Pain

Stille, Nervenarzt (1960),352 in a study of the basis for the beneficial effect of PHT on pain, found that PHT (20 mg/kg) reduces the cortical response to single electrical stimuli or low-frequency series stimulation of the reticular formation in rabbits. The author states that PHT differs from the barbiturates and chlorpromazine in that it does not change the arousal reaction produced by frequent electrical stimulation of the mesencephalic reticular formation, nor the EEG arousal reaction to sensory stimulation.

352. Stille, G., On the question of the action of diphenylhydantoin in states of pain: a neurophysiological analysis, Nervenarzt, 31: 109-112, 1960.

Seeman, Chau-Wong and Moyyen, Canadian Journal of Physiology and Pharmacology (1972),1524, 2941 found that anesthetizing membrane concentrations of PHT or morphine in guinea pig brain synaptosomes and human erythrocytes were close to those predicted by the Meyer-Overton rule of anesthesia, indicating that they both have local anesthetic properties. 

1524. Seeman, P., Chau-Wong, M., and Moyyen, S., The membrane binding of morphine, diphenylhydantoin, and tetrahydrocannabinol, Canad. J. Physiol. Pharmacol., 50: 1193-1200, 1972.
2941. Seeman, P., The membrane actions of anesthetics and tranquilizers, Pharamacol. Rev., 24(4): 583-655, 1972.

Grafova, Danilova and Kryzhanovskii, Bulletin of Experimental Biology and Medicine (USSR) (1979),2550 studied the effects of PHT on the application of tetanus toxin, strychnine, penicillin, potassium chloride and ouabain to rat dorsal spinal cord. PHT (100 mg/kg, intramuscularly) suppressed the pain syndrome caused by potassium chloride and ouabain, but had only a weak action against that produced by tetanus toxin, strychnine and penicillin.

See also Ref. 2202

2550. Grafova, V. N., Danilova, E. I., Kryzhanovskii, C. N., Analgesic effects of antiopileptic agents in pain of spinal origin, Bull. Exp. Biol. Med., 88(8): 147-51, 1979.
2202. Grafova, V. N. and Danilova, E. I., Action of antiepileptic drugs on myoclonia of spinal origin, Bull. Exp. Biol. Med., 90(11): 1503-6, 1980.

Kendig, Courtney and Cohen, Journal of Pharmacology and Experimental Therapeutics (1979),2212 compared the anesthetic molecular properties and frequency-dependent sodium channel blocking actions of PHT, phenobarbital, the local anesthetic benzocaine, and the volatile general anesthetic diethyl ether at the frog node of Ranvier. Some blockage of resting sodium channels was seen with all the agents tested, but frequency-dependent sodium channel-block was produced only by PHT and phenobarbital.

2212. Kendig, J., Courtney, K.R. and Cohen, E.N., Anesthetics: molecular correlates of voltage and frequency-dependent sodium channel block in nerve, J. Pharmacol. Exp. Ther., 210(3): 446-52, 1979.

Foong, Satoh and Takagi, Journal of Pharmacological Methods (1982),2503 reported that PHT (40-120 mg/kg, intraperitoneally) suppressed bradykinin-induced aversive behavior in a rat tooth-pulp pain model.

2503. Foong, F. W., Satoh, M., Takagi, H., A newly devised reliable method for evaluating analgesic potencies of drugs on trigeminal pain, J. Pharmacol. Methods, 7: 271-78, 1982.

Fromm, Chattha, Terrence and Glass, European Journal of Pharmacology (1982),2515 studied the effects of PHT and carbamazepine (CBZ) on segmental and periventricular intemeurons of the spinal trigeminal nucleus oralis of cats. Therapeutic serum levels of PHT and CBZ facilitated segmental inhibition, but depressed the periventricular inhibition, while also depressing the response of trigerninal nucleus neurons to an unconditioned maxillary nerve stimulus. The authors note that the depression of neuronal activity by PHT and CBZ is selective, leaving some inhibitory pathways functioning normally, thus greatly enhancing their effectiveness. They suggest that PHT and CBZ may act to control pain in trigeminal neuralgia, and abnormal electrical activity in the nervous system more generally, by a relative facilitation of inhibitory feedback mechanisms. See also Ref. 1838.

2515. Fromm, G. H., Chattha, A. S., Terrence, C. F., Glass, J. D., Do phenytoin and carbamazepine depress excitation and/or facilitate inhibition?, Eur. J. Pharmacol., 78: 403-9, 1982.
1838. Fromm, G. H., Glass, J. D., Chattha, A. S. and Terrence, C. F., Role of inhibitory mechanisms in trigeminal neuralgia, Neurology, 30: 417, 1980. 

