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C Post

Publications and source records attributed to C Post.

At least 55 records · Page 3Linked to original sources
PubMed1991

The antinociceptive effect of intrathecally administered adenosine analogs in mice correlates with the affinity for the A1-adenosine receptor.

In the present study, the antinociceptive effects after intrathecal injection of each of 6 N6-substituted adenosine analogs and of 2-phenylaminoadenosine were compared with the affinity for the A1- and A2-adenosine receptors. Adenosine analogs, substituted in the N6-position, had stereoselective structure-dependent antinociceptive effects in the tail flick and hot plate assays after intrathecal injection in mice. The antinociceptive activity for N6-R- and S-phenylisopropyladenosine (R- and S-PIA), N6-R- and S-1-phenylethyladenosine, N6-1,1-dimethyl-2-phenylethyladenosine (methylPIA), and N6-cyclooctyladenosine correlated with the affinity for central A1-adenosine receptors. An adenosine analog, 2-phenylaminoadenosine, selective for A2-adenosine receptors was inactive in the two tests. These results strongly suggest that spinal A1-adenosine receptors are responsible for the antinociceptive effects of adenosine and its analogs after intrathecal injection.

Adenosine↗
PubMed1990

Behavioral effects after intrathecal administration of cholinergic receptor agonists in the rat.

Behavioral effects of nicotine and cytisine, and the cholinesterase inhibitors physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (THA), administered intrathecally (IT) at the lumbar level in the rat have been evaluated. Antinociceptive dose relationships were established using the tail immersion test. Total activity, locomotion and rearing were also measured in computerized test boxes. The nicotinic receptor antagonist, mecamylamine, and the muscarinic receptor antagonist, atropine, were used to study the selectivity of the effects. Physostigmine and THA significantly decreased total activity, locomotion and rearing as compared to control animals. The motor effects of physostigmine were completely antagonized only partly. Mecamylamine had no antagonistic effect. Nicotine did not affect any activity parameter. Cytisin reduced total activity and locomotion 1-6 min after dose. IT physostigmine, 15 micrograms, increased tail immersion latency for 30 min. No significant increase in response latency in this test was observed after the IT administration of nicotine or THA, whereas cytisine elicited a small increase. The IT administration of THA, nicotine and cytisine was also associated with gnawing, vocalization and hyperactivity and in the case of THA, diarrhoea. These effects were blocked by mecamylamine. Physostigmine antinociception as well as the behavioral effects including total activity, locomotion and rearing caused by physostigmine and by THA are most probably due to an action on spinal muscarinic receptors. Nicotinic receptors do not seem to be involved in spinal antinociception. Some aversive behavioral effects caused by the IT administration of nicotinic receptor agonists could, however, be attenuated by the spinal administration of the antagonist mecamylamine, which may indicate the involvement of nicotinic receptors in afferent sensory transmission.

Alkaloids↗
PubMed1990

Antinociceptive actions of alpha 2-adrenoceptor agonists in the rat spinal cord: evidence for antinociceptive alpha 2-adrenoceptor subtypes and dissociation of antinociceptive alpha 2-adrenoceptors from cyclic AMP.

The antinociceptive actions of intrathecal injections of two alpha 2-adrenergic agonists, UK-14,304 and guanfacine, were investigated in rats after pretreatment of the animals with the noradrenaline neurotoxin N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) 14 days in advance. The chronic noradrenaline depletion induced by DSP4 caused a marked increase in sensitivity of the antinociceptive action of UK-14,304 in the tail-flick test. By contrast, the antinociceptive effect of guanfacine was not appreciably affected by the DSP4 treatment. The antinociceptive effects of both UK-14,304 and guanfacine were blocked by intraperitoneal injections of yohimbine, a result indicating that both drugs induced their actions by activating alpha 2-adrenoceptors. Both UK-14,304 and guanfacine were found to reduce the production of cyclic AMP (cAMP) in the spinal cord, as determined using an in vitro radioisotopic method. The cAMP inhibitory effects of both agonists were effectively blocked by yohimbine, but not by prazosin, a finding indicating the alpha 2-adrenergic nature of the response. However, the cAMP inhibitory effect of UK-14,304 was not potentiated by pretreatment with DSP4, a finding in marked contrast with the strong potentiation of the antinociceptive action of UK-14,304 induced by the chronic depletion of endogenous noradrenaline. Moreover, intrathecal injections of forskolin, which increased the endogenous levels of spinal cord cAMP fivefold, did not modify the antinociceptive effects of UK-14,304 or guanfacine in neither normal nor DSP4-treated animals. It is suggested that there exist pharmacologically differing alpha 2-adrenergic receptor pathways capable of mediating antinociceptive effects at the level of the spinal cord. The cAMP inhibitory actions of spinal cord alpha 2-adrenoceptors appear not to be directly linked with the antinociceptive actions of these receptors.

