Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible involvement of central serotonergic pathways in the mechanism of action of nefopam was investigated in male albino mice. Nefopam (15 mg/kg i.p.) did not alter the concentration of serotonin or its metabolite 5-hydroxyindole acetic acid in frontal cortex or spinal cord. Lesions of the ascending serotonergic pathways were made by systemic administration of p-chloroamphetamine (PCA). Serotonin depletion in all serotonergic systems was obtained by means of p-chlorophenylalanine (PCPA). Two different nociceptive assays were used, the formalin test and the increasing temperature hot plate test. PCPA pretreatment significantly reduced the effect of nefopam (15 mg/kg) in the formalin test. In contrast, nefopam-induced analgesia was not affected by PCA pretreatment, either in the formalin test or in the increasing temperature hot plate test. In conclusion, the data suggest that descending serotonergic pathways are involved in nefopam-induced antinociception.
 ...
PMID:Involvement of central serotonergic pathways in nefopam-induced antinociception. 244 3

Recent immunohistochemical studies indicate the presence of a bulbospinal substance P (SP) system, as well as a bulbospinal serotonin (5-HT) system, involved in spinal pain transmission. Although electrophysiological studies indicate that SP may modulate the effects of 5-HT on postsynaptic spinal nociceptive neurons, the functional relationship between SP and 5-HT on "pain behavior" remains obscure. To bridge this gap between mechanism and behavior, the purpose of the present study was to determine specific postsynaptic behavioral effects of SP and 5-HT on local spinal nociceptive reflexes in spinally transected animals. Administration of the 5-HT agonists 5-methoxydimethyltryptamine (5-MeODMT) (0, 0.5, 1.5, 2.0 mg/kg) and quipazine (0, 5, 10, 20 mg/kg) 2 days after transection significantly expanded the receptive field (RF) areas of three spinal reflexes, as previously reported. Intrathecal administration of SP alone (0, 0.25, 2.5, 7.5 ng) also resulted in hyperalgesia, indicated by a significant expansion of the RF areas of all three nociceptive reflexes. However, administration of SP, in animals pretreated with 5-HT agonists, decreased the 5-HT-induced expansion of RF size. Therefore, SP had opposite effects on spinal nociceptive reflexes depending on whether or not the animal was pretreated with 5-HT agonists, i.e., hyperalgesia in the absence of 5-HT agonists, and analgesia in the presence of 5-HT agonists. The two effects of SP on local spinal reflexes may be related to the anatomical organization of the two spinal SP systems: 1) SP released from primary afferents facilitates nociceptive reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differential effects of substance P on serotonin-modulated spinal nociceptive reflexes. 244 89

The involvement of endogenous serotonergic pathways in the mediation of antinociception has been indicated by electrophysiological, pharmacological and behavioral experiments. However, manipulation of the indole pathway, either by lesioning of raphe nuclei or drug intervention, often produces disparate results. In particular, serotonin (5-HT) synthesis inhibition with p-chlorophenylalanine (PCPA) has been reported to produce either hyperalgesia or analgesia, depending upon the type of pain measurement examined. In the present study, we sought to evaluate the effects of PCPA on (1) behavioral responses to noxious stimulation, and (2) levels of serotonin, tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in raphe nuclei (pallidus, obscurus, magnus and dorsalis) and spinal cord regions by HPLC with electrochemical detection. Treatment of rats with 400 or 600 mg/kg of PCPA for 3 consecutive days resulted in significant elevations in pain thresholds assessed by tail withdrawal from radiant heat as well as vocalization to electric shock of the tail. The effect of PCPA on vocalization threshold was particularly striking, for the majority of animals showed a nociceptive-specific attenuation of this response. Although the PCPA induced changes in indole content of the various raphe nuclei were not unequivocally dose-dependent, differential reductions of serotonin and 5-HIAA were clearly detected in the various raphe regions. Nuclei raphe pallidus and obscurus were depleted of 5-HT and 5-HIAA to the greatest extent, whereas levels detected in nuclei raphe magnus and dorsalis were reduced by 30-40% from control values. Metabolism of 5-HT and 5-HIAA appeared unaffected by PCPA in all regions examined except the dorsal portion of the spinal cord. These findings collectively suggest that the effects of PCPA are not uniform throughout the central nervous system and raise the possibility that discrepancies in the behavior literature may be attributed to drug-induced changes in some, but not all serotonergic pathways.
 ...
PMID:Differential effects of p-chlorophenylalanine on indoleamines in brainstem nuclei and spinal cord of rats. I. Biochemical and behavioral analysis. 244 10

