Changes in nociception after 6-hydroxydopamine lesions of descending catecholaminergic pathways in mice (original) (raw)
Related papers
öStudies have shown that 5-hydroxytryptamine (5-HT) plays an important role in the descending pathway of pain modulation from brainstem to the spinal cord. Using selective 5-HT receptor antagonists, the present study investigated which type of 5-HT receptor(s) in the spinal cord was involved in the morphine-induced anti-nociception in intact rats, in rats with nerve injury and in rats with in£ammation. The hindpaw withdrawal latencies decreased signi¢cantly after sciatic nerve injury and hindpaw in£ammation compared with intact rats. Intrathecal administration of 25 or 10 Wg of the selective 5-HT 1A recepter antagonist spiroxatrine, but not 1 Wg of spiroxatrine, signi¢cantly blocked the increased hindpaw withdrawal latencies to thermal and mechanical stimulation induced by intra-periaqueductal gray injection of 1 Wg of morphine in intact rats. Intrathecal injection of the 5-HT 2 receptor antagonist RS 102221 and the 5-HT 3 receptor antagonist MDL 72222 had no signi¢cant e¡ects on the increased hindpaw withdrawal latencies to both noxious stimulations induced by intra-periaqueductal gray injection of morphine. Furthermore, intrathecal administration of spiroxatrine, but not RS 102221 nor MDL 72222, signi¢cantly attenuated the increased hindpaw withdrawal latencies induced by intra-periaqueductal gray administration of morphine in rats with nerve injury and in rats with in£ammation. The results demonstrate that the 5-HT 1A receptor, not 5-HT 2 nor 5-HT 3 receptor, plays an important role in the descending pathway of anti-nociception from the brainstem to the spinal cord in intact rats, in rats with nerve injury and in rats with in£ammation. ß 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.
Pain, 1992
Recent anatomical evidence indicates that the pontine A7 catecholamine cell group provides the major noradrenergic innervation of the spinal cord dorsal horn (laminae I-IV>. The experiments described in this report were designed to determine if these neurons modulate nociception at the level of the spinal cord. To this end, the antinociceptive effect of electrical stimulation applied at various sites along several tracks through the dorsolateral pontine tegmentum was determined in lightly anesthetized rats. The latency of the withdrawal response of the hind feet to noxious radiant thermal stimulation applied to the dorsal surface was used as a measure of nociception. The results indicated that the most potent and consistent antinociception was produced at sites near the A7 cell group. In addition, intrathecal injection of a-noradrenergic antagonists blocked the antinociception produced by electrical stimulation at sites near the A7 group. These observations indicate that the antinociception produced by stimulation near the A7 cell group was mediated by spinally projecting noradrenergic neurons. The results of these experiments provide evidence that pontospinal noradrenergic neurons located in the A7 cell group are important components of the descending neuronal system that modulates nociception.
Brain Research, 1987
A systematic study of the role of descending, ascending and both aspects of noradrenergic pathways in the analgesic action of morphine was undertaken. The neurotoxin 6-hydroxydopamine (6-OHDA) was microinjected into the medullary A l region, the dorsal bundle (DB), locus coeruleus (LC) or the cerebral ventricles (i.c.v.) to deplete noradrenaline (NA) in these pathways. The afialgesic effect of systemically administered morphine 7-15 mg/kg was generally tested 7-12 days postlesion, and at the end of the experiment, brain and spinal cord regions were extracted and NA and dopamine (DA) measured by I-I'PLC to verify the placement of lesions. Medullary A 1 lesions profoundly depleted spinal cord NA with only a modest effect on mesencephalic levels. Such lesions inhibited the effect of morphine in a pressure test, but not in thermal tests (tail flick and hot plate) for nociception. DB lesions reduced NA in the cortex, hippocampus, hypothalamus and midbrain, but not in the spinal cord, and potentiated morphine analgesia in thermal tests for nociception. DA levels in the striatum were normal in this group. In another group where different stereotaxic coordinates were used. the pattern of NA depletion was similar, but DA levels in the striatum were reduced. In this group, potentiation of analgesia was no longer observed. LC lesions depleted NA throughout the neuraxis and potentiated morphine analgesia in both pressure and thermal tests for nociception. I.c.v. 6-OHDA depleted NA to a comparable degree to LC lesions, but striatal DA levels also were reduced and potentiation of morphine analgesia was not observed. These results indicate that central NA pathways are critical to the expression of morphine analgesia. The effect of depletion of NA in both ascending and descending aspects is the same as depletion in ascending pathways only, suggesting that this pathway is an important mediator of morphine analgesia. Simultaneous depletion of DA in the striatum can reverse the potentiating action of NA depletion indicating a critical role for DA with respect to NA pathways and mechanisms of analgesia.
