The present study demonstrates that 10 Hz EA produces a more potent inhibitory effect than does 100 Hz EA in a paclitaxel-induced neuropathic pain rat model. Similarly, in a previous study, 2 Hz EA induced robust and longer lasting inhibition of mechanical allodynia compared to 100 Hz EA in a caudal trunk nerve injury-induced neuropathic pain model (Kim et al., 2004
). It was also found that 2 Hz EA had greater and more prolonged effects on mechanical allodynia and thermal hyperalgesia than did 100 Hz EA in a nerve injury-induced neuropathic pain rat model (Han, 2003
; Sun et al., 2002
). Thus, lower frequency EA has a potent inhibitory effect on peripheral nerve injury-induced allodynia and hyperalgesia, both metabolic/toxic and traumatic. In a clinical study, acupuncture produced significant improvement in primary and/or secondary symptoms in 77% of patients with diabetic neuropathy, and 67% of the patients were able to stop or reduce their medications significantly (Abuaisha et al., 1998
). In HIV-infected individuals, acupuncture significantly reduced the scores for pain/aching/burning, pins and needles, and numbness in the hands and feet (Phillips et al., 2004
). In patients with spinal cord injury-induced pain, 24 of 36 showed significant improvement after electroacupuncture treatment (Rapson et al., 2003
). Additionally, our unpublished data shows that multiple EA treatments in paclitaxel-injected rats alleviate mechanical hyperalgesia for two to three weeks after the termination of EA treatment. Taken together, these studies show that acupuncture may be useful in the management of neuropathic pain.
The effects of opioid receptor antagonists on acupuncture analgesia could differ depending on conditions. In the present study, all three opioid receptor antagonists blocked EA anti-allodynia and anti-hyperalgesia in paclitaxel-caused neuropathy, indicating that all three opioid receptor subtypes are involved in EA effects on paclitaxel-evoked peripheral neuropathy model. In contrast, our previous study demonstrated that μ and δ but not κ opioid receptors are involved in EA anti-hyperalgesia in a CFA-induced inflammatory pain model (Zhang et al., 2004
). It has also been demonstrated that μ and δ but not κ receptors were involved in EA anti-hyperalgesia in a capsaicin-induced inflammatory pain model (Kim et al., 2009
) and that EA also inhibited pain through the μ and δ receptors in a caudal trunk injury-induced neuropathic pain model (Kim et al., 2004
). These data convincingly show that EA inhibits allodynia and hyperalgesia through different opioid receptors in different situations. The underpinned mechanisms warrant further investigation.
The three opioid receptors, μ, δ and κ, have their own endogenous ligands, endomorphins, enkephalin, and dynorphin, in the spinal cord. These opioids are concentrated in the superficial dorsal horn to exert inhibitory effects on nociceptive transmission (Bodnar and Klein, 2006
). Previous studies have demonstrated that EA stimulation frequency determines the type of opioid peptide released in the central nervous system: 2 Hz induces endomorphin and enkephalin; 100 Hz induces dynorphin; 15 Hz induces all three opioids (Han, 2003
). Our study showed that the three opioid receptor antagonists blocked EA’s inhibitory effect, leading us to postulate that 10 Hz EA inhibited the paclitaxel-induced neuropathic pain by activating all three opioid receptor subtypes. Since opioid receptors are localized in primary afferent fibers of the spinal cord (Ji et al., 1995
), EA-induced opioids may inhibit pain through presynaptic mechanisms (Heinke et al., 2011
). In addition, as demonstrated in previous studies, opioid receptors are down-regulated in the spinal cord and dorsal root ganglia in a couple of neuropathic pain animal models (Obara et al., 2009
; Takasaki et al., 2006
; Zhang et al., 1998
). Whether opioid receptors are changed in an animal model of chemotherapy-induced neuropathy has not been investigated and warrants further investigation.
In a study using a DOReGFP reporter mouse, in which a green fluorescent protein (GFP) is covalently bound to a δ opioid receptor (DOR) through a gene suppressant strategy, it was demonstrated that μ and δ opioid receptors are expressed by different subsets of primary afferents and respectively contribute to heat and mechanical pain control (Scherrer et al., 2009
). In contrast, a recent study using in situ hybridization, single-cell polymerase chain reaction, and immunostaining demonstrated that δ receptors coexist with μ receptors in small peptidergic dorsal root ganglion neurons. Further, both μ and δ receptor agonists reduce depolarization-induced Ca2+
currents in single small dorsal root ganglion neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord (Wang et al., 2010
). Our data show that both μ and δ opioid receptor antagonists block EA-produced anti-mechanical allodynia and hyperalgesia, suggesting that these two receptors are involved in EA modulation of mechanical pain.
In summary, our experiments show that EA significantly inhibits chemotherapy-induced neuropathic pain through three subtypes of spinal opioid receptors. The results support that EA may be a useful complementary treatment for neuropathic pain patients.