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

Since cholecystokinin (CCK) has been suggested to be an endogenous opiate antagonist, we tried to evaluate if this peptide could be involved in the development of tolerance to morphine. Naive rats were chronically administered morphine, either alone or concomitantly with proglumide or benzotript, two putative CCK receptor antagonists. Chronic treatments with both CCK antagonists alone were also established. Drugs were administered by the oral route, dissolved in the drinking water. At the end of the chronic treatments, the development of tolerance to morphine was assessed by an evaluation of the analgesic responses evoked by graded doses of acutely injected morphine in the tail-flick and hot plate tests. Proglumide and benzotript were able to inhibit the shift to the right of the dose-response curve for morphine, i.e. they prevented the development of tolerance to morphine-induced analgesia. Chronically given alone, the two CCK antagonists never modified the responses to the acute challenge with morphine. We also determined the development of physical dependence by looking at the withdrawal syndrome precipitated by graded doses of acutely injected naloxone. In these experiments the concomitant treatment with morphine and proglumide or benzotript did not modify the occurrence of dependence. These observations are consistent with the hypothesis of CCK being an endogenous opiate antagonist, involved in the development of tolerance to morphine-induced analgesia but not of dependence. Moreover, tolerance to and dependence on morphine can be pharmacologically dissociated.
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PMID:Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin. 358 Aug 99

Adenosine triphosphate (ATP) injected intravenously in mice was found to have dose-dependent analgesic activity in the hot plate and phenylquinone-induced stretching assays. ATP prolonged the hot plate latency (ED50 value of 1 (0.7-1.4) mg/kg) and inhibited phenylquinone-induced writhing (ED50 value of 0.4 (0.31-0.52) mg/kg). Low doses of ATP produced a potent antinociceptive effect without any significant depression of locomotor activity. Treatment of mice for either 4 days or 14 days with ATP did not result in development of physical dependence on or tolerance to ATP. The analgesic action of ATP was not antagonized by naloxone at 1 and 5 mg/kg. ATP analgesia was antagonized, in a dose-related fashion, by Ca++ ion injected intracerbroventricularly which may indicate that Ca++ plays a role in ATP-induced antinociception.
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PMID:Characteristics of analgesia induced by adenosine triphosphate. 368 52

The effect of D-Phenylalanine (D-Phe), putative carboxypeptidase A inhibitor and its four derivatives (T1-T4) on analgesia, development of tolerance and physical dependence to morphine, and on degradation of both exogenous and endogenous enkephalins was investigated. Systemic administration of either D-Phe or its derivatives produced naloxone-reversible analgesia in the hot-plate test in mice. Naloxone-precipitated morphine withdrawal syndrome was attenuated in mice after systemic subacute administration (7 days, 1.2 mmol/kg, sc) of D-phe derivatives, the development of tolerance to morphine being unchanged. In the presence of either D-Phe or its derivatives in incubation mixture (up to 10(-3) mol/l) the hydrolysis of exogenous 3H-Met5-and 3H-Leu5-enkephalin in striatal homogenates was slightly inhibited. Moreover, the addition of D-Phe or its derivatives seemed to increase the per cent of recovered endogenous Met5-enkephalin released from veratridine-depolarized striatal particles. In contrast, bestatin, an amino-peptidase inhibitor, and a mixture of dipeptides (Tyr-Tyr, Leu-Leu, Leu-Gly) markedly inhibited degradation of both endogenous and exogenous enkephalins in vitro. The results obtained in this study suggest that that pharmacological activity of D-Phe is not directly related to the endogenous opiate system.
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PMID:The effects of D-phenylalanine and its derivatives on enkephalin degradation in vitro: relation to analgesia and attenuation of the morphine withdrawal syndrome. 376 85

