BACKGROUND: The authors investigated the role of different voltage-sensitive 
calcium channels expressed at presynaptic afferent terminals in substance P 
release and on nociceptive behavior evoked by intraplantar formalin by examining 
the effects of intrathecally delivered N- (ziconotide), T- (mibefradil), and 
L-type voltage-sensitive calcium channel blockers (diltiazem and verapamil).
METHODS: Rats received intrathecal pretreatment with saline or doses of 
morphine, ziconotide, mibefradil, diltiazem, or verapamil. The effect of these 
injections upon flinching evoked by intraplantar formalin (5%, 50 μl) was 
quantified. To assess substance P release, the incidence of neurokinin-1 
receptor internalization in the ipsilateral and contralateral lamina I was 
determined in immunofluorescent-stained tissues.
RESULTS: Intrathecal morphine (20 μg), ziconotide (0.3, 0.6, and 1 μg), 
mibefradil (100 μg, but not 50 μg), diltiazem (500 μg, but not 300 μg), and 
verapamil (200 μg, but not 50 and 100 μg) reduced paw flinching in phase 2 
compared with vehicle control (P < 0.05), with no effect on phase 1. Ziconotide 
(0.3, 0.6, and 1 μg) and morphine (20 μg) significantly inhibited neurokinin-1 
receptor internalization (P < 0.05), but mibefradil, diltiazem, and verapamil at 
the highest doses had no effect.
CONCLUSION: These results emphasize the role in vivo of N-type but not T- and 
L-type voltage-sensitive calcium channel blockers in mediating the 
stimulus-evoked substance P release from small primary afferents and suggest 
that T- and L-type voltage-sensitive calcium channel blockers exert 
antihyperalgesic effects by an action on other populations of afferents or 
mechanisms involving postsynaptic excitability.