Suppression of stretch reflex activity after spinal or systemic treatment with AMPA receptor antagonist NGX424 in rats with developed baclofen tolerance.
OBJECTIVE
Baclofen (a GABA(B) receptor agonist) is the most commonly used anti-spasticity agent in clinical practice. While effective when administered spinally or systemically, the development of progressive tolerance represents a serious limitation for its long-term use. The goal of the present study was to characterize the treatment potency after intrathecal or systemic treatment with the selective AMPA receptor antagonist NGX424 on stretch reflex activity (SRA) and background muscle activity (BMA) in rats with developed baclofen tolerance.


METHODS
Animals were exposed to 10 min of spinal ischaemia to induce an increase in BMA and SRA. Selected animals were implanted with an intrathecal PE-5 catheter and infused intrathecally with baclofen (1 µg·h⁻¹ ) for 14 days. Before and after baclofen infusion, changes in BMA and SRA were measured at 2 day intervals. After development of baclofen tolerance, the animals were injected intrathecally (1 µg) or subcutaneously (3, 6 or 12 mg·kg⁻¹) with NGX424, and changes in BMA and SRA were measured.


RESULTS
Intrathecal or systemic delivery of NGX424 significantly suppressed the BMA and SRA in baclofen-tolerant animals. This effect was dose dependent. The magnitude of BMA and SRA suppression seen after 1 µg (intrathecal) or 12 mg·kg ⁻¹ (s.c.) of NGX424 injection was similar to that seen during the first 5 days of baclofen infusion. CONCLUSIONS AND IMPLICATIONS These data demonstrate that the use of NGX424 can represent an effective therapy to modulate chronic spasticity in patients who are refractory or tolerant to baclofen treatment.
Department of Anesthesiology, University of the Ryukyus, Okinawa, Japan.
Masakatsu
M
Oshiro
Michael P
MP
Hefferan
Osamu
O
Kakinohana
Nadezda
N
Lukacova
Kazuhiro
K
Sugahara
Tony L
TL
Yaksh
Martin
M
Marsala
D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000494:pharmacology; D009128:Muscle Spasticity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D012026:Reflex, Stretch / Q000187:drug effects*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*
D058786:GABA-B Receptor Agonists; D007546:Isoquinolines; D009125:Muscle Relaxants, Central; D018091:Receptors, AMPA; D013777:Tetrazoles; C082309:tezampanel; D001418:Baclofen