Morphine responsiveness and seizure proneness

Mansour, Alfred; Valenstein, Elliot S.

doi:10.1016/0014-4886(84)90145-6

Cited by 12 publications

(5 citation statements)

References 19 publications

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“…The EKCinduced convulsions produced a change in morphine responsiveness comparable to that seen following an equal number of electroconvulsive shocks. This result is consistent with our earlier findings (9) which indicated that the changes were not specific to the kind of convulsion induced and could be produced by repeated metrazol, ECS, or kindled convulsions. The magnitude of the changes does depend, to some extent, on the number of convulsions induced; we found that animals receiving 23 ECSs showed a more pronounced change in sensitivity to EKC than animals given only seven ECSs.…”

Section: Discussionsupporting

confidence: 93%

“…Previous research in our laboratory demonstrated that animals receiving a series of convulsions by amygdala stimulation, metrazol, or electroconvulsive shock (ECS) showed generalized nonlethal clonic convulsions to doses of morphine that produced no convulsive effects in their respective controls (8,9). The changes in morphine responsiveness were enduring and could be detected to 3 months after an animal's last amygdala-kindled convulsion.…”

Section: Introductionmentioning

confidence: 98%

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Changes in responsiveness to mu and kappa opiates following a series of convulsions

Mansour

Valenstein

1985

Experimental Neurology

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After a series of seven electroconvulsive shocks, mice (C57BL/6J) showed a marked change in their response to opiates. Although very large doses of mu agonists induce convulsions in normal control mice, our evidence indicated that this was accomplished through nonopiate mechanisms: they could not be blocked by naltrexone and the pattern of drug potencies (codeine greater than morphine greater than levorphanol) was not consistent with an opiate response. In contrast, after electroconvulsive shock small doses of mu agonists induced convulsions that could be blocked by naltrexone and the pattern of drug potency (levorphanol greater than morphine greater than codeine) was consistent with an opiate mechanism. Kappa drugs, on the other hand, produced convulsions in both control and ECS animals, although there was an enhanced responsiveness in the latter. Furthermore, the convulsions produced by kappa drugs were blocked by naltrexone and showed stereoselectivity in both control and ECS animals. The changes in responsiveness to mu and kappa opiates cannot be explained on the basis of a general increase in seizure susceptibility, as sensitivity to the nonopiate convulsant, strychnine, was not enhanced after electroconvulsive shock. The results point to a qualitative change in response to mu agonists after electroconvulsive shock, but only a change in sensitivity to kappa agonists.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 98%

Changes in responsiveness to mu and kappa opiates following a series of convulsions

Mansour

Valenstein

1985

Experimental Neurology

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“…Thus, the profile of tramadol is not unusual in that analgesic doses of opioids display some anticonvulsant activity, but high-doses produce seizures that are not fully naloxone-reversible, and opioids probably produce seizures in epilepsy-prone, kindled, or seizure-experienced animals (Corrada and Longo, 1961;Frenk, 1983;Mansour and Valenstein, 1984;Tortella et al, 1984;Czuczwar and Frey, 1986;Reigel et al, 1988;Potschka et al, 2000;Manocha et al, 2005). The mechanistic explanation for these effects is not clear.…”

Section: Discussionmentioning

confidence: 99%

Unexceptional Seizure Potential of Tramadol or Its Enantiomers or Metabolites in Mice

Raffa¹,

Stone²

2008

J Pharmacol Exp Ther

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Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites [M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol)] of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD 50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED 50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 o C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (ϩ)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine.Tramadol is a centrally acting analgesic that is widely used throughout the world (in more than 100 countries). Tramadol produces its multimodal antinociceptive and analgesic effects via two mechanisms (Raffa and Friderichs, 1996): one is opioid, and the other is nonopioid (Hennies et al., 1988;Friderichs et al., 1991Friderichs et al., , 1992Raffa et al., 1992Raffa et al., , 1993Raffa et al., , 1995Dayer et al., 1997;Ide et al., 2006). The opioid component involves weak affinity (approximately 1 M) of the parent drug and approximately 300-fold greater affinity of the M1 metabolite of tramadol (Wu et al., 2002) for -opioid receptors (Hennies et al., 1988;Raffa et al., 1992;Lai et al., 1996;Gillen et al., 2000). The nonopioid component is related to inhibition of neuronal 5-hydroxytryptamine (5-HT; serotonin) and norepinephrine reuptake (Friderichs et al., 1991;Codd et al., 1995). The opioid component, predominant in the (ϩ)enantiomer, and the nonopioid component, predominant in the (-)enantiomer Raffa et al., 1992;Codd et al., 1995), combine in a complementary and sometimes synergistic manner to produce antinociception, but in an additive or subadditive manner in several side-effect measures (Raffa et al., 1993). The total contribution from all ...

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“…In line with this clinical finding, small doses of fentanyl decreased the focal seizure threshold (ADT) in the amygdala kindling model of temporal lobe epilepsy in rats ( Schwark et al ., 1986 ). Epilepsy may also increase the sensitivity to proconvulsant action of morphine; e.g., extremely low doses of morphine elicited seizures in genetically epilepsy‐prone rats ( Reigel et al ., 1988 ) and amygdala kindled rats showed a heightened sensitivity to morphine's convulsive effects which could be blocked by naloxone ( Mansour & Valenstein, 1984 ). Indeed, increased opioid receptor binding has been described in patients with temporal lobe epilepsy and different models of epilepsy, including amygdala kindling ( Lee et al ., 1986 ; Frost et al ., 1988 ; Fisher & Frost, 1991 ; Engel & Rocha, 1992 ; Rocha et al ., 1993 ), which may explain the increased susceptibility to proconvulsant effects of opioid analgesics.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy

Potschka

Friderichs

Löscher

2000

British J Pharmacology

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1 The centrally acting analgesic tramadol has recently been reported to cause seizures at recommended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic eects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher anity for mu receptors and may thus contribute to the eects of the parent compound. Furthermore, the pharmacological eects of tramadol appear to be related to the dierent, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (+)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse eects determined in kindled rats were compared to those in nonkindled rats. 2 At doses within the analgesic range, (+)-tramadol and its enantiomers induced anticonvulsant eects in kindled rats. However, at only slightly higher doses seizures occurred. With (+)-tramadol, generalized seizures were observed at 30 mg kg 71 in most kindled but not in nonkindled rats. The (7)-enantiomer induced myoclonic seizures at 30 mg kg 71 in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg 71 . Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. 3 The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse eects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures.

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Morphine responsiveness and seizure proneness

Cited by 12 publications

References 19 publications

Changes in responsiveness to mu and kappa opiates following a series of convulsions

Changes in responsiveness to mu and kappa opiates following a series of convulsions

Unexceptional Seizure Potential of Tramadol or Its Enantiomers or Metabolites in Mice

Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy

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