 |
Analgesic actions of mu- and kappa-opiate agonists in rats.
The antinociceptive profiles of mu- and kappa-opiate agonists were determined in a combined tail immersion plus tail pressure nociceptive test in rats. Combined analysis of potencies for pressure against heat noxia enabled differentiation between all mu- and kappa-agonists tested, thus confirming previous studies in other animal species and paralleling observations from studies on isolated tissue preparations. The distinct antinociceptive profiles produced by mu- and kappa-agonists provide further quantitative evidence that these agents are behaviourally different. Topics: Analgesics, Opioid; Animals; Cyclazocine; Dose-Response Relationship, Drug; Ethylketocyclazocine; Hot Temperature; Male; Nociceptors; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu | 1983 |