PubMed · 8190618
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B Johansson. 1994. [Backache--current orthopedic viewpoints].. https://pubmed.ncbi.nlm.nih.gov/8190618/
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Several isoforms of neuronal nitric oxide synthase (nNOS) have been identified. Antisense approaches have been developed which can selectively down-regulate nNOS-1, which corresponds to the full-length nNOS originally cloned from the brain, and nNOS-2, a truncated form lacking two exons which is generated by alternative splicing, as demonstrated by decreases in mRNA levels. Antisense treatment also lowers nNOS enzymatic activity. Down-regulation of nNOS-1 prevents the development of morphine tolerance. Whereas morphine analgesia is lost in control and mismatch-treated mice given daily morphine injections for 5 days, mice treated with antisense probes targeting nNOS-1 show no decrease in their morphine sensitivity over the same time period. Conversely, an antisense probe selectively targeting nNOS-2 blocks morphine analgesia, shifting the morphine dose-response curve over 2-fold to the right. Both systems are active at the spinal and the supraspinal levels. An antisense targeting inducible NOS is inactive. Studies with NG-nitro-L-arginine, which does not distinguish among NOS isoforms, indicate that the facilitating nNOS-2 system predominates at the spinal level while the inhibitory nNOS-1 system is the major supraspinal nNOS system. Thus, antisense mapping distinguishes at the functional level two isoforms of nNOS with opposing actions on morphine actions. The ability to selectively down-regulate splice variants opens many areas in the study of nNOS and other proteins.
Recent work has suggested that heroin and morphine-6beta-glucuronide (M6G) both act through a novel mu opioid receptor subtype distinct from those mediating morphine's actions. This very high affinity 3H-M6G site is selectively competed by 3-methoxynaltrexone. In vivo, 3-methoxynaltrexone (2.5 ng, i.c.v.) selectively antagonizes the analgesic actions of heroin and M6G without interfering with mu (morphine and [D-Ala2,MePhe4,Gly(ol)5]enkephalin), delta ([D-Pen2,D-Pen5]enkephalin), kappa1 (U50,488H) or kappa3 (naloxone benzoylhydrazone) analgesia. In dose-response studies, 3-methoxynaltrexone (2.5 ng, i.c.v.) significantly shifted the ED50 values for heroin and its active metabolite, 6-acetylmorphine, without affecting the morphine curve. These results indicate that 3-methoxynaltrexone selectively blocks a novel 3H-M6G binding site which is responsible for the analgesic actions of heroin and M6G. This ability to selectively antagonize heroin actions opens new possibilities in the development of therapeutics for the treatment of opioid abuse.
The present study was designed to investigate a role of the subnucleus reticularis dorsalis (SRD) in the analgesia produced by a low dose of naloxone during carrageenan-induced inflammation. Male Sprague-Dawley rats were divided into the following two groups: (1) rats with bilateral lesions of the SRD (n = 13) and 2) sham-operated rats (n = 24). In each group, effects of a low dose of naloxone (5 microg/kg, i.p.) on thermal nociception were examined 4 h, 7 and 28 days after the induction of unilateral inflammation. Carrageenan (6 mg in 0.15 ml saline) was injected subcutaneously into the plantar surface of the left hindpaw. The analgesic effect was assessed by prolongation of the paw withdrawal latency (PWL) to heating. Prior to carrageenan injection, a low dose of naloxone did not prolong PWLs in either group. Four hours after carrageenan, a low dose of naloxone produced a prolongation of PWLs in both sham-operated and SRD-lesioned rats. Seven days after carrageenan, naloxone failed to produce analgesia in the SRD-lesioned rats but did produce analgesia in the sham-operated rats. At 28 days, a low dose of naloxone induced hyperalgesia in the inflamed paw of both groups, whereas naloxone was ineffective in the contralateral non-inflamed paw. These results suggest that the SRD plays a role in naloxone-induced analgesia during the subacute phase of inflammation (e.g. 7 days after induction of inflammation).