Orphanin FQ or nociceptin (OFQ/N(1-17)) is a recently discovered peptide which, upon intracerebroventricular administration, reverses opioid-mediated analgesias. OFQ/N(1-17) terminals are located in the periaqueductal gray (PAG), a structure known to be involved in pain modulation, suggesting that the functional anti-opioid effects of OFQ/N(1-17) are mediated by PAG neurons. To test this, subsequent microinjections of morphine or kainic acid and OFQ/N(1-17) were made into the PAG of awake rats. Administration of OFQ/N(1-17) attenuated the tail flick inhibition produced by both morphine and kainic acid microinjection. OFQ/N(1-17) attenuation of antinociception produced by a neuroexcitant indicates that OFQ/N(1-17) reverses opioid antinociception by inhibiting PAG output neurons.
Tolerance to the antinociceptive effect of morphine is mediated at least in part by morphine's action within the periaqueductal gray (PAG). The objective of the present study was to determine whether both ventral and lateral-dorsal PAG regions contribute to the development of tolerance. It was found that the antinociceptive efficacy of microinjecting morphine (5 microg/0.4 microl) into the ventral but not the lateral-dorsal PAG diminished with successive injections. Control experiments indicated that this decrease was caused by tolerance to morphine and was not a result of cell death caused by repeated microinjections or habituation from repeated behavioral testing. The finding of greater susceptibility of the ventral compared with the lateral-dorsal PAG to the development of tolerance adds to a growing literature distinguishing antinociception from these two regions.
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