Participation of opiate, serotonergic and noradrenergic components in the antinociceptive action of intrathecally administered morphine was evaluated by measuring the ability of subcutaneously administered doses of naloxone, methysergide and phentolamine to alter analgesia. Morphine produced a dose-dependent elevation of the tail-flick latency, due exclusively to local spinal actions. For example, 10 nmol of the drug, when administered intrathecally in rats with bilateral lesions of the dorsolateral funiculus, produced an increase in the tail-flick latency, that was similar to that observed in intact animals. Furthermore, morphine was ineffective when administered intracerebroventricularly into the fourth ventricle of intact rats. The spinal antinociceptive action of the opiate was antagonized by naloxone (ID50 = 0.035 mg/kg, s.c.) but was also significantly attenuated by methysergide (ID50 = 4.28 mg/kg, s.c.). Phentolamine was ineffective. Doses of methysergide that were most effective in reversing the spinal action of morphine also produced hyperalgesia when administered alone. On the other hand, when the dorsolateral funiculus was lesioned, the hyperalgesia was no longer observed, yet the antagonist remained effective against morphine. These data suggested that the doses of methysergide needed to antagonize the action of morphine were in the same range as those needed to block the synaptic actions of serotonin (5-HT) released from the tonically-acting, descending pain inhibitory nerves. The results demonstrate that local opiate, as well as serotonergic, mechanisms mediate the antinociceptive action of morphine in the spinal cord. The recruitment of a serotonergic component may be related to an action of opiates within the spinal cord, to cause the release of serotonin from the terminal fields of the spinipetal serotonergic nerves.
 ...
PMID:A local serotonergic component involved in the spinal antinociceptive action of morphine. 255 80

The antinociceptive properties of intrathecally (i.t.) administered [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAMPGO) and [D-Pen2, D-Pen5]enkephalin (DPDPE), selective opioid agonists for mu (mu) and delta (delta) sites, respectively, were compared in rats. DAMPGO and DPDPE elevated tail-flick latency (TFL) in a dose-dependent manner, and the spinal antinociceptive actions of both drugs were reversed by the opiate antagonist naloxone. These findings suggest that both DAMPGO and DPDPE interact with spinal opiate receptors to elevate TFL. Another set of experiments was done to determine the involvement of local spinal serotonin (5-HT) or norepinephrine (NE) in DAMPGO and DPDPE-induced spinal analgesia. Both the alpha 1 noradrenergic receptor antagonist WB-4101 and the alpha 2 blocker yohimbine failed to alter the antinociceptive actions of DAMPGO and DPDPE. Similarly, the 5-HT receptor antagonists pindolol, ritanserin and ICS 205-930 (selective for 5-HT1, 5-HT2 and 5-HT3 sites, respectively) failed to inhibit opioid-induced spinal analgesia. Thus, while DAMPGO and DPDPE produce antinociception via an interaction with spinal opioid receptors, apparently neither drug activates endogenous monoaminergic systems.
 ...
PMID:A comparative analysis of monoaminergic involvement in the spinal antinociceptive action of DAMPGO and DPDPE. 255 89

Acute exposure to continuous (CCWS) or intermittent (ICWS) cold-water swims elicits non-opioid and opioid forms of analgesia respectively. Intrathecal administration of methysergide blocks ICWS, but not CCWS analgesia. The present study evaluated the role of serotonin (5-HT) receptor subtypes in the mediation of CCWS and ICWS analgesia on the tail-flick and jump tests following administration of methysergide, a non-specific 5-HT antagonist and pirenpirone and ketanserin, two 5-HT2 receptor subtype antagonists. Systemic methysergide was more effective in reducing CCWS analgesia (50-58%, 0.1-1.0 mg/kg) than ICWS analgesia (21%, 5 mg/kg) on both pain tests. Systemic pirenpirone (0.04-0.2 mg/kg) and ketanserin (1-5 mg/kg) were also more effective in reducing CCWS analgesia (43-57%) on both tests than ICWS analgesia (pirenpirone: 0.4 mg/kg, 34%; ketanserin: 5 mg/kg, 21%) on the tail-flick test. Indeed, both 5-HT2 receptor antagonists potentiated ICWS analgesia on the jump test. While serotonin antagonist effects upon hypothermia could not account for CCWS analgesia effects, similar potentiations in ICWS analgesia and hypothermia were observed following pirenpirone and ketanserin. Finally, both 5-HT2 receptor antagonists differentially reduced CCWS hypothermia and potentiated ICWS hypothermia. These data suggest differential serotonergic modulation of the two forms of swim analgesia with opioid-mediated ICWS analgesia acting through spinal 5-HT1 receptors and non-opioid-mediated CCWS analgesia acting through supraspinal 5-HT2 receptors.
 ...
PMID:Reduction in opioid and non-opioid forms of swim analgesia by 5-HT2 receptor antagonists. 260 92