Buprenorphine was administered as sublingual tablets to 70 patients suffering from chronic pain of malignant or non-malignant origin. Daily doses ranging from 0.4 mg to 3.2 mg were administered and good analgesia was reported by the majority of patients. The most common unwanted effects were drowsiness/sleepiness, nausea and/or vomiting and sweating which appeared to be dose related but the incidence of dizziness was not related to daily dose. The incidence of all these unwanted effects except drowsiness/sleepiness decreased after the first week's treatment. No buprenorphine related changes in vital signs or laboratory values were observed and no signs of tolerance or physical dependence were seen in the short term period after discontinuation of treatment. A significant positive correlation between buprenorphine plasma concentration and daily dose was observed but there was no correlation between plasma levels and pain relief.
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PMID:A long-term open, clinical and pharmacokinetic assessment of sublingual buprenorphine in patients suffering from chronic pain. 401 31

Rats chronically implanted with osmotic minipumps in the left lateral ventricle were used to study the ability of dermorphin to produce tolerance and physical dependence. The development of tolerance, assessed by evaluating the time reduction of analgesia, catalepsy and rigidity, occurred in a dose-dependent fashion over a maximum period of 48 h. After 3 days of peptide infusions into the rat brain, the dependent state was established and was revealed by precipitating the withdrawal syndrome with intraperitoneal naloxone injections. Escape behavior, shaking, salivation and rhynorrhea were the main symptoms, qualitatively similar to those obtained in rats made dependent on morphine. Considering that dermorphin displays strong analgesic activity, the well-known combination of antinociception tolerance and dependence capacities of opiates also seems to be valid for dermorphin.
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PMID:Tolerance and physical dependence induced by dermorphin in rats. 404 26

Antinociceptive tolerance, cross-tolerance and an expression of physical dependence to morphine (MRP) and (+/-)-ethylketazocine (EKC) were quantitatively compared using two inbred strains of mice. The measure of analgesia was the area of a time-response curve (escape reaction, 52 degrees C heated plate). (-)-EKC was 1.5 to 1.8 times more potent than MRP in both C57B1/6J (C57) and DBA/2J (DBA) mice. The latter strain was significantly more sensitive to both analgesics. Paradoxically, after an identical dose, the MRP content in DBA plasma, brain and spinal cord was only 56 to 73% of that in C57 tissues. Mice rendered tolerant to MRP (32 mg/kg s.c./b.i.d./1 week) exhibited equivalent cross-tolerance to EKC. In contrast, mice made tolerant to EKC (32 mg/kg s.c./b.i.d./1 week) retained substantial sensitivity to MRP. Comparisons between drugs and strains indicate that analgesic tolerance and physical dependence did not develop in parallel.
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PMID:Genotype-dependent behavioral sensitivity to mu vs. kappa opiate agonists. II. Antinociceptive tolerance and physical dependence. 609 14

A 70 year old hypertensive patient who had undergone a gastrectomy experienced withdrawal symptoms 10 h after a second epidural injection of morphine (150 micrograms X kg-1) for postoperative analgesia. A clonidine treatment had been stopped 129 h earlier. These symptoms disappeared shortly after a third epidural injection of morphine. Clonidine was then reintroduced. The later progressive interruption of epidural morphine analgesia did not introduce any further symptoms of withdrawal. Since physical dependence on a drug is related to repeated and prolonged administration of that drug, opiate withdrawal symptoms were highly unlikely after epidural morphine used to relieve immediate postoperative pain. Abrupt discontinuation of a long-term treatment by clonidine may produce a withdrawal syndrome, but clinical and biological signs usually occur earlier than noted in this case. Recent experimental and clinical data has provided support for the existence of a complex presynaptic regulation of noradrenergic transmission in the central nervous system, both alpha 2 and opiate receptors being implicated. The activation of such presynaptic receptors inhibits further transmitter release. Suddenly stopping the chronic administration of alpha 2 or opiate agonists was responsible for a rebound excitation of these noradrenergic neurons, inducing a withdrawal syndrome. The related withdrawal symptoms may have resulted from an interaction between the discontinuation of clonidine and the decrease in morphine activity. Practitioners should be warned of this possible side-effects.
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PMID:[Withdrawal syndrome during epidural administration of morphine after stopping treatment with clonidine]. 609 36

