MULTIPLE ALPHA-2-ADRENERGIC RECEPTOR SUBTYPES .2. EVIDENCE FOR A ROLE OF RAT R(ALPHA-2A), ADRENERGIC-RECEPTORS IN THE CONTROL OF NOCICEPTION, MOTOR BEHAVIOR AND HIPPOCAMPAL SYNTHESIS OF NORADRENALINE

In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 {5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline}, inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R(alpha-2A))/human alpha-2A (H-alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R(alpha-2A)/H-alpha-2A AR antagonist, {2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R(alpha-2A) AR as compared to H-alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 {2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)4,4-dimethyl-1,3-(2H,4H)-isoquinolinedione} prazosin, corynanthine, spiroxatrine and {1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)-imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H-alpha-2A AR antagonist, {2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane} (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R(alpha-2A) sites (0.85), modest with H-alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R(alpha-2A) sites (0.80) but less marked with H-alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62). Correlations for enhancement of NA synthesis were likewise pronounced with R(alpha-2A) sites (0.88) yet less marked with H-alpha-2A sites (0.70), alpha-2B sites (0.65) and alpha-2C sites (0.55). In conclusion, these data suggest that the R(alpha-2A) AR subtype is involved in the mediation of the antinociceptive and motor actions of alpha-2 AR agonists in the rat. Further, a R(alpha-2A) autoreceptor is implicated in the control of the hippocampal synthesis of NA. These data do not, however, formally rule out an involvement of other alpha-2 AR subtypes.