Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala.
Clinically, it has been reported that chronic pain induces depression, anxiety, and reduced quality of life. The endogenous opioid system has been implicated in nociception, anxiety, and stress. The present study was undertaken to investigate whether chronic pain could induce anxiogenic effects and changes in the opioidergic function in the amygdala in mice. We found that either injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by sciatic nerve ligation produced a significant anxiogenic effect at 4 weeks after the injection or surgery. Under these conditions, the selective mu-opioid receptor agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO)- and the selective delta-opioid receptor agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)-stimulated [35S]GTPgammaS binding in membranes of the amygdala was significantly suppressed by CFA injection or nerve ligation. CFA injection was associated with a significant increase in the kappa-opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride (ICI199,441)-stimulated [35S]GTPgammaS binding in membranes of the amygdala. The intracerebroventricular administration and microinjection of a selective mu-opioid receptor antagonist, a selective delta-opioid receptor antagonist, and the endogenous kappa-opioid receptor ligand dynorphin A caused a significant anxiogenic effect in mice. We also found that thermal hyperalgesia induced by sciatic nerve ligation was reversed at 8 weeks after surgery. In the light-dark test, the time spent in the lit compartment was not changed at 8 weeks after surgery. Collectively, the present data constitute the first evidence that chronic pain has an anxiogenic effect in mice. This phenomenon may be associated with changes in opioidergic function in the amygdala.
Narita
Minoru
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan. narita@hoshi.ac.jp
Kaneko
Chihiro
C
Miyoshi
Kan
K
Nagumo
Yasuyuki
Y
Kuzumaki
Naoko
N
Nakajima
Mayumi
M
Nanjo
Kana
K
Matsuzawa
Kiyomi
K
Yamazaki
Mitsuaki
M
Suzuki
Tsutomu
T
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000701:Analgesics, Opioid; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000209:etiology* / Q000378:metabolism*; D001522:Behavior, Animal; D001549:Benzamides / Q000008:administration & dosage; D002908:Chronic Disease; D003975:Diazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004399:Dynorphins / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage; D005620:Freund's Adjuvant; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D010879:Piperazines / Q000008:administration & dosage; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012585:Sciatica / Q000209:etiology / Q000503:physiopathology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D014149:Tranquilizing Agents / Q000494:pharmacology
D000701:Analgesics, Opioid; D001549:Benzamides; D009292:Narcotic Antagonists; D009294:Narcotics; D010879:Piperazines; D011759:Pyrrolidines; D013460:Sulfur Isotopes; D014149:Tranquilizing Agents; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C058468:ICI 199441; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013004:Somatostatin; D009271:Naltrexone; D004399:Dynorphins; D005620:Freund's Adjuvant; C044610:etizolam; C055382:naltrindole; D003975:Diazepam