5-HT1A receptors and the tail-flick response. V. Opposite modulation of 5-HT1A receptor-induced spontaneous tail-flicks by alpha 1A- as compared with alpha 2D-adrenoceptors in rat lumbar spinal cord.
Spontaneous tail-flicks (STFs) in the rat are mediated by postsynaptic serotonin (5-HT)1A receptors in lumbar spinal cord (Bervoets et al., 1993). In this study, we examined the role of alpha 1- as compared with alpha 2-adrenoceptors in their modulation. STFs elicited by the 5-HT1A agonist 8-OH-DPAT were potently blocked by the alpha 1-adrenoceptor antagonist prazosin, as well as by WB 4101 and 5-methylurapidil, antagonists with a preference for the alpha 1A-subtype of adrenoceptor. In contrast, several alpha 2-antagonists, for example, idazoxan and the preferential alpha 2D-antagonist BRL 44408, (biphasically) potentiated 8-OH-DPAT-induced STFs. Whereas STFs were unaffected by the alpha 1-adrenoceptor agonist cirazoline, they were blocked both by the alpha 2-agonist UK 14,304 and by the preferential alpha 2D-agonists guanfacine and guanabenz. The intrathecal administration onto lumbar spinal cord of prazosin or of the preferential alpha 1A-antagonist benoxathian (which does not cross the blood-brain barrier) blocked STFs evoked by s.c. injection of 8-OH-DPAT. Intrathecal UK 14,304 acted similarly. Conversely, STFs elicited by intrathecal 8-OH-DPAT were blocked by s.c. prazosin or UK 14,304. Cirazoline and the preferential alpha 1A-agonist methoxamine (which does not cross the blood-brain barrier) elicited STFs upon intrathecal administration onto lumbar but not cervical spinal cord. The action of cirazoline was blocked by s.c. prazosin but not by 5-HT1A antagonists such as (-)-alprenolol, indicating that the alpha 1-adrenoceptors mediating STFs lie downstream of 5-HT1A receptors. Further, cirazoline-induced STFs were not affected by alpha 2-agonists and -antagonists, suggesting that the alpha 2-adrenoceptors inhibiting STFs are localized presynaptically to these alpha 1-adrenoceptors. In rats in which lumbar spinal cord pools of noradrenaline were depleted by 6-hydroxydopamine, STFs evoked by cirazoline were potentiated, indicating supersensitivity of postsynaptic alpha 1-adrenoceptors. In contrast, 8-OH-DPAT-induced STFs were diminished. In conclusion, spinal populations of alpha 1 (alpha 1A)- and alpha 2 (alpha 2D)- adrenoceptors respectively mediate and inhibit the induction of STFs by 5-HT1A receptor agonists, the actions of which depend on a functionally intact, descending, noradrenergic projection to lumbar spinal cord.
Bervoets
K
K
Institut de Recherches Servier, Paris, France.
Millan
M J
MJ
D015116:5,7-Dihydroxytryptamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008161:Lumbosacral Region; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology / Q000648:ultrastructure*; D013118:Spinal Cord Diseases / Q000139:chemically induced / Q000503:physiopathology; D013623:Tail / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D015116:5,7-Dihydroxytryptamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine