PubMed · 14159595
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R B CAPPS. 1964. ACUTE HEPATITIS.. https://pubmed.ncbi.nlm.nih.gov/14159595/
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UNLABELLED: Elevations in nitric oxide (NO) have been implicated in the development of morphine antinociceptive tolerance. This study was conducted to establish the role of specific isoforms of NO synthase (NOS) in morphine tolerance development using genetically modified mice. METHODS: Three groups of mice (endothelial NOS [eNOS]-deficient, neuronal NOS [nNOS]-deficient, and NOS-competent) were used in this experiment. On Day 1, the analgesic response (radiant heat tail-flick) to a challenge dose of morphine (4 mg/kg) was determined over 3 hr. Tolerance was induced on Days 1-5 by administering morphine subcutaneously (10 mg/kg) or L-arginine, a NO precursor, intraperitoneally (200 mg/kg), twice daily. Analgesic response to the challenge dose was determined again on Day 6. RESULTS: Following sustained morphine administration, nNOS-deficient mice exhibited less tolerance development when compared to the control group, although measurable tolerance still occurred. Mice deficient in eNOS evidenced a degree of tolerance similar to that of control. Prolonged L-arginine administration produced significant functional tolerance to morphine in NOS-competent and eNOS-deficient mice. The loss of morphine responsivity after L-arginine administration was similar to that after morphine pretreatment. L-Arginine did not affect the antinociceptive response to morphine in mice deficient in nNOS, suggesting that the small degree of morphine-induced tolerance in this group occurs through an alternate pathway. CONCLUSIONS: These data demonstrate the pivotal role of the neuronal isoform of NOS in development of morphine antinociceptive tolerance. Furthermore, tolerance development appears to be predominantly a NO-mediated process, but likely is augmented by a secondary (non-NO) pathway.
Although tricyclic antidepressants are among the drugs of choice for the treatment of neuropathic pain, their mechanism of action in this regard remains unknown. Because previous reports suggest these agents may influence gamma-aminobutyric acid (GABA) neurotransmission, and GABAB receptors are known to participate in the transmission of pain impulses, the present experiments were undertaken to examine whether the administration of desipramine alters GABAB receptor subunit expression and function in the dorsal horn of the rat spinal cord. For the study, rats were injected (i.p.) once daily with desipramine (15 mg/kg) for 7 consecutive days, during which their thermal withdrawal threshold was monitored, and after which GABAB receptor function, and the levels of GABAB receptor subunit mRNA, were quantified in the spinal cord dorsal horn. The results indicate that 4-7 days of continuous administration of desipramine are necessary to observe a significant increase in the thermal pain threshold. Moreover, it was found that 7 days of treatment with desipramine enhances GABAB receptor function, as measured by baclofen-stimulated [35S]GTPgammaS binding, and increases mRNA expression for the GABAB(1a) and GABAB(2), but not GABAB(1b), subunits. These findings suggest the antinociceptive effect of desipramine is accompanied by a change in spinal cord GABAB receptor sensitivity that could be an important component in the analgesic response to this agent.
The involvement of putative mu(1)-opioid receptors in the antinociception induced by the dermorphin tetrapeptide analogues Try-D-Arg-Phe-beta-Ala (TAPA) and Tyr-D-Arg-Phe-beta-Ala-NH(2) (TAPA-NH(2)) was determined in mice, using a tail-pressure test and a formalin test. TAPA and TAPA-NH(2) injected i.c.v. and i.t. produced dose-dependent antinociception in both assays. In the tail-pressure test, the antinociception induced by i.c.v. or i.t. injected TAPA, but not TAPA-NH(2), was significantly attenuated by pretreatment with naloxonazine, a selective antagonist for putative mu(1)-opioid receptors. Moreover, naloxonazine also significantly attenuated the antinociception induced by i.c.v. injected TAPA, but not TAPA-NH(2), in the formalin test. In contrast, the antinociception induced by both TAPA and TAPA-NH(2) given i.t. was significantly attenuated by pretreatment with naloxonazine in the formalin test. The present results suggest that TAPA and TAPA-NH(2) should be considered selective agonists for putative mu(1)- and mu(2)-opioid receptors, respectively. The C-terminal amidation of TAPA-NH(2) may be critical for distinguishing between putative mu(1)- and mu(2)-opioid receptors.