Abstract
Intracerebroventricular injection of orexin-A (hypocretin-1) has been shown to elicit
the analgesic responses. However, the locations of central sites that may mediate
these effects have not been clearly elucidated. This study was performed using male
Sprague Dawley rats to investigate the antinociceptive effects of intra-periaqueductal
gray matter (PAG) administration of orexin-A, 5 minutes prior to formalin (50 μL of
2%) injection. Orexin-A had no effect on tail-flick test as thermal and acute model.
In the formalin test, intra-PAG injection of orexin-A (10 nM) decreased the formalin-induced
nociceptive behaviors in the interphase and phase 2, but not in phase 1, indicating
an antinociceptive role of exogenous orexin-A in the PAG. While Orexin-A failed to
produce a dose-dependent decrease in formalin-evoked behaviors in phase 1, it may
have induced a dose-dependent decrease in formalin-evoked behaviors in early phase
2. Control injections of orexin-A into the sites near the PAG resulted in less or
no reduction in pain, indicating that the analgesia observed is probably due to a
site of action within the PAG rather than at surrounding neural structures. The antinociceptive
effect of orexin-A was compared with intra-PAG administration of morphine (.5 μL of
20 mM, 5 minutes before the formalin injection). Morphine decreased the formalin-induced
nociceptive behaviors in all phases. To investigate whether the orexin has a special
action on the early part of the second phase, or its delayed effects are related to
its pharmacokinetics, the orexin-A was injected into the PAG, 10 minutes before the
formalin injection. No difference was observed between 5 and 10 minutes injection
of orexin-A prior to formalin injection. The antinociceptive effect of orexin was
blocked by intra-PAG injection of SB-334867, a putative type 1 orexin receptor antagonist,
suggesting the involvement of orexin receptor type 1 in antinociception produced with
intra-PAG injection of orexin-A. The results showed that the orexin-A plays an antinociceptive
role in PAG in the interphase and the late phase of formalin test through type 1 orexin
receptor dependent mechanism.
Perspective
Orexin is produced exclusively in the lateral hypothalamus, where it is known to modulate
the pain processing through PAG. The antinociceptive effect of orexin in PAG may provide
a role for this neurotransmitter in the up-down modulating pain system and further
support the development of orexin-1 agonists for pain treatment.
Key words
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Article info
Publication history
Published online: December 13, 2010
Accepted:
September 17,
2010
Received in revised form:
July 21,
2010
Received:
March 9,
2010
Footnotes
Supported by grants from the Neuroscience Research Center, Shahid Beheshti University, and Iran National Science Foundation (INSF), Tehran, Iran.
Identification
Copyright
© 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.