Adrenergic alpha-Agonists↗
PubMed1990

Functional supersensitivity of antinociceptive spinal cord alpha 2-adrenoceptors, induced by depletion of endogenous noradrenaline, is associated with an enhanced sensitivity for guanine nucleotide regulation of 3H-clonidine binding.

In spinal cords from normal mice, 3H-clonidine bound to alpha 2-adrenoceptors with an apparant Kd of 4.6 nM and capacity (Bmax) of 430 fmol/mg protein. The non-hydrolyzable GTP analogue Gpp(NH)p was found to dose-dependently reduce the binding of 3H-clonidine the effect of Gpp(NH)p being essentially maximal at 10(-4) M. Gpp(NH)p was found to reduce the apparent affinity as well as the apparent number of binding sites for 3H-clonidine; the Kd of 3H-clonidine being 16 nM and the Bmax 300 fmol/mg protein when 10(-4) M of the nucleotide was present. In mice pretreated with the noradrenaline neurotoxin DSP4 for 14 days prior to assay, the specific binding of nearly saturating concentrations (10-30 nM) of 3H-clonidine was virtually the same as for control mice. However, for the DSP4 treated animals the down-regulation of 3H-clonidine binding induced by 10(-4) M Gpp(NH)p was significantly higher than for control mice. Thus, at a 3H-clonidine concentration of 10 nM the down-regulation induced by Gpp(NH)p was 64.1 +/- 2.6% for the DSP4 versus 58.9 +/- 2.3% for the control mice (P less than 0.05). At a 3H-clonidine concentration of 30 nM the down-regulation was 52.4 +/- 1.4% for DSP4 versus 41.8 +/- 4.1% for control mice (P less than 0.05). DSP4 pretreatment also potentiated the antinociceptive effect of intrathecal clonidine, as assessed by the tail-flick and hot plate tests. It is suggested that the functional supersensitivity induced by DPS4 for clonidine is related to the increased sensitivity for guanine nucleotide regulation of the spinal cord alpha 2-adrenoceptors.

Animals↗
PubMed1990

Effects of intrathecal injection of the adenosine receptor agonists R-phenylisopropyl-adenosine and N-ethylcarboxamide-adenosine on nociception and motor function in the rat.

R-phenylisopropyl-adenosine, which has an affinity for the adenosine A1 receptor higher than that for the A2 receptor, and N-ethylcarboxamide-adenosine, which has near equal affinity for the A1 and A2 receptors, were injected intrathecally into rats to evaluate differences in antinociceptive effect and motor impairment. Using the tail-immersion test, both compounds had antinociceptive effects. Motor function was evaluated during spontaneous movement in a free space. N-ethylcarboxamide-adenosine rapidly impaired motor function even after low intrathecal doses. R-phenylisopropyl-adenosine also induced motor impairment, but only after high intrathecal doses, and onset was much slower. These results suggest that the receptor selectivity of R-phenylisopropyl-adenosine is diminished at higher doses and that the motor impairment is an A2-receptor-mediated effect. A selective A1 receptor agonist, e.g., R-phenylisopropyl-adenosine, which produces a good antinociceptive effect without motor impairment, is more promising as a drug of possible use for the future treatment of clinical pain.

Adenosine↗
PubMed1989

Increased neuropeptide-converting enzyme activities in cerebrospinal fluid of opiate-tolerant rats.