Behavioural Brain Research, 1995
The effects of 5-hydroxytryptamine (5-HT) and ligands selective for particular 5-HT receptor subtypes on the transmission of nociceptive information in the spinal cord are complex. In these studies, we have focused on their interactions with two endogenous mediators of pain suppression, noradrenaline (NA) and adenosine. Spinal antinociception by 5-HT is blocked by ~-adrenoreceptor antagonists and depletion of endogenous NA by 6-hydroxydopamine, while it is potentiated by blockade of NA reuptake with desipramine. These observations provide evidence for a 5-HT receptor-mediated increase in the release of NA from the spinal cord. This action appears to be due to activation of a 5-HTx-like receptor as it is mimicked by some 5-HT1 receptor ligands (mCPP, TFMPP and 5-Me-O-DMT), but not by DOI (5-HT2) or 2-Me-5-HT (5-HT3). An additional component of 5-HT action is via release of adenosine. Antinociception by 5-HT is blocked by the adenosine receptor antagonist 8-phenyltheophyUine, and 5-HT has been shown to release adenosine from the spinal cord in in vitro and in vivo paradigms. Methylxanthine-sensitive antinociception is seen with some 5-HT1 receptor ligands (CGS 12066B, mCPP), but not with others or with DOI or 2-Me-5-HT. Further characterization of the 5-HT receptor subtype involved in adenosine release will require the use of additional approaches.
Antinociceptive role of 5-HT1A receptors in rat spinal cord
British Journal of Anaesthesia, 2002
Background. Intrathecal administration of 5-hydroxytryptamine (5-HT) is antinociceptive to noxious heat and electrical stimuli. The contributions of different receptor subtypes to the antinociceptive effects of 5-HT are controversial. The main reasons for this are the poor receptor subtype selectivity of some agonist drugs and the dif®culty of restricting drug action to the spinal cord in some experimental paradigms. This study investigated the roles of different 5-HT receptor subtypes involved in the spinal cord control of the nociception produced by these two nociceptive testing paradigms. Methods. Tail-¯ick latency and electric current threshold for nociception were measured in an acute pain model that allowed the study of the antinociceptive effects of intrathecally administered drugs that were due to actions of these drugs at spinal cord receptors. Experiments were performed in male Wistar rats with chronically implanted lumbar subarachnoid catheters. Dose±response curves for spinally mediated antinociceptive effects of agonists selective for 5-HT receptor subtypes were constructed. Results. The 5-HT 1 agonist 1-(3-chlorophenyl)-piperazine dihydrochloride caused a dosedependent antinociceptive effect, measured by both nociceptive tests. However, 8-hydroxy-DPAT (selective 5-HT 1A agonist) produced antinociception assessed by electric current but not tail¯ick. A 5-HT 1A-selective antagonist, 4-[3-(benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)-piperazine, reversed the antinociception in the electrical test produced by both of these agonists but the tail-¯ick latency effects after intrathecal 1-(3-chlorophenyl)-piperazine were not suppressed by this antagonist. Conclusions. We conclude that 5-HT 1A receptors in the spinal cord are involved in the nociceptive mechanisms assessed by noxious electrical stimuli. Other 5-HT 1 receptors (non 5-HT 1A receptors) are involved in the spinally mediated antinociception assessed by thermal noxious stimuli.
Brain Research, 1995
Electrical stimulation of the brain, particularly in the periventricular grey areas, caused long-lasting increases in behavioural escape thresholds to heating and mechanical stimuli applied to the facial region of the rat. The brain stimulation selectively suppressed responses to noxious stimuli. Responses to non-noxious stimuli, evoked by low threshold brush, were unaffected. The same animals that were studied in the behavioural tests were then anaesthetized with urethane and the inhibitory effect of the same brain stimulation was studied in single neurones recorded in the caudal trigeminal nucleus. A clear correlation (rs = 0.63) emerged between degree of behavioural antinociception and the amount of inhibition seen in nociceptive neurones. In addition the mean duration of the inhibition (6 min) was similar to the mean duration of the antinociceptive effect (7.3 min). Other classes of non-nociceptive neurones were unaffected by the stimulation. The neurones were also studied using iontophoretically applied monoamine candidates for the inhibitory neurotransmitter, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). The profile of the effects of NA most closely fitted that of the inhibitory neurotransmitter. This profile was expressed in terms of depression and excitation of different classes of neurones, and by the duration of effects. The depressant effects could be antagonized by iontophoretic idazoxan. In addition clonidine induced long-lasting depression of firing. 5-HT was more likely than NA to excite nociceptive neurones and to depress non-nociceptive neurones. Only NA consistently elevated thermal response thresholds in a similar manner to that produced by brain stimulation. These results provide some support for the hypothesis that selective descending inhibition of nociceptive responses in neurones of the rat caudal trigeminal nucleus is mediated by NA, possibly by an action at α2-adrenoceptors.
