Paclitaxel is an important chemotherapeutic agent from the bark of Taxus brevifolia
], which is widely used to treat various tumors [2
]. However, despite its role against the tumors, its usage is often limited, due to the painful peripheral neuropathy occurring after its administration [5
]. Symptoms commonly reported are sensory neuropathies, which are paresthesia, loss of tendon reflexes, numbness and pain in the upper and lower extremities. Although these neuropathies decrease patients’ quality of life (QoL), there is still no optimal treatment method or drug to alleviate these neuropathies [5
]. Thus, an effort to explore novel treatments is needed.
Bee venom acupuncture (BVA), a treatment method that injects diluted bee venom into acupoints, is widely used in traditional Korean medicine against various diseases, such as adhesive capsulitis [7
], idiopathic Parkinson’s disease [8
], knee osteoarthritis [9
], and musculoskeletal pain diseases [10
]. Especially, BVA has been reported to have potent analgesic effect in studies conducted using various animal models of pain [11
], and two case series also reported that BVA treatment may help to reduce the chemotherapy-induced peripheral neuropathy (CIPN), including paclitaxel-induced neuropathy [16
]. Recently, our laboratory has demonstrated that BVA treatment could significantly alleviate mechanical and cold allodynia in a rat model of oxaliplatin-induced neuropathic pain [12
]. Moreover, although the precise mechanism of BVA analgesic effect is unknown, we have also demonstrated that this analgesic effect was mediated by the descending noradrenergic pain modulation pathway via the activation of spinal α-adrenergic receptor, which was consistent with other previously conducted studies [11
Thus, the aims of this study were, firstly, to examine whether the BVA has suppressive effects against paclitaxel-induced mechanical hyperalgesia and neuronal hyperexcitation in the spinal cord, and secondly, to observe the role of BVA components, such as melittin and phospholipase A2 (PLA2) in their analgesic effect, and finally, to investigate which α-adrenergic receptor subtypes mediate the analgesic effect of BVA in the spinal cord.
Multiple injection of paclitaxel can occur peripheral neuropathy, which can limit its usage and decreases patients’ QoL. Although the treatments such as gabapentin, pregabalin, and morphine have been used to alleviate the neuropathic pain, these treatments have, themselves, various side effects, such as nausea, vomiting, somnolence, dizziness, suicidal thought, and drug dependence [22
]. Therefore, an effort to search for effective treatment options is critically needed. In traditional Korean medicine, BVA has been used to treat musculoskeletal pain and arthritis from the past [10
]. In addition, these days, BVA has also been founded to be effective in treating patients with CIPN [16
]. Thus, in this study, we experimented to find out whether BVA can alleviate the paclitaxel-induced neuropathy and to clarify the mechanism that lies behind it.
Our data showed that BVA treatment at ST36, not LI11, had a significant analgesic effect. It should be noted that ST36 acupoint is closer to the hind paw, where mechanical test was performed, than LI11 acupoint. It is consistent with the previous study in which BVA had more potent analgesic effect when treated closer to the tested area [14
]. Then, we examined the time course of the analgesic effect of the BVA at ST36. The result showed that the analgesic effect was significant until two hours after BVA treatment. Our previous study also showed that the analgesic effect of BVA was effective until two hours after BVA treatment in oxaliplatin-induced cold allodynia [14
]. Considering that moderate concentration of morphine without side effects was no longer effective in oxaliplatin-induced cold allodynia at two hours after administration [12
], this result would be clinically significant.
The spinal wide dynamic range (WDR) neuron receives non-nociceptive and nociceptive inputs via A- and C-fibers, and descending pain modulatory systems synapse at the WDR neuron [28
]. Therefore, the spinal WDR neuron is suitable for assessing the degree of pain. In addition, the hyperexcitation of spinal WDR neuron was observed previously in a rat model of paclitaxel-induced hyperalgesia [29
]. In our study, electrophysiological data confirmed that hyperexcitation of WDR neurons is induced by paclitaxel. We further demonstrated that BVA treatment could significantly inhibit this paclitaxel-induced hyperexcitation in the spinal WDR cells.