Rats were given a continuous subcutaneous infusion at constant rate with either morphine, the opioid agonist/antagonist analgesic dezocine or saline. Tolerance to the antinociceptive effect of morphine or dezocine was complete on day 8, when cisterna magnum cerebrospinal fluid (CSF) was sampled under anesthesia. The activity of the enzymes cleaving dynorphin A (DCE) and substance P (SPE) was measured in the CSF. It was found that the animals treated with morphine had a 2- to 3-fold increase in both DCE and SPE activities. The animals treated with dezocine showed a similar increase in the activity of DCE, whereas SPE did not significantly change. These enzymes may therefore play a role in the development of tolerance to opioid analgesic drugs. The experiments show that chronic opioid treatment affects peptidergic mechanisms.

Animals↗
PubMed1989

Immunohistochemical and behavioral analysis of spinal lesions induced by a substance P antagonist and protection by thyrotropin releasing hormone.

Using behavioural, morphological and immunohistochemical analysis, the effect of intrathecal administration of a substance P antagonist, Spantide [D-Arg1, D-Trp7,9, Leu11)-SP), was studied. Antisera raised against markers for motoneurons, local spinal neurons, descending bulbospinal systems and primary afferents were used. The effect of some drugs, including thyrotropin releasing hormone (TRH), on Spantide-induced effects were also analyzed. After injection of 2 micrograms of Spantide at the lumbar level, a marked necrosis of the spinal cord was observed extending for about 5-6 segments, affecting mostly the ventral horns. Thus, calcitonin gene related peptide (CGRP)-like immunoreactivity (LI) in motoneurons completely disappeared and no motoneurons could be seen in cresyl violet-stained sections. The first changes were observed 6 h after Spantide injection and at 24 h a complete necrosis was seen. Marked reductions in the number of 5-hydroxytryptamine (5-HT)- and substance P-positive fibers were also observed. The effects were less dramatic in the dorsal horns, but at the site of maximal effects there was a disturbance also of CGRP-, substance P-, and neuropeptide tyrosine (NPY)-positive fibers in the superficial layers of the dorsal horn. These effects could be completely counteracted by multiple intravenous injections of TRH as well as with 5-methoxy-N, N-dimethyltryptamine (5-MeDMT), a 5-HT agonist. The behavioural analysis showed parallel changes, with permanent motor impairment after Spantide-treatment and complete absence of these symptoms when TRH or 5-MeDMT was given in addition. Finally, the effect of Spantide on 5-HT, noradrenaline, substance P and CGRP levels was measured biochemically. The present results are discussed in the light of recent findings that Spantide can cause a dramatic reduction in spinal blood flow.

Animals↗
PubMed1989

Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing.

Antinociceptive effects have been demonstrated after systemic and spinal administration of the adrenoceptor agonist clonidine and cholinomimetic drugs in animals and human. The present investigation was undertaken in rats to study the possible interactions between spinal noradrenergic and cholinergic mechanisms in modulating the reaction to nociceptive stimuli. Using the tail immersion test, an additive antinociceptive effect was found between intrathecal (IT) clonidine (10 micrograms) and physostigmine (15 micrograms, IT). The effect of clonidine was attenuated by atropine (15 micrograms, IT). Physostigmine (15 micrograms, IT) antinociception, which was of short duration was abolished by atropine (15 micrograms, IT) and attenuated by phentolamine (20 micrograms, IT). Neostigmine (5 micrograms, IT) produced a prolonged antinociceptive response. In animals pretreated with 6-hydroxydopamine IT, leading to a selective depletion of spinal cord noradrenaline, physostigmine (15 micrograms, IT) was ineffective in altering the nociceptive test response. Neither clonidine, nor physostigmine produced changes in latency times in the hot plate test (58 degrees C) in the doses employed. In conclusion, a clear-cut interaction exists between spinal noradrenergic and cholinergic systems for antinociception. To explain the interactions, several possible mechanisms may be considered, including cholinomimetic effects produced by clonidine, and the presence of muscarinic receptors in the dorsal horn of the spinal cord.

Adrenergic alpha-Agonists↗
PubMed1989

Characterization of the antinociception induced by intrathecally administered carbachol.

