Effekte der intrathekal applizierten Glycin-Transporter-Inhibitoren ALX-5407 und ALX-1393 auf das nozizeptive Verhalten von Ratten im Chronic Constriction Injury Modell für neuropathischen Schmerz

An important factor in the development and main¬tenance of
neuropathic pain is a loss of glycinergic inhibition in the spinal
cord. Here glycine is the major inhibitory neuro¬transmitter, but
it also has excitatory functions as an obligate co-agonist of
glutamate at the NMDA re¬ceptor. Glycine concentration in the
synaptic cleft is controlled by glycine transporter 1 and glycine
transporter 2. Inhibition of these two glycine transporters can
influence glycinergic neuro¬transmission. The goal of this study
was to determine whether the intrathecal application of glycine
transporter inhibitors ALX 5407 and ALX 1393, which would raise
glycine levels in the synaptic cleft, can influence the nociception
of rats. As gly¬cine acts on both the inhibitory glycine receptor
and the excitatory NMDA receptor, we ex¬pected to see differential
effects. Bennett and Xie´s chronic constriction injury model was
used as a model for neuro¬pathic pain. Hyperalgesia and allodynia
develop ten to twelve days after loose ligation of the left sciatic
nerve and can be measured to quantify neuropathic pain. An
intrathe¬cal PE10 catheter was inserted into the vertebral canal to
enable application of both gly¬cine transporter in¬hibitors (three
dos¬ages respectively: 10, 50 and 100 μg dis¬solved in 10 μl 100 %
DMSO; n = 8) in the vicinity of the dorsal horn of the spinal cord.
Following the treatment, me¬chanical paw withdrawal threshold was
measured using a von Frey-filament and thermal paw withdrawal
latency was measured using a modified Har¬greaves method. Both
measurements were made for 240 minutes. The glycine transporter 1
inhibitor ALX 5407 had dose dependent differential effects on the
noci¬cep¬tion of rats. Antinociceptive effects were obtained after
application of the low and the high concentrations and
pronociceptive effects were obtained after applica¬tion of the
intermediate concentration. The pronociceptive actions were most
prominent in the un¬injured right paw. There were no side effects.
The glycine transporter 2 inhibitor ALX 1393 exerted exclusively
antinociceptive ef¬fects that were significant only after
appli¬cation of the high concentration. Additionally, at the high
concentration, we observed severe neurological side effects in four
of eight animals (pareses, paralysis, res¬piratory depres¬sion and
analgesia). The pronociceptive effects of glycine transporter 1
inhibitor ALX 5407 can be ex¬plained by an in¬creased activation of
NMDA receptor through un¬hampered spill over of synaptically
released glycine. The antinociceptive effects of both glycine
transporter inhibitors and the neurological side effects of the
glycine transporter 2 inhibitor ALX 1393 are likely to be mediated
by the gly¬cine receptor. This study shows, that neuropathic pain
behaviour can be significantly in¬fluenced in vivo by manipulating
glycine concentration through a singular intra¬the¬cal injection of
spe¬cific glycine transporter inhibitors. The study of glycinergic
neurotransmission with the aid of glycine transporter inhibi¬tors
promises future development of potent and versatile therapeutics.
These may have potential to treat neuropathic pain, act as muscle
relaxants and analgesics and also function as cognitive enhancers
and treatments for schizo¬phrenia.