Repetitive treatment with diluted bee venom reduces neuropathic pain via potentiation of locus coeruleus noradrenergic neuronal activity and modulation of spinal NR1 phosphorylation in rats.
We previously demonstrated that a single injection of diluted bee venom (DBV) temporarily alleviates thermal hyperalgesia, but not mechanical allodynia, in neuropathic rats. The present study was designed to determine whether repetitive injection of DBV produces more potent analgesic effects on neuropathy-induced nociception and whether those effects are associated with increased neuronal activity in the locus coeruleus (LC) and with the suppression of spinal NMDA receptor NR1 subunit phosphorylation (pNR1). DBV (.25 mg/kg) was administered subcutaneously twice a day for 2 weeks beginning on day 15 post-chronic constrictive injury surgery. Pain responses were examined and potential changes in LC Fos expression and spinal pNR1 expression were determined. Repetitive DBV administration significantly reduced mechanical allodynia, as well as thermal hyperalgesia. The activity of LC noradrenergic neurons was increased and spinal pNR1 expression was significantly suppressed by repetitive DBV as compared with those of vehicle or single DBV injection. These suppressive effects of repetitive DBV on neuropathic pain and spinal pNR1 were prevented by intrathecal pretreatment of idazoxan, an alpha-2 adrenoceptor antagonist. These results indicate that repetitive DBV produces potent analgesic effects on neuropathic pain and this is associated with the activation of the LC noradrenergic system and with a reduction in spinal pNR1.


CONCLUSIONS
The results of current study demonstrate that repetitive administration of DBV significantly suppresses neuropathic pain. Furthermore, this study provides mechanistic information that repetitive treatment of DBV can produce more potent analgesic effect than single DBV treatment, indicating a potential novel strategy for the management of chronic pain.
Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea.
Suk-Yun
SY
Kang
Dae-Hyun
DH
Roh
Seo-Yeon
SY
Yoon
Ji-Young
JY
Moon
Hyun-Woo
HW
Kim
Hye-Jung
HJ
Lee
Alvin J
AJ
Beitz
Jang-Hern
JH
Lee
D059331:Adrenergic Neurons / Q000187:drug effects* / Q000648:ultrastructure; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001514:Bee Venoms / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D019329:Idazoxan / Q000494:pharmacology; D008125:Locus Coeruleus / Q000473:pathology*; D008297:Male; D016253:Microscopy, Immunoelectron; D009043:Motor Activity / Q000187:drug effects; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D045442:Rotarod Performance Test; D012585:Sciatica / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D058669:Adrenergic alpha-2 Receptor Antagonists; D018712:Analgesics, Non-Narcotic; D001514:Bee Venoms; C409466:NR1 NMDA receptor; D016761:Oncogene Proteins v-fos; D016194:Receptors, N-Methyl-D-Aspartate; D014446:Tyrosine 3-Monooxygenase; D019329:Idazoxan