TY - JOUR
T1 - New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5α-reduced neuroactive steroids
AU - Pathirathna, Sriyani
AU - Brimelow, Barbara C.
AU - Jagodic, Miljen M.
AU - Krishnan, Kathiresan
AU - Jiang, Xin
AU - Zorumski, Charles F.
AU - Mennerick, Steven
AU - Covey, Douglas F.
AU - Todorovic, Slobodan M.
AU - Jevtovic-Todorovic, Vesna
N1 - Funding Information:
This study was supported by the Career Development Awards, K08-DA00428 (to S.M.T.) and K08-DA00406 (to V.J.-T.) from NIDA, NIH grant AG 11355 (to V.J.-T.), NIH grant GM 47969 (to D.F.C and C.F.Z.), NIH grants NS 40488 and AA 12952 (S.M.), the Bantly Foundation (C.F.Z.), and the Klingenstein Foundation (S.M.). V.J.-T. is an Established Investigator of the American Heart Association.
PY - 2005/4
Y1 - 2005/4
N2 - Neurosteroids are potent blockers of neuronal low-voltage activated (T-type) Ca2+ channels and potentiators of GABAA ligand-gated channels, but their effects in peripheral pain pathways have not been studied previously. To investigate potential analgesic effects and the ion channels involved, we tested the ability of locally injected 5α-reduced neurosteroids to modulate peripheral thermal nociception to radiant heat in adult rats in vivo and to modulate GABAA and T-type Ca2+ channels in vitro. The steroid anesthetic alphaxalone (ALPX), the endogenous neurosteroid allopregnanolone (3α5αP), and a related compound ((3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile, (ACN)), induced potent, dose-dependent, enantioselective anti-nociception in vivo and modulation of both T-type Ca2+ currents and GABAA-mediated currents in vitro. Analgesic effects of ALPX were incompletely antagonized by co-injections of the GABAA receptor antagonist bicuculline. The neurosteroid analogue ((3α,5α)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), a compound with GABAergic but not T-type activity, was not analgesic. However, (3β,5α,17β)-17- hydroxyestrane-3-carbonitrile (ECN)), which has effects on T-type channels but not on GABAA receptors, also induced potent enantioselective peripheral anti-nociception. ECN increased pain thresholds less than ALPX, 3α5αP and ACN. However, when an ineffective dose of CDNC24 was combined with ECN, anti-nociceptive activity was greatly enhanced, and this effect was bicuculline-sensitive. These results strongly suggest that GABA A channels do not contribute to baseline pain transmission, but they can enhance anti-nociception mediated by blockade of T-type Ca2+ channels. In conclusion, we demonstrate that potent peripheral analgesia induced by 5α-reduced neurosteroid is mediated in part by effects on T-type Ca2+ channels. Our results also reveal a role of GABA-gated ion channels in peripheral nociceptive signaling.
AB - Neurosteroids are potent blockers of neuronal low-voltage activated (T-type) Ca2+ channels and potentiators of GABAA ligand-gated channels, but their effects in peripheral pain pathways have not been studied previously. To investigate potential analgesic effects and the ion channels involved, we tested the ability of locally injected 5α-reduced neurosteroids to modulate peripheral thermal nociception to radiant heat in adult rats in vivo and to modulate GABAA and T-type Ca2+ channels in vitro. The steroid anesthetic alphaxalone (ALPX), the endogenous neurosteroid allopregnanolone (3α5αP), and a related compound ((3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile, (ACN)), induced potent, dose-dependent, enantioselective anti-nociception in vivo and modulation of both T-type Ca2+ currents and GABAA-mediated currents in vitro. Analgesic effects of ALPX were incompletely antagonized by co-injections of the GABAA receptor antagonist bicuculline. The neurosteroid analogue ((3α,5α)-3-hydroxy-13,24-cyclo-18,21- dinorchol-22-en-24-ol (CDNC24), a compound with GABAergic but not T-type activity, was not analgesic. However, (3β,5α,17β)-17- hydroxyestrane-3-carbonitrile (ECN)), which has effects on T-type channels but not on GABAA receptors, also induced potent enantioselective peripheral anti-nociception. ECN increased pain thresholds less than ALPX, 3α5αP and ACN. However, when an ineffective dose of CDNC24 was combined with ECN, anti-nociceptive activity was greatly enhanced, and this effect was bicuculline-sensitive. These results strongly suggest that GABA A channels do not contribute to baseline pain transmission, but they can enhance anti-nociception mediated by blockade of T-type Ca2+ channels. In conclusion, we demonstrate that potent peripheral analgesia induced by 5α-reduced neurosteroid is mediated in part by effects on T-type Ca2+ channels. Our results also reveal a role of GABA-gated ion channels in peripheral nociceptive signaling.
KW - Adult rats
KW - Dorsal root ganglia
KW - Peripheral nociceptors
KW - T-channel blockers
KW - Thermal anti-nociception
UR - http://www.scopus.com/inward/record.url?scp=20144373040&partnerID=8YFLogxK
U2 - 10.1016/j.pain.2005.01.009
DO - 10.1016/j.pain.2005.01.009
M3 - Article
C2 - 15777868
AN - SCOPUS:20144373040
SN - 0304-3959
VL - 114
SP - 429
EP - 443
JO - Pain
JF - Pain
IS - 3
ER -