In subsequent experiments, we administered BVA, melittin, or PLA2 at ST 36, to observe the role of different BV components in the analgesic effect of BVA against paclitaxel-induced mechanical hyperalgesia. Melittin is a major component of the BV, occupying 50% of its total dry weight. PLA2 occupies 12%. Our results showed that 0.5 mg/kg of melittin was more powerful than 1 mg/kg of BVA or 0.12 mg/kg of PLA2. In our previous study, we showed that intraperitoneal injection of PLA2 could significantly decrease the cold and mechanical allodynia induced by single oxaliplatin injection in mice [30
]. Moreover, although not on chemotherapy induced pain model, other lab has reported that melittin injected at ST36 had a powerful analgesic effect against complete Freund’s adjuvant-induced rheumatoid arthritis, showing a similar effect to BVA [31
]. In this study, the analgesic effect of BVA or melittin was blocked by spinal α2
-adrenergic receptor antagonist (idazoxan), showing that BVA and melittin act on similar spinal adrenergic receptors to inhibit mechanical hyperalgesia induced by paclitaxel.
EA (electro-acupuncture) is a modified acupuncture which utilizes electrical current to treat pain. BVA is another form of acupuncture which uses chemical compounds; bee venom. The two different forms of acupuncture have similarities and differences. One of the similarities is that the endogenous analgesic systems are involved in both of their analgesic mechanisms, and the difference is that the analgesic effects of EA are mainly mediated by the opioidergic system [32
], whereas those of the BVA are mostly mediated by the noradrenergic system [33
]. However, despite this difference, EA and BVA were both reported to be effective in different types of allodynia assessed using thermal [34
] and chemical [12
] stimulations. These results show that other inhibitory systems, such as serotonergic, GABA, and/or cholinergic systems, may also play an important role, along with opioidergic and adrenergic system, in the action of EA and BVA. Furthermore, interaction of periaqueductal gray (PAG) and locus coeruleus (LC) in the brain should also play an important part in their analgesic effect, as both the EA and BVA were reported to activate PAG [35
] and LC [36
], which are important opioid and noradrenaline producing site in the CNS, respectively.
BVA induced analgesia was shown to be mediated by spinal α2
-adrenergic receptor [11
], and it increased c-Fos expression in LC and A5 cell group (A5) [37
]. Moreover, BVA reduced c-Fos expression in the spinal dorsal horn of rats with formalin or acetic acid-induced pain [13
]. Considering that both the LC and A5 are part of the descending noradrenergic pathway [40
], it is suggested that BVA suppresses conduction of afferent nociceptive signals in the spinal dorsal horn affecting descending noradrenergic pathway. Our data are consistent with previous studies showing that spinal α2
-adrenergic receptor mediates BVA-induced analgesia. Furthermore, the pain attenuating effect of melittin was also blocked by spinal α2
-adrenergic receptor antagonist (idazoxan) showing that melittin, the richest component of the BV, also acts on spinal α2
-adrenergic receptor to inhibit mechanical hyperalgesia induced by paclitaxel.
Drug combination is widely used to treat dreadful diseases, such as AIDS and cancer. The main aim of drug combination is to reduce dose and toxicity, and to delay the induction of drug resistance. Our previous study showed the combined effect of BVA and morphine on oxaliplatin-induced neuropathic pain [12
]. BVA treated with morphine showed prolonged analgesic effects compared to the BVA or morphine alone. Moreover, another article showed that BVA could enhance the analgesic effect of intrathecal injection of clonidine in chronic constriction injury-induced neuropathic pain model [41
]. Because such combined effect on paclitaxel-induced neuropathic pain has yet to be studied, further studies are needed to examine the combined effect of BVA with other drugs, like morphine, clonidine, SSRI, SNRI, gabapentin, and cannabinoid. Furthermore, in the future studies, it will be interesting to investigate the effect of various components of the BVA on paclitaxel-induced neuropathic pain model, as several active components exist in the BV, such as melittin [42
] and PLA2 [30
], which have been reported to be effective in other pain models.