The effects in mice of glycine, beta-alanine and diazepam on the analgesic response to morphine, on the intensity of tolerance and on the physical dependence on the analgesic have been examined. The two amino acids increased the analgesic response to morphine in a dose-related manner. However, both compounds were ineffective in the analgesic test (hot plate) when administered without morphine. Diazepam was ineffective in the analgesic test and it did not alter morphine analgesia, except when administered in a high dose which decreased and analgesic response. Glycine, either in single or repeated doses, did not modify tolerance to morphine, whereas beta-alanine induced a dose-related partial antagonism, which promptly reached a plateau. Diazepam induced a small decrease in the intensity of tolerance to the analgesic. The abstinence syndrome to morphine, induced by naloxone administration to primed mice, was reduced by single doses of glycine or beta-alanine. Diazepam behaved as a weak inhibitor of the abstinence syndrome when administered at a high dose. The potentiation of morphine analgesia and the antagonism of the abstinence syndrome induced by the amino acids may be related to their hyperpolarizing action in the c.n. system. The effects of beta-alanine on morphine tolerance cannot be explained by the same mechanism.
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PMID:Effects of glycine, beta-alanine and diazepam upon morphine-tolerant-dependent mice. 610 98

In previous studies, we observed that dynorphin- (1-13), but not dynorphin-(1-9), can significantly inhibit morphine- or beta-endorphin-induced analgesia despite not having any appreciable analgesic activity itself. Dynorphin-(1-13) showed no inhibitory effect on Sandoz FK33824-induced analgesia. In the present study, we examined the effect of dynorphin on morphine-, beta-endorphin-, D-ala2-D-leu5-enkephalin- or Sandoz FK33824-induced analgesia in both naive, morphine-tolerant and morphine-dependent mice. It was found that although dynorphin may inhibit morphine- or beta-endorphin-induced analgesia in naive animals, the peptide is not effective in inhibiting D-ala2-D-leu5-enkephalin- or Sandoz FK33824-induced analgesia. Dynorphin is also effective in blocking spontaneous withdrawal jumping in morphine-dependent animals. It is suggested that dynorphin-(1-13) may play a modulatory role in regulating analgesia due to morphine or beta-endorphin, but not that due to enkephalin. The action of peptides on morphine- or beta-endorphin-induced analgesia in the naive state is different from that of the tolerant state, suggesting that dynorphin may be involved in the development of morphine tolerance and physical dependence.
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PMID:Possible regulatory role of dynorphin on morphine- and beta-endorphin-induced analgesia. 611 98

U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide) displays analgesic actions in a variety (thermal, pressure and irritant) of assays in mice and rats. Naloxone and MR-2266 block this analgesic effect; thus it is mediated by opioid receptors. However, when compared to morphine analgesia, the naloxone and MR-2266 pA2 values for U-50,488 analgesia were much lower and higher, respectively. Likewise, although tolerance occurs to both morphine and U-50,488 analgesia, there was no cross-tolerance between these drugs, and U-50,488 does not cause morphine-type physical dependence. These observations suggest that different opioid receptors mediate the analgesic effects of morphine and U-50,488. The effects of U-50,488 appear to be mediated by the so-called kappa opioid receptor. In contrast to U-50,488, other reputed kappa opioid agonists displayed varying degrees of mu agonist (ketazocine and ethylketocyclazocine) and narcotic antagonist (bremazocine) activities. Thus U-50,488 is a more selective kappa agonist. This conclusion is further supported by binding studies; of all compounds tested, U-59,488 displacement of [3H]ethylketocyclazocine binding was uniquely not blocked by high concentrations of dihydromorphine. In addition to analgesia, this selective kappa agonist also causes opioid receptor-mediated sedation, diuresis and corticosteroid elevations. U-50,488 is a useful tool for studying contrasting kappa and mu opioid receptor-mediated effects.
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PMID:U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist. 612 21


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