Bee venom injection produces a peripheral anti-inflammatory effect by activation of a nitric oxide-dependent spinocoeruleus pathway.
Our recent data, obtained using a zymosan-induced inflammatory air pouch model in mice, have demonstrated that subcutaneous bee venom (BV) injection into the hind limb selectively activates the contralateral brain stem locus coeruleus (LC) and then via a descending noradrenergic pathway and subsequent adrenal medullary catecholamine release induces a potent anti-inflammatory effect. While the efferent limb of this BV-induced neuroimmune anti-inflammatory pathway is well documented, the afferent limb of this pathway is poorly understood. In particular the spinal mechanisms involved with BV activation of the LC are currently unknown. Spinal nitric oxide (NO) and its synthase (NOS) have been shown to play an important role in the transmission and amplification of neuronal information from the spinal cord to the brain stem. In the present study we evaluated whether spinal NO plays a role in BV-induced LC activation, since we have previously shown that LC activation underlies this 'BV-induced anti-inflammatory effect' (BVAI) using the mouse air pouch model. Intrathecal (i.t.) pretreatment with l-nitro arginine methyl ester (l-NAME, non-selective NOS inhibitor), hemoglobin (NO scavenger) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, soluble guanylate cyclase inhibitor) abolished BVAI on zymosan-induced leukocyte migration into the air pouch. Moreover, i.t. injection of l-N-iminoethyl-lysine (l-NIL, inducible NOS inhibitor), but not 7-nitroindazole (7-NI, neuronal NOS inhibitor), also inhibited BVAI. BV injection significantly increased both the number of Fos immunoreactive neurons and tyrosine hydroxylase-Fos double labeling neurons in the contralateral LC in zymosan-induced inflamed mice. Importantly this increase in Fos expression in the LC was also completely inhibited by i.t. injection of l-NIL, but not by i.t. injection of 7-NI. Collectively these results indicate that spinal NO generated from inducible NOS is involved in the BV-induced LC activation that underlies BVAI.
Yoon
Seo-Yeon
SY
Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwang-ju, South Korea.
Kwon
Young-Bae
YB
Kim
Hyun-Woo
HW
Roh
Dae-Hyun
DH
Seo
Hyoung-Sig
HS
Han
Ho-Jae
HJ
Lee
Hye-Jung
HJ
Beitz
Alvin J
AJ
Lee
Jang-Hern
JH
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001514:Bee Venoms / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects; D008125:Locus Coeruleus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001514:Bee Venoms; D004791:Enzyme Inhibitors; D007191:Indazoles; D016761:Oncogene Proteins v-fos; D009569:Nitric Oxide; D014446:Tyrosine 3-Monooxygenase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester