Abstract
Because nociceptin/orphanin FQ (N/OFQ) has both pronociceptive (hyperalgesia) and antinociceptive actions in pharmacological experiments, and there is no significant difference in the nociceptive responses between NOP−/− mice and their wild-type (NOP+/+) littermates, the physiological role of N/OFQ in pain regulation remains to be determined. Under the hypothesis that the use of molecularly distinct nociception test may reveal the pain modality-specific role of N/OFQ, we attempted to examine the physiological role of N/OFQ in pain transmission by using newly developed algogenic-induced nociceptive flexion test in NOP−/− and NOP+/+ mice or NOP antagonist-treated mice. The nociceptive flexor responses upon intraplantar injection of bradykinin or substance P, which stimulates polymodal substance P-ergic fibers, were markedly potentiated in NOP−/− mice, compared with those in its NOP+/+ mice. However, there were no significant changes in NOP−/− mice with adenosine triphosphate or prostaglandin I2 agonist, which stimulates glutamatergic but not substance P-ergic fibers. The nocifensive responses induced by substance P (i.t.) were also potentiated in NOP−/− mice. On the other hand, there were no significant differences in NK1-like immunoreactivity, [3H]substance P binding, or NK1 gene expression in the dorsal horn of the spinal cord between NOP−/− and NOP+/+ mice. In addition, NOP antagonists decreased the threshold in nociception tests driving spinal substance P neurotransmission. All these findings suggest that the N/OFQ-ergic neuron may play an in vivo inhibitory role on the second-order neurons for primary polymodal substance P-ergic fibers in the spinal cord.
Footnotes
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Parts of this study were supported by Special Coordination Funds of the Science and Technology Agency of the Japanese Government, Research Grant from Environmental Agency, Government of Japan, grants-in-aid from the Ministry of Education, Science, Culture and Sports of Japan, and a grant for Human Frontier Science Program.
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DOI: 10.1124/jpet.102.046326
- Abbreviations:
- N/OFQ
- nociceptin/orphanin FQ
- NOP
- nociceptin/orphanin FQ peptide receptor
- MK-801
- (−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
- ANF
- algogenic-induced nociceptive flexion
- i.pl.
- intraplantar injection
- SBL
- scratching, biting, and licking
- RT-PCR
- reverse transcription-polymerase chain reaction
- ABL
- algogenic-induced biting and licking
- NMDA
- N-methyl-d-aspartate
- CNQX
- 6-cyano-2,3-dihydroxy-7-nitroquinoxaline
- ONO-54918-07
- 15-cis-(4-n-propylclohexyl)-16,17.18,19.20-pentanor-9-deoxy-6,9-α-nitriloprostaglandin F1
- CP-99994
- (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine
- Received October 30, 2002.
- Accepted January 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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