Procaine and lidocaine stimulate corticotropin-releasing hormone secretion by explanted rat hypothalami through a sodium conductance-independent mechanism.
We have previously shown that procaine and lidocaine stimulate corticotropin-releasing hormone (CRH) secretion by explanted rat hypothalami. This effect was of interest in light of the fact that both lidocaine and CRH administration to experimental animals can produce kindled seizures which cross-sensitize with electrically kindled seizures, and of recent data suggesting that limbic hyperexcitability, perhaps mediated through CRH, may be involved in the pathophysiology of affective illness. Because a prominent effect of the local anesthetics is to decrease neuronal firing by blocking sodium conductance, we were surprised by the capacity of these agents to cause CRH secretion and pituitary-adrenal activation and wished to further elucidate the possible mechanism(s) of these effects. To accomplish this, we first explored the effect of the sodium channel blocker tetrodotoxin (TTX) on basal and stimulated immunoreactive CRH (iCRH) secretion by explanted rat hypothalami. In contrast to procaine and lidocaine, TTX inhibited rather than stimulated iCRH secretion. Moreover, TTX inhibited lidocaine-induced iCRH secretion but had no influence on the response of the CRH neuron to procaine. To explore other potential mechanisms of action, we examined the effect of the calcium channels blocker verapamil and of pharmacologic antagonists to serotonergic, alpha-adrenergic and cholinergic receptors. The latter was particularly of interest because of structural similarities between procaine or lidocaine and acetylcholine (ACh) and because it has been shown that these anesthetic agents interact with the ACh receptor. Verapamil and blockade of serotonergic, alpha-adrenergic and cholinergic receptors did not inhibit the effects of procaine or lidocaine on iCRH secretion, whereas both GABA and dexamethasone exerted inhibitory effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Calogero
A E
AE
Developmental Endocrinology Branch, National Institute of Child Health and Human Developmental, National Institute of Mental Health, Bethesda, Maryland.
Kling
M A
MA
Gallucci
W T
WT
Bernardini
R
R
Chrousos
G P
GP
Gold
P W
PW
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004347:Drug Interactions; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011343:Procaine / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D015222:Sodium Channels / Q000502:physiology*
D002121:Calcium Channel Blockers; D018377:Neurotransmitter Agents; D015222:Sodium Channels; D011343:Procaine; D003346:Corticotropin-Releasing Hormone; D008012:Lidocaine