GABAergic synaptic response and its opioidergic modulation in periaqueductal gray neurons of rats with neuropathic pain

Abstract

BackgroundNeuropathic pain is a chronic and intractable symptom associated with nerve injury. The periaqueductal gray (PAG) is important in the endogenous pain control system and is the main site of the opioidergic analgesia. To investigate whether neuropathic pain affects the endogenous pain control system, we examined the effect of neuropathic pain induced by sacral nerve transection on presynaptic GABA release, the kinetics of postsynaptic GABA-activated Cl- currents, and the modulatory effect of μ-opioid receptor (MOR) activation in mechanically isolated PAG neurons with functioning synaptic boutons.ResultsIn normal rats, MOR activation inhibited the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) to 81.3% of the control without any alteration in their amplitude. In neuropathic rats, the inhibition of mIPSC frequency by MOR activation was 82.4%. The frequency of GABAergic mIPSCs in neuropathic rats was 151.8% of normal rats without any difference in the mIPSC amplitude. Analysis of mIPSC kinetics showed that the fast decay time constant and synaptic charge transfer of mIPSCs in neuropathic rats were 76.0% and 73.2% of normal rats, respectively.ConclusionsThese results indicate that although the inhibitory effect of MOR activation on presynaptic GABA release is similar in both neuropathic and normal rats, neuropathic pain may inhibit endogenous analgesia in the PAG through an increase in presynaptic GABA release.

Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray

“…We show here that chemogenetic activation of GABAergic neurons or inhibition of glutamatergic neurons can lead to hypersensitivity to mechanical and thermal stimuli, suggesting that any disruption of the balance between activity of the vlPAG excitatory and inhibitory neurons might contribute to the maintenance of chronic pain (Hahm et al, 2011; Ho et al, 2013; Lau and Vaughan, 2014). Future studies should explore the plastic changes in GABAergic and glutamatergic neurons that might contribute to the maintenance of chronic pain.…”

“…It has been hypothesized that GABAergic interneurons exert tonic inhibition of vlPAG glutamatergic neurons, which are thought to be output neurons that project to the RVM (Jacquet, 1988; Roychowdhury and Fields, 1996; Vaughan et al, 1997; Wang and Wessendorf, 2002; Morgan et al, 2008; Park et al, 2010; Hahm et al, 2011; Ho et al, 2013). These glutamatergic neurons have been hypothesized to play a role in an analgesic modulatory pathway (McGaraughty et al, 2003; Maione et al, 2006; Starowicz et al, 2007), but this has not been selectively demonstrated.…”

“…It is tempting to speculate that output from the vlPAG has a purely analgesic action. However, the vlPAG comprises diverse subpopulations of neurons with distinct neurochemical properties that regulate excitatory and inhibitory neurotransmission (Behbehani and Fields, 1979; Moss and Basbaum, 1983; Moss et al, 1983; Moreau and Fields, 1986; Behbehani et al, 1990; Behbehani, 1995; Vaughan et al, 1997; Hahm et al, 2011; Ho et al, 2013). Microinjection of glutamate receptor agonists or GABA antagonists into the vlPAG leads to global activation of neurons and produces antinociceptive effects to noxious stimuli (Moreau and Fields, 1986; Ness and Gebhart, 1987; Carstens et al, 1988; Jacquet, 1988; Jones and Gebhart, 1988; Jensen and Yaksh, 1989; Sandkühler et al, 1989; Carstens et al, 1990; Budai and Fields, 1998; Morgan et al, 2003).…”

Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model

“…Microinjection of MOR agonists into periaqueductal gray matter (PAG) results in potent analgesia in naïve animals [26,27], suggesting that the PAG is a major site mediating antinociception of MOR agonists via the descending pathway and receives inhibitory regulation by tonic GABA release [28,29]. Results from our laboratory and others have revealed that GABAergic transmission in PAG neurons was enhanced in various pain models such as the FBC model and rats with peripheral nerve ligation [30,31]. Although oxaliplatin-induced neuropathy is not well characterized, it is possible that elevating GABAergic inhibition to PAG neurons might elicit greater inhibition of PAG neurons for the descending pain inhibitory system, and may be involved in the development and/or maintenance of chronic pain.…”

Effectiveness of GABA agonist for treatment in mice with complete freud’s adjuvants induced chronic pain: molecular modeling approach

“…Until now, chronic pain treatment is still a challenge because of its complex mechanism. Morphine as the first treatment have a lot of weakness and the effectiveness of this drug for chronic pain treatment is still debated (Baron et al, 2010;Hahm et al, 2011). So, we need an alternative new strategy, one of them is GABAergik agonist drugs such as gabapentin and baclofen (Wang et al, 2007).…”