Repetitive motor cortex stimulation reinforces the pain modulation circuits of peripheral neuropathic pain.

Recent evidence indicates that motor cortex stimulation (MCS) is a potentially effective treatment for chronic neuropathic pain. However, the neural mechanisms underlying the attenuated hyperalgesia after MCS are not completely understood. In this study, we investigated the neural mechanism of the effects of MCS using an animal model of neuropathic pain. After 10 daily sessions of MCS, repetitive MCS reduced mechanical allodynia and contributed to neuronal changes in the anterior cingulate cortex (ACC). Interestingly, inhibition of protein kinase M zeta (PKMζ), a regulator of synaptic plasticity, in the ACC blocked the effects of repetitive MCS. Histological and molecular studies showed a significantly increased level of glial fibrillary acidic protein (GFAP) expression in the ACC after peripheral neuropathy, and neither MCS treatment nor ZIP administration affected this increase. These results suggest that repetitive MCS can attenuate the mechanical allodynia in neuropathic pain, and that the activation of PKMζ in the ACC may play a role in the modulation of neuropathic pain via MCS.

Changes in cytokine expression after electroacupuncture in neuropathic rats.

The production of proinflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) plays a key role in chronic pain such as neuropathic pain. We investigated changes in cytokine expression in injured peripheral nerves and dorsal root ganglia (DRG) following electroacupuncture (EA) treatment. Neuropathic pain was induced by peripheral nerve injury to the left hind limb of Sprague-Dawley rats under pentobarbital anesthesia. Two weeks later, the nerve-injured rats were treated by EA for 10 minutes. The expression levels of IL-1ß, IL-6, and TNF-α in peripheral nerves and DRG of neuropathic rats were significantly increased in nerve-injured rats. However, after EA, the cytokine expression levels were noticeably decreased in peripheral nerves and DRG. These results suggest that EA stimulation can reduce the levels of proinflamtory cytokines elevated after nerve injury.

Modulation of N-type calcium currents by presynaptic imidazoline receptor activation in rat superior cervical ganglion neurons.

Presynaptic imidazoline receptors (R(i-pre)) are found in the sympathetic axon terminals of animal and human cardiovascular systems, and they regulate blood pressure by modulating the release of peripheral noradrenaline (NA). The cellular mechanism of R(i-pre)-induced inhibition of NA release is unknown. We, therefore, investigated the effect of R(i-pre) activation on voltage-dependent Ca(2+) channels in rat superior cervical ganglion (SCG) neurons, using the conventional whole-cell patch-clamp method. Cirazoline (30 µM), an R(i-pre) agonist as well as an α-adrenoceptor (R(α)) agonist, decreased Ca(2+) currents (I(Ca)) by about 50% in a voltage-dependent manner with prepulse facilitation. In the presence of low-dose rauwolscine (3 µM), which blocks the α(2)-adrenoceptor (R(α2)), cirazoline still inhibited I(Ca) by about 30%, but prepulse facilitation was significantly attenuated. This inhibitory action of cirazoline was almost completely prevented by high-dose rauwolscine (30 µM), which blocks R(i-pre) as well as R(α2). In addition, pretreatment with LY320135 (10 µM), another R(i-pre) antagonist, in combination with low-dose rauwolscine (3 µM), also blocked the R(α2)-resistant effect of cirazoline. Addition of guanosine-5-O-(2-thiodiphosphate) (2 mm) to the internal solutions significantly attenuated the action of cirazoline. However, pertussis toxin (500 ng ml(1)) did not significantly influence the inhibitory effect of cirazoline. Moreover, cirazoline (30 µM) suppressed M current in SCG neurons cultured overnight. Finally, omega-conotoxin (omega-CgTx) GVIA (1 µM) obstructed cirazoline-induced current inhibition, and cirazoline (30 µM) significantly decreased the frequency of action potential firing in a partly reversible manner. This cirazoline-induced inhibition of action potential firing was almost completely occluded in the presence of omega-CgTx. Taken together, our results suggest that activation of R(i-pre) in SCG neurons reduced N-type I(Ca) in a pertussis toxin- and voltage-insensitive pathway, and this inhibition attenuated repetitive action potential firing in SCG neurons.