The antinociceptive effect of intrathecally administered carbachol at the L1/L2 level in the rat was evaluated using the tail immersion test. A dose dependent increase in the nociceptive reaction times was evident following intrathecal carbachol in the dose range of 2.5-15 micrograms. At doses of 20 micrograms and above, although still effective in the test, motor impairment was pronounced. The antinociception was antagonized with atropine, and with either pirenzepine (PZ) or AFDX 116, which are selective M1 and M2 muscarinic receptor blocking drugs, respectively. Spinal cholinergic pain modulation was also studied in rats pretreated with DSP4 (N-2-chloroethyl-N-ethyl-2-bromobenzylamine), which causes a selective depletion of the noradrenergic nerve fibres in the CNS. The increased latency times after spinal carbachol were attenuated in animals depleted of spinal noradrenaline by DSP4. In conclusion, spinal analgesia by carbachol in the rat may therefore be mediated through both M1 and M2 muscarinic receptor stimulation in the spinal cord. It is also concluded that this spinal cholinergic pain modulation is interacting with spinal noradrenergic nerve terminals, but that the mechanism of the interaction remains to be established.

Analgesics↗
PubMed1989

Adaptive changes in alpha-2 adrenoceptor mediated responses: analgesia, hypothermia and hypoactivity.

The acute effects of the alpha-2 adrenoceptor agonists, clonidine and guanfacine, upon antinociception, hypothermia and motor activity were compared under conditions of receptor antagonism, denervation, and chronic administration of a tricyclic antidepressant compound. The analgesic actions of clonidine and guanfacine were antagonised by idazoxan, an alpha-2 receptor antagonist, but potentiated by pretreatment with the noradrenaline neurotoxin DSP4, and attenuated by chronic treatment with desipramine (DMI). Clonidine- and guanfacine-induced hypothermia was antagonised by idazoxan, potentiated by prior treatment with DSP4 and attenuated by chronic administration with DMI. Both clonidine and guanfacine produced decreases in motor activity that were attenuated by idazoxan but unaffected by prior DSP-4 treatment. Chronic DMI administration also attenuated clonidine-induced hypoactivity but potentiated guanfacine-induced hypoactivity. These diverse results describe both similar and differential adaptive mechanisms modulating the functional effect of alpha-2 receptor systems in the central nervous system.

Adaptation, Physiological↗
PubMed1989

Guanfacine inhibits excitatory amino acid release from rat cerebral cortex through a non-adrenergic mechanism.

The effect of guanfacine on the release of excitatory amino acids from rat cerebral cortex slices was assessed after preloading the slices with 3H-D-aspartate. It was found that guanfacine dose-dependently inhibited the veratridine stimulated release of the excitatory amino acid analogue; the ED50 of guanfacine being 6.4 +/- 2.3 microM (mean +/- S.E.M.) and the veratradine stimulated efflux being completely abolished at about 48 microM of guanfacine. Guanfacine also inhibited the veratridine stimulated release of endogenous aspartate and glutamate with similar potency to the inhibition of 3H-D-aspartate efflux. The inhibitory effect of guanfacine on the veratridine stimulated 3H-D-aspartate efflux was neither affected by high concentrations of the alpha 2-adrenoceptor blocker idazoxan nor by high concentrations of the alpha 1-adrenoceptor blocker prazosin. It is concluded that guanfacine inhibits the neural excitatory amino acid release in the rat cortex by a novel non-alpha 2/alpha 1-adrenergic mechanism.

Amino Acids↗
PubMed1989

Intrathecal somatostatin in cat and mouse studies on pain, motor behavior, and histopathology.

