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Algogen-specific pain processing in mouse spinal cord: differential involvement of voltage-dependent Ca(2+) channels
Akemi Kato1, Tsuyako Ohkubo, Kenji Kitamura
1Department of Pharmacology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan.
Abstract:
1. The effects of intrathecal (i.t.) administration of N-, P/Q- or L-type voltage-dependent Ca(2+)-channel blockers were tested in two pain models involving bradykinin (BK)- and alpha,beta-methylene ATP (alpha,beta meATP)-induced activation of primary afferent neurons in mice. 2. The nociceptive response (amount of time spent licking and biting the hindpaw) induced by intraplantar injection of BK (500 pmol mouse(-1)) was significantly attenuated by both omega-conotoxin GVIA (N-type blocker) and calciseptine (L-type) but not by omega-agatoxin IVA (P/Q-type). 3. The nociceptive response induced in a similar way by alpha,beta meATP (100 nmol) was significantly inhibited by both the above N- and P/Q-type Ca(2+)-channel blockers but not by the L-type blocker. 4. The nociceptive responses elicited by BK and alpha,beta meATP were dose-dependently inhibited by a tachykinin-NK1-receptor antagonist (L-703,606) and an N-methyl-D-aspartate (NMDA)-receptor antagonist (D-AP5), respectively. 5. Intrathecal administration of substance P (SP) (1.8 nmol) or NMDA (350 pmol) elicited algesic responses, such as licking, biting and scratching of the hindquarters. The SP-induced algesic behaviour was significantly inhibited by the L-type blocker but not by the N-type. The NMDA-induced response was not affected by either the N- or the P/Q-type blocker. 6. These findings suggest that BK and ATP most likely excite different types of sensory neurons in the periphery and that within the spinal cord the former stimulates peptidergic transmission regulated by presynaptic N- and postsynaptic L-type Ca(2+) channels, while the latter stimulates glutamatergic transmission regulated by presynaptic N- and P/Q-type channels.
Insights
This study investigated how different calcium channel blockers affect pain signaling in mice. Bradykinin-induced pain involved N- and L-type channels, while ATP-induced pain involved N- and P/Q-type channels, suggesting distinct pain pathways.
Area of Science:
- Neuroscience
- Pain Research
- Pharmacology
Background:
- Voltage-dependent calcium channels (Ca(2+)) play crucial roles in neuronal excitability and neurotransmitter release.
- Bradykinin (BK) and alpha,beta-methylene ATP (alpha,beta meATP) are known to activate primary afferent neurons, contributing to pain signaling.
- Understanding the specific roles of different Ca(2+) channel subtypes in pain pathways is essential for developing targeted analgesics.
Purpose of the Study:
- To elucidate the involvement of N-, P/Q-, and L-type voltage-dependent Ca(2+) channels in pain models induced by BK and alpha,beta meATP.
- To differentiate the roles of these Ca(2+) channel subtypes in spinal cord neurotransmission for distinct pain mediators.
Main Methods:
- Intrathecal administration of specific Ca(2+) channel blockers (omega-conotoxin GVIA, calciseptine, omega-agatoxin IVA) in mice.
- Assessment of nociceptive responses (licking, biting, scratching) following intraplantar injection of BK or alpha,beta meATP.
- Evaluation of the effects of tachykinin-NK1 and NMDA receptor antagonists on BK- and alpha,beta meATP-induced pain.
Main Results:
- BK-induced nociception was attenuated by N-type and L-type Ca(2+) channel blockers, but not P/Q-type.
- Alpha,beta meATP-induced nociception was inhibited by N-type and P/Q-type Ca(2+) channel blockers, but not L-type.
- Substance P-induced responses were blocked by L-type blockers, while NMDA-induced responses were unaffected by N- or P/Q-type blockers.
Conclusions:
- BK and ATP activate distinct peripheral sensory neurons.
- Spinal cord processing of BK involves presynaptic N- and postsynaptic L-type Ca(2+) channels in peptidergic transmission.
- Spinal cord processing of ATP involves presynaptic N- and P/Q-type Ca(2+) channels in glutamatergic transmission.