N-Acetyl-Cysteine Causes Analgesia by Reinforcing the Endogenous Activation of Type-2 Metabotropic Glutamate Receptors

Abstract

BackgroundPharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors) causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System xc- or Sxc-). We examined the analgesic activity of the Sxc- activator, N-acetyl-cysteine (NAC), in mice developing inflammatory or neuropathic pain.ResultsA single injection of NAC (100 mg/kg, i.p.) reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p.) or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). NAC still caused analgesia in mGlu3−/− mice, but was inactive in mGlu2−/− mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund’s adjuvant (CFA) model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI) of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC-induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sxc-) and activator of G-protein signaling type-3 (AGS3) in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord.ConclusionsThese data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors. NAC has an excellent profile of safety and tolerability when clinically used as a mucolytic agent or in the management of acetaminophen overdose. Thus, our data encourage the use of NAC for the experimental treatment of inflammatory pain in humans.

Evidence for Glutamate as a Neuroglial Transmitter within Sensory Ganglia

“…Some components of the vesicular docking mechanism are seen at the level of the somatic membrane within the ganglion (Figure S1). Alternatively, channels and transporters through which non-vesicular release of glutamate occurs are also present, including the cystine-glutamate antiporter [46], gap junctions (connexin 43) [23], the P2X7 channel [28], [47], or reverse transport through GLAST or GLT1 [21], [43]. Although we did not see glutamate immuno-staining in SGCs it is possible that this due to the limited sensitivity of immunocytochemistry.…”

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

“…In addition to the direct inhibition of the activation of MMP-9 in DRGs as revealed by Colorimetric quantitative detection in this study, previous studies indicated that NAC may alleviate neuropathic pain and inflammatory pain through reducing nitric oxide metabolites [42], scavenging reactive oxygen species (ROS) [43], and enhancing endogenous activation of type-2 metabotropic glutamate receptors (mGluR) in spinal cord [44]. The gelatin lytic activity and expression of MMP-9 could also be abolished indirectly by NAC via its ROS scavenging effect [45].…”

Behavioral assessment of acute inhibition of system xc - in rats

“…; Sigma Chemical Co., St Louis, MO), an inhibitor of system x c − (Bernabucci et al 2012; Gout et al 2001; Sontheimer and Bridges 2012), was dissolved in isotonic saline and brought to a pH between 6.0 and 8.0 using NaOH. Testing commenced two hours following acute sulfasalazine treatment as described below.…”