Regulation of Spinal Substance P Release by Intrathecal Calcium Channel Blockade

Abstract

Background We 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 channels 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%, 50μl) 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 (20μg), ziconotide (0.3, 0.6 and 1μg), mibefradil (100μg, but not 50μg), diltiazem (500μg, but not 300μg) and verapamil (200μg, but not 50 and 100μg) reduced paw flinching in phase 2 as compared to vehicle control (P < 0.05), with no effect upon phase 1. Ziconotide (0.3, 0.6 and 1μg) and morphine (20μg) 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-, but not T- and L-type voltage sensitive calcium channels in mediating the stimulus evoked substance P release from small primary afferents and suggest that T- and L-type voltage sensitive calcium channels blockers exert antihyperalgesic effects by an action on other populations of afferents or mechanisms involving post synaptic excitability.

N- and L-Type Voltage-Dependent Ca<SUP>2+</SUP> Channels Contribute to the Generation of After-Discharges in the Spinal Ventral Root After Cessation of Noxious Mechanical Stimulation

“…The effect of ω-conotoxin GVIA on after-discharges was similar to that of morphine and a neurokinin 1-receptor antagonist, respectively, administered intravenously (25). These results are supported by studies indicating that N-type VDCCs were inhibited by μ-opioid receptors in the DRG (35,36) and that N-type VDCC blockers inhibited the release of substance P in the spinal cord (8,37,38).…”

Substance P stimulates proliferation of spinal neural stem cells in spinal cord injury via the mitogen-activated protein kinase signaling pathway

“…In present study, we did not analyze the pain behavior after SP injection, and there was no behavioral change or extraordinary reaction after injection compared with the control group. However, many studies suggested that SP of the spinal cord is linked closely to nociceptive change [40][41][42]; so, a welldesigned study is needed to clarify the pain behavior after SP injection.…”

N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/− mice

“…Later clinical studies established that SNX-111 effectively reduced the pain associated with cancer or AIDS (Staats et al, 2004). More recently, intrathecal administration of SNX-111, but not the L-type blockers diltiazem or verapamil, suppressed the internalization of neurokinin-1, the G-protein coupled receptor that is activated by substance P (Takasusuki and Yaksh 2011). These results demonstrate that N-type Ca 2+ channels play a key role in the transmission of nociceptive signaling in the spinal cord.…”