The present study was performed to examine whether neuropathic pain alters presynaptic GABA release and postsynaptic GABA-activated Cl- currents and whether opioidergic modulation of the GABAergic inhibitory synaptic response might be affected by neuropathic pain. Our results show that neuropathic pain increases the frequency of presynaptic GABA release and decreases both the fast decay time constant and the synaptic charge transfer of postsynaptic GABA-activated Cl- currents, regardless of whether MOR agonists are present. In addition, neuropathic pain did not alter the inhibitory effect of MOR activation on GABAergic mIPSCs.
Neuropathic pain associated with peripheral neuropathy can manifest as severe and intractable pain. However, the mechanism of this severe and intractable pain remains unclear. The PAG is an important component of the endogenous pain control system and is the main site of the powerful analgesic effects by morphine or opioid peptides . In a previous report, we suggested that MOR-induced inhibition of GABAergic inhibitory synaptic influence in the PAG is the main mechanism of the opioidergic endogenous pain control system . If GABAergic synaptic inhibition of PAG neurons is potentiated by neuropathic pain, this may represent a potential mechanism of neuropathic pain. Although the exact mechanisms are not clear, there have been reports supporting this hypothesis. Activation of the descending pain control system was shown to be important in the maintenance of neuropathic pain . The PAG-mediated inhibition of nociception may be activated by persistent nociceptive input, possibly reflecting the long-term changes in the nociceptive circuitry that occur in neuropathic pain states . In this study, neuropathic rats showed an increase in the frequency of presynaptic GABA release in PAG neurons (Figure 4). This finding indicates that endogenous pain control mechanisms in the PAG may be inhibited in animals suffering from neuropathic pain. Thus, this study suggests that neuropathic pain inhibits the efficiency of the endogenous pain control system in the PAG, thereby inducing severe and intractable pain.
Although neuropathic pain does not alter the amplitude of postsynaptic GABAergic response, the kinetics of mIPSC was slightly inhibited in neuropathic rats (Figure 5, Table 1). Neuropathic rats showed a reduction in the fast decay time with a reduced half-width time and synaptic charge transfer of mIPSCs. These findings might indicate that GABAergic inhibitory input to the PAG neurons can be decreased in neuropathic rats, which means that endogenous pain control mechanisms in the PAG may be activated in neuropathic rats. However, the decrease in the fast decay time and synaptic charge transfer of mIPSCs (76.0% and 73.2% of the normal rats, respectively) was significantly less than the increase in presynaptic release of GABA (151.8% of the normal rats, Figure 4). Thus, the changes in mIPSC kinetics in neuropathic rats may not show a significant influence to the inhibitory effect of the decreased presynaptic GABA release in neuropathic rats on endogenous pain control mechanisms in the PAG.
Morphine and opioid peptides exert their powerful analgesic effects through the endogenous pain control system, especially in the PAG . The efficiency of opioid receptor agonists, especially the MOR agonist morphine, has been reported in recent studies of central and peripheral neuropathic pain disorders [31–34]. However, the development of long-term side effects, such as immunological problems, physical dependency, and misuse or abuse, is a limitation to the use of opioid analgesics in patients with neuropathic pain . Furthermore, and the effectiveness of opioid agonists on neuropathic allodynia and hyperalgesia remains controversial. Several studies have supported the effectiveness of opioid receptor agonists on neuropathic pain [3–14]. However, some studies have raised questions about the efficiency of opioid analgesics on neuropathic pain in humans  and animals [16–18, 35]. Other studies have indicated that the PAG is important in opioidergic analgesia of neuropathic pain. Neuropathic pain that is induced by peripheral nerve injury has been effectively alleviated by electrical stimulation of the PAG , microinjection of opioid agonists into the PAG , and supraspinal administration of morphine into the PAG . Although the analgesic mechanisms have not been clearly elucidated, these studies suggest that the endogenous pain control system, including the PAG, is very important in the control of neuropathic pain syndrome and that opioid receptors are involved in this system. In the present study, MOR agonists inhibited GABAergic inhibitory synaptic activity in the PAG of neuropathic rats, and this inhibitory effect of MOR activation was not significantly different between neuropathic and normal rats (Figure 2, 3, and 4). Thus, the results of this study suggest that MOR agonists can effectively exert an analgesic effect on neuropathic pain through the modulation of the endogenous pain control system in the PAG and that the analgesic effectiveness of opioid peptides in neuropathic animals is similar to that in normal animals. However, because neuropathic pain may inhibit the endogenous pain control mechanism in the PAG in the resting state (as described above), it is possible that the analgesic action of exogenous opioid agonists is less effectively in a neuropathic pain state.
While the majority of proximal dendrites are still attached to the neurons, the mechanical dissociation can alter the majority of distal dendrites. Although the remaining dendritic as well as somatic synapses are well elucidated to be still functioning , it cannot be ruled out that the dendritic synapses may be modulated in a different manner shown in the present study.