The effect of systemic morphine on serotonin (5-HT) metabolism within the dorsal raphe nucleus (DRN) has been investigated by in vivo 5-hydroxyindole electrochemical (peak '3') detection in freely moving rats. Morphine caused a weak and delayed, but naloxone-reversible, increase in peak '3'. This increase was poorly, if at all, correlated with the morphine-induced analgesia. Finally, stress and/or noxious stimulation had no effect on this signal. These results are compared with our previous studies using the same methodological approaches and show that morphine caused a significant and specific increase in 5-HT metabolism at the levels of nucleus raphe magnus (NRM) and medullary dorsal horn. Furthermore, as shown in the present paper, there was also a good correlation between the time course of such increases and the analgesic effect of morphine. These findings are discussed with reference to the involvement of 5-HT mechanisms in the so-called DRN-NRM-dorsal horn 'intrinsic analgesic system'.
 ...
PMID:A comparison of the effects of morphine on 5-HT metabolism in the periaqueductal gray, ventromedial medulla and medullary dorsal horn: in vivo electrochemical studies in freely moving rats. 277 31

The effects of acute and chronic treatment with tricyclic antidepressants (TCA) upon antinociception induced by intrathecally administered serotonin (5-HT), norepinephrine (NE), and morphine were assessed at weekly intervals by the tail-flick method in the rat. Acute pretreatment with either clomipramine (28.5 mumol/kg, s.c.) or desipramine (85.5 mumol/kg, s.c.) enhanced the analgesia induced by both intrathecally-administered morphine (7.5 nmol) and 5-HT (241 nmol), compared to saline (1 ml/kg) but only desipramine facilitated the effects of intrathecally administered NE (0.49 nmol). The chronic (22 day) administration of both tricyclic antidepressants resulted in loss of the enhancement of the effects of morphine (day 22) and 5-HT (day 15); only desipramine (day 15) abolished the facilitation of NE. In a similar study, acute pretreatment with the non-tricyclic antidepressant inhibitor of the reuptake of NE, nisoxetine, (97.5 mumol/kg, s.c.), amplified the effects of intrathecally administered NE and morphine but not 5-HT-induced analgesia. Although chronic (22 day) treatment with nisoxetine caused a loss of the effects of enhancement of morphine (day 8), there was no effect upon the action of NE and antinociception induced by 5-HT was facilitated (day 22). Receptor binding studies indicated that chronic (22 day) treatment with clomipramine, desipramine or nisoxetine reduced the affinity of opiate [3H]naloxone) receptors in the spinal cord. These results demonstrate that (1) acute treatment with trycyclic antidepressants enhanced analgesia induced by intrathecally injected morphine, and (2) the chronic administration of trycyclic antidepressants resulted in a loss of enhancement of the effects of morphine, given intrathecally, which appeared to be independent of alterations in the activity of NE or 5-HT but may be associated with the development of subsensitive opiate receptors.
 ...
PMID:Effect of chronic treatment with tricyclic antidepressants upon antinociception induced by intrathecal injection of morphine and monoamines. 283 78

Anatomical and electrophysiological studies have demonstrated that enkephalinergic, noradrenergic, and serotonergic pathways projecting from the brain-stem to the dorsal horn inhibit nociceptive transmission at the spinal level. Previous attempts to delineate interactions between opioids, norepinephrine (NE), and serotonin (5-HT) in the production of spinal analgesia have produced conflicting results. The present study determined the effect of intrathecal (i.t.) pretreatment with opioid, NE, and 5-HT antagonists upon i.t. monoamine- and morphine-induced antinociception as assessed with the rat tail-flick model. Naloxone, at a dose which antagonized i.t. morphine analgesia, had no effect upon i.t. NE but inhibited i.t. 5-HT antinociception. Corynanthine or yohimbine (NE antagonists) reduced analgesia elicited by i.t. NE but not morphine, while pretreatment with methysergide or ketanserin (5-HT antagonists) attenuated both i.t. 5-HT- and morphine-induced antinociception. These results suggest that (1) an opioid link mediates spinal 5-HT but not NE antinociception, and (2) 5-HT but not NE participates in spinal morphine analgesia.
 ...
PMID:Opioid-monoamine interactions in spinal antinociception: evidence for serotonin but not norepinephrine reciprocity. 284 36

In the cat there is no convincing evidence that a particular compound mediates a supraspinal control of spinal transmission of nociceptive information. There is good evidence that opioid peptides are released segmentally in response to nociceptive input to the spinal cord and that this acts to inhibit motoneurons and to reduce transmission of nociceptive information to supraspinal areas. In the cat there is no evidence that stimulation at supraspinal sites producing analgesia results in a spinal release of opioid peptides. In the rat evidence for the latter has been obtained but there are no data from other species. Tonically present supraspinal inhibition of spinal transmission of nociceptive information in the cat does not involve opioid peptides. Indirect evidence favours a role for 5-hydroxytryptamine and noradrenaline in supraspinal control of spinal processing of nociceptive transmission. Peripheral antagonists of 5-HT have reduced spinal inhibition from stimulation at supraspinal sites but the site of action is unknown. Progress with noradrenaline involvement has been hindered by lack of a suitable antagonist. Although the amino acids, glycine and GABA are involved in segmental inhibition of transmission of nociceptive information, no convincing evidence has indicated their involvement in supraspinal controls.
 ...
PMID:Pharmacology of descending control systems. 285 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>