Effects of intrathecal (i.t.) somatostatin (SST) on nociception, motor function, and spinal cord pathology were evaluated in cats and mice. Cats chronically implanted with i.t. lumbar catheters received either a single injection of 2 mg SST i.t. (group I, N = 4), four repetitive injections on consecutive days of 2 mg SST i.t. (group II, N = 4) or saline i.t. (group III, N = 2). No analgesic effects were observed following single or repeated SST injections as evaluated by the skin twitch response. However, significant impairment of hind leg motor function ranging from unbalanced gait to paralysis was observed following the first SST i.t. injection. Histological examination of spinal cords six days after the first SST injection in group II showed multiple pyknotic neurons in all cats. Some cats showed focal demyelination in the posterior column of the spinal cord white matter. Mice received a single percutaneous injection of 50 micrograms SST i.t. (group I, N = 7), 5 micrograms SST i.t. (group II, N = 3), or saline i.t., (group III, N = 5). No analgesic effects were observed in groups II and III as evaluated by the hot plate (HP) and tail flick (TF) tests. Injection of 50 micrograms SST i.t. (group I) caused reversible flaccid hind leg paralysis in all mice and concomitant increases in HP and TF latencies. Histologic examination revealed focal demyelination in the spinal cord in three out of seven mice in this group. Present data substantiate neurotoxic effects of i.t. SST and lack of behaviorally defined antinociception at innocuous dosages.

Animals↗
PubMed1989

Cholinergic mechanisms in pain and analgesia.

There is now substantial evidence that acetylcholinesterase inhibitors and muscarinic receptor agonists increase the pain threshold after both systemic and spinal administration. In rats, physostigmine gave a significant dose-dependent increase in latency times in the tail immersion test following intrathecal administration. The effect was antagonized with atropine. Neostigmine gave more prolonged latencies as did the muscarinic receptor agonist carbachol. Spinal cholinergic pathways for antinociception interacted with the spinal opioid and adrenergic nerve tracts. No cross-tolerance to the selective alpha 2-adrenoreceptor agonist guanfacine or to morphine was seen in rats tolerant of spinal carbachol antinociception. The mechanism of spinal cholinergic antinociception is not known but a muscarinic interneuron may explain the interactions with other neurotransmitters. Clinically, the centrally active cholinesterase inhibitor physostigmine has been shown to give postoperative pain relief although of short duration. Severe neurogenic pain has been successfully treated with physostigmine or distigmine.

Analgesia↗
PubMed1988

Evidence for crosstolerance to the analgesic effects between morphine and selective alpha 2-adrenoceptor agonists.

Rats were injected subcutaneously (s.c.) with morphine (5 mg/kg) until tolerance developed to its antinociceptive action, or with 0.9% saline which was used as vehicle for morphine. Subsequently, both groups of animals were given an intrathecal (i.th.) dose of either noradrenaline (2 micrograms), clonidine (12.5 micrograms) or guanfacine (12.5 micrograms), that had been found previously to be reliably antinociceptive. In the saline-treated animals, these doses of noradrenaline, clonidine or guanfacine induced clear antinociceptive effects, but not in the morphine-group. It is therefore concluded that cross-tolerance to the antinociceptive effects of systemic morphine and the alpha-adrenoceptor agonists was obtained. The cross-tolerance between morphine on one hand, and noradrenaline, clonidine and guanfacine on the other, implies that a substantial opiate-adrenoceptor interaction exists in antinociceptive processes.

Adrenergic alpha-Agonists↗
PubMed1988

Intrathecal noradrenaline restores 5-methoxy-N,N-dimethyltryptamine induced antinociception abolished by intrathecal 6-hydroxydopamine.

Intrathecal administration of 6-hydroxydopamine (6-OHDA) abolished the antinociceptive effects of acute administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 mg/kg, s.c.) in the hot-plate, tail-flick and shock titration tests of nociception. The antinociceptive effects of 5-MeODMT, abolished by the prior intrathecal 6-OHDA treatment, were restored by intrathecal administration (2 or 1 microgram) of noradrenaline (NA), immediately prior to 5-MeODMT, in all three tests of nociception. Biochemical analysis confirmed severe NA depletions (95 percent loss) in the lumbar and thoracic regions of the spinal and much lesser dopamine depletions (25-35 percent loss). Intrathecal 5,7-dihydroxytryptamine (5,7-DHT) attenuated 5-MeODMT induced antinociception in the tail-flick test and combined NA + 5-MeODMT induced antinociception in the hot-plate and tail-flick tests. Intrathecal administration of 5,7-DHT caused a severe depletion of 5-hydroxytryptamine in the lumbar region of the spinal cord. The present findings demonstrate further the modulatory role of NA upon serotonergic systems in nociception and indicate the necessity of NA availability for induction of 5-MeODMT analgesia.

5,7-Dihydroxytryptamine↗