Nucleic acid deletions and copy number in rats.

Rats fed either a cereal-based or purified diet of variable folate content (deficient, replete, or supplemented) inadvertently were infected with sialodacryoadenitis virus, which resulted in an increased frequency of hepatic mitochondrial DNA (mtDNA) deletions that persisted for three weeks after the period of acute signs of disease. The amount of the "common deletion" (4.8 kb, bases 8103-12937) in liver was measured by quantitative co-amplification of the mitochondrial D-loop and the mitochondrial deletion, using a real-time quantitative polymerase chain reaction assay. The relative abundance of mtDNA was determined by co-amplifying mitochondrial D-loop versus the rat beta-actin gene. Virus-infected rats had more mtDNA deletions (P < 0.0001) and higher copy number (P < 0.0001) than did uninfected animals. There was no effect of diet on frequency of deletions. Diet affected mtDNA relative abundance in the infected, but not the uninfected rats. Relative abundance was higher (P = 0.004) in rats of the high folate group than in rats of the low-folate or folate-replete groups, and was significantly higher in rats of the cereal diet group than that in those of the purified diet group. In conclusion, sialodacryoadenitis virus infection in rats was associated with increased frequency of hepatic mtDNA deletions. Thus, sialodacryoadenitis virus infection mitigated biological processes in the liver of rats, and mtDNA damage was modulated by diet.

Histamine-induced modulation of nociceptive responses.

Because previous studies suggest an antinociceptive role for the neuromodulator histamine (HA) in the periaqueductal grey or the nearby dorsal raphe (PAG/DR), a detailed pharmacological investigation of the effects of intracerebral HA on the hot-plate nociceptive test was performed in rats. Intracerebral microinjections of HA (1 microgram) into the PAG/DR or into the median raphe evoked a mild, reversible antinociceptive response; injections into lateral or dorsal midbrain evoked either a delayed response or no response, respectively. In the PAG/DR, the HA dose-response curve had an inverted U-shape, showing that HA can induce both antinociceptive (0.3-3 micrograms) and pro-nociceptive (10-30 micrograms) responses. Larger doses of HA (e.g., 100 micrograms) produced irreversible and highly variable antinociceptive responses that were accompanied by behavioral and histopathological changes; such effects, indicative of toxicity, were not observed after 0.3 microgram of HA, the peak antinociceptive dose. HA (0.3 microgram) antinociception was completely inhibited by intracerebral co-administration of the opiate antagonist naloxone (1 ng), the H1-receptor antagonist temelastine (20 pg), and the H2-receptor antagonist tiotidine (1 ng); none of these drugs altered nociceptive scores in the absence of HA. These results show that: (1) HA, a neurotransmitter in the PAG, can evoke antinociception in the absence of other behavioral or toxic effects; and (2) HA antinociception depends on the activation of both opiate and HA receptors in the PAG/DR.(ABSTRACT TRUNCATED AT 250 WORDS)