Hitchcock and Teixeira, Applied Neurophysiology (1982),2597 compared the effects of PHT (1.25-50 mg/kg), sodium valproate and carbamazepine (CBZ) on the neurotransmitter-related enzymatic activity of the rat anterior mesencephalic periaqueductal grey matter, which is an integrative center for pain systems. PHT caused the greatest reduction in glutamate dehydrogenase and CABA, and it was the only drug to increase semi-aldehyde dehydrogenase activity. The authors hypothesize that PHT and CBZ, but not sodium valproate, may activate central pain-suppressive systems by reducing the inhibitory effect of GABA on the periaqueductal grey pain suppressive pathways.

2597. Hitchcock, E., Teixeira, M., Anticonvulsant activation of pain-suppressive systems, Appl. Neurophysiol., 45: 582-93, 1982.

Yaari and Devor, Neuroscience Letters (1985),3090 reported that intraaortic PHT (1-10 mg) or topically applied PHT in doses as low as 100 µM to exposed desheathed neuromas, in rats, reduced or blocked abnormal spontaneous neuroma discharges. In spite of its marked suppression of this discharge, and in contrast to the action of local anesthetics, PHT did not block conduction of nerve impulses evoked by direct stimulation of the neuroma. PHT's actions were thus selective for the abnormal activity. The authors note that spontaneous discharges from nerve-end neuromas and from other sites of nerve injury and disease have been implicated as a cause of paresthesias and pain associated with amputation, peripheral nerve trauma and a wide range of other neurological conditions. They suggest that the clinical analgesic action of PHT may, at least in part, result from direct suppression of ectopic impulses generated in the region of nerve damage.

3090. Yaari, Y., Devor, M., Phenytoin suppresses spontaneous ectopic discharge in rat sciatic nerve neuromas, Neurosci. Lett., 58(1): 117-22, 1985.

McLean, Society for Neuroscience Abstracts (1986),2782 evaluating mechanisms of neuropathic pain relief, used mouse dorsal root ganglion cells and ganglia obtained from patients undergoing surgery for chronic pain. To simulate the rapid burst firing observed in human sensory nerves in association with pain, calcium concentration in the extracellular medium was lowered to 0.1 mM. Both PHT (2 µg/ml) and carbamazepine (2 µg/ml) inhibited the rapid burst firing induced by the low calcium in both mouse and human ganglia. Resting membrane properties were unaffected. The author notes that the effects of both PHT and CBZ were selective for sustained repetitive activity and occurred at levels corresponding to their free fractions in plasma. The author concludes that this limitation of rapid firing could explain, at least in part, the success of PHT and CBZ in treating neuropathic pain.

2782. McLean, M., Carbamazepine and phenytoin limit rapid firing of action potentials of dorsal root ganglion neurons in cell culture, Soc. Neurosci. Abstr., 12 (Pt 2): 1015, 1986.

McLean and Blumenkopf, Neurology (1987), 3637 noting that patients experiencing neuropathic pain have high-frequency bursts of action potentials (AP), studied cultured mouse and human dorsal root ganglion neurons by adding baclofen or forskolin to the bathing solution to induce sustained repetitive firing of APs. Subsequent addition of phenytoin or carbamazepine resulted in limitation of firing to a few APs at the beginning of the pulse. The authors state that the limitation of sustained repetitive firing of dorsal root ganglion neurons may explain, in part, the analgesic effect of phenytoin and carbamazepine in some patients with neuropathic pain.

3637. McLean, M.J. and Blumenkopf, B., Anticonvulsants limit repetitive firing of action potentials induced by baclofen and forforskolin in cultured mammalian dorsal root ganglion neurons, Neurology, 37(S1): 236, 1987.

Reichlin and Mothon, Annals of Neurology (1991), 3638 examined phenytoin's and carbamazepine's effects on basal and picrotoxin-induced somatostatin release. A PHT concentration of 10 -4 M had no effect on basal somatostatin secretion from rat cerebral cell cultures, but significantly blocked picrotoxin-induced release of the peptide. Veratridine-stimulated somatostatin release was not blocked by PHT. The authors state that their findings may clarify the mechanism by which carbamazepine and phenytoin act in epilepsy and trigeminal neuralgia. They suggest that release of pain-mediating neuropeptides, such as substance P and substance K, and neurotransmitters in multisynaptic afferent pain pathways may be inhibited by these drugs.

3638. Reichlin, S. and Mothon, S., Carbamezepine and phenytoin inhibit somatostatin release from dispersed cerebral cells in culture, Ann. Neurol., 29: 413-417, 1991.

See also Refs.

3639. Sharif, R.N., Yashpal, K. and Henry, J.L., Phenytoin-induced anti-hyperalgesia but not antinociception in the rat tail-flick test, Soc. Neurosci. Abstr., 25(PT2):771.4, 1999.

3640. Backonja, M.M., Anticonvulsants (antineuropathics) for neuropathic pain syndromes, Clin. J. Pain, 16:S67-S72, 2000.

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