The heme oxygenase-carbon monoxide pathway has been shown to play an important role
in many physiological processes and is capable of altering nociception modulation in
the nervous system by stimulating soluble guanylate cyclase (sGC). In the central
nervous system, the locus coeruleus (LC) is known to be a region that expresses the
heme oxygenase enzyme (HO), which catalyzes the metabolism of heme to carbon monoxide
(CO). Additionally, several lines of evidence have suggested that the LC can be
involved in the modulation of emotional states such as fear and anxiety. The purpose
of this investigation was to evaluate the activation of the heme oxygenase-carbon
monoxide pathway in the LC in the modulation of anxiety by using the elevated plus
maze test (EPM) and light-dark box test (LDB) in rats. Experiments were performed on
adult male Wistar rats weighing 250-300 g (n=182). The results showed that the
intra-LC microinjection of heme-lysinate (600 nmol), a substrate for the enzyme HO,
increased the number of entries into the open arms and the percentage of time spent
in open arms in the elevated plus maze test, indicating a decrease in anxiety.
Additionally, in the LDB test, intra-LC administration of heme-lysinate promoted an
increase on time spent in the light compartment of the box. The
intracerebroventricular microinjection of guanylate cyclase, an sGC inhibitor
followed by the intra-LC microinjection of the heme-lysinate blocked the
anxiolytic-like reaction on the EPM test and LDB test. It can therefore be concluded
that CO in the LC produced by the HO pathway and acting via cGMP plays an
anxiolytic-like role in the LC of rats.
Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 39,59-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress.
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