Electrical stimulation of the brain, particularly in the periventricular grey areas, caused long-lasting increases in behavioural escape thresholds to heating and mechanical stimuli applied to the facial region of the rat. The brain stimulation selectively suppressed responses to noxious stimuli. Responses to non-noxious stimuli, evoked by low threshold brush, were unaffected. The same animals that were studied in the behavioural tests were then anaesthetized with urethane and the inhibitory effect of the same brain stimulation was studied in single neurones recorded in the caudal trigeminal nucleus. A clear correlation (r S = 0.63) emerged between degree of behavioural antinociception and the amount of inhibition seen in nociceptive neurones. In addition the mean duration of the inhibition (6 min) was similar to the mean duration of the antinociceptive effect (7.3 min). Other classes of non-nociceptive neurones were unaffected by the stimulation. The neurones were also studied using iontophoretically applied monoamine candidates for the inhibitory neurotransmitter, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). The profile of the effects of NA most closely fitted that of the inhibitory neurotransmitter. This profile was expressed in terms of depression and excitation of different classes of neurones, and by the duration of effects. The depressant effects could be antagonized by iontophoretic idazoxan. In addition clonidine induced long-lasting depression of firing. 5-HT was more likely than NA to excite nociceptive neurones and to depress non-nociceptive neurones. Only NA consistently elevated thermal response thresholds in a similar manner to that produced by brain stimulation. These results provide some support for the hypothesis that selective descending inhibition of nociceptive responses in neurones of the rat caudal trigeminal nucleus is mediated by NA, possibly by an action at a2-adrenoceptors.
European Journal of Pharmacology, 1992
The prcscnt study cxamincd the involvcmcnt of spinal noradrcncrgic mechanisms in spinal antinociccption by the S-hydroxytryptaminc (5HT) rcccptor-scicctive agonists CGS i?.OhhB (S-FIT,,,; ~lquin(~x~linc), TFMPP G-HT,,.; 7-tril~uort~mcthyl-4~4-mcthyl-I-pipcrazinyl~-pyrrolof1.7-M-trifluorctmcthylphcnyl-pipcrazinff and DO1 is-HT,; I-(2,5-dimethoxy-4-irtdopheIlyl)-3aminopropane) using the rat hot plate test. Effects of ru-adrcnorcccptor antagonists iphcntolaminc. yohimhinc). the adrcncrgic neurotoxin 6-hydroxydopaminc, and the sclcctivc noradrcncrgic uptake hlockcr dcsipraminc wcrc dctcrmincd. CGS 12OhhB. TFMPP and DOI produced dose-rclatcd antinociccption. The antinociccptivc effect of each agent was rcducod hy protrcatment with both ph~nt~l~rnin~ and yuhimbinc (IS-60 I.tg). Prctrc~~tmc~t with 6-hydr~)x!~d~~n~il~~ (I!10 pg. intruth~c~l) for 7-10 days, which rcduccd spinal cord levc!s of noradrenaline by X7%, inhihitod the action of TFMPP Eitnd S-HT), but not CGS I2066B or DOI. Prctrcatmcnt with dcsipraminc (2.5 mg/kg, systemic) potcntiatcd the action of TFMPP but nod, CGS 120668 or DOI (or 2-methyl-5HT). These results suggest that antinociccption by TFMPP is dcpcndcnt on rclci~se of cndogcnous nt~rildrc~l:dinc from the spinal cord, white that produced by CGS 12066B and DO1 is not. As TFMPP cxhihits u close similarity to S-HT in thcsc cxp~rimcnt~, the 5-HT rcccptor subtype being activated to induct ~(~r;ldrcn~Ilin~ rclcusc may either bc 21 S-HT,,. or :I S-HT,, suhtypc. Other mechanisms account for the ohscrvcd hlc>ckildc of the ;mion of CGS 12066B and DO1 hy ;u-udrc~~orcccptor antagonists.