In our current study, we investigated the role of spinal
glutamate recycling in the development of orofacial inflammatory
pain. DL-threo-β-
benzyloxyaspartate (
TBOA) or
methionine sulfoximine (MSO) was administered intracisternally to block spinal
glutamate transporter and
glutamine synthetase activity in astroglia. Intracisternal administration of high dose
TBOA (10 μg) produced
thermal hyperalgesia in naïve rats but significantly attenuated the
thermal hyperalgesia in rats that had been pretreated with
interleukin (IL)-1β or Complete
Freund's Adjuvant (CFA). In contrast, intracisternal injection of MSO produced anti-hyperalgesic effects against thermal stimuli in CFA-treated rats only. To confirm the paradoxical antinociceptive effects of
TBOA and MSO, we examined changes in c-Fos expression in the medullary dorsal horn produced by thermal stimulation in naïve, IL-1β-, or CFA-treated rats, after intracisternal
injections of
TBOA and MSO. Intracisternal administration of
TBOA significantly increased c-Fos immunoreactivity in naïve rats. In contrast, intracisternal administration of
TBOA significantly decreased the up-regulation of c-Fos immunoreactivity in the medullary dorsal horn of IL-1β- and CFA-treated rats. However, intracisternal injection of MSO blocked the up-regulation of c-Fos immunoreactivity in CFA-treated rats only. We also investigated the effects of
botulinum toxin type A (
BoNT-A) on
TBOA-induced paradoxical antinociception in CFA-treated rats, as
BoNT-A inhibits the release of
neurotransmitters, including
glutamate.
BoNT-A treatment reversed behavioral responses produced by intracisternal administration of
TBOA in CFA-treated rats. These results suggest that the paradoxical responses produced by blocking
glutamate transporters under inflammatory
pain conditions are mediated by the modulation of
glutamate release from presynaptic terminals. Moreover, blockade of
glutamate reuptake could represent a new therapeutic target for the treatment of chronic inflammatory
pain conditions.