PubMed · 6960121
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M Keeri-Szanto. 1982. Demand analgesia.. https://pubmed.ncbi.nlm.nih.gov/6960121/
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A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Try-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.
The contribution of a peripheral action of morphine in the augmented antinociceptive effect of this substance was re-evaluated in a well established rat model of peripheral unilateral mononeuropathy (chronic constriction of the common sciatic nerve), using a relatively low dose of systemic morphine (1 mg/kg i.v.) and local low doses of specific antagonists of kappa- (nor-binaltorphimine) or delta-(naltrindole) opioid receptors. Vocalization thresholds to paw pressure were used as a nociceptive test. Escalating doses of nor-binaltorphimine (10-30 micrograms injected locally into the nerve injured paw) significantly and dose dependently reduced the effect of morphine on this paw but not on the contralateral paw, an effect which plateaued at 30 micrograms. By contrast, the local injection of naltrindole (30-40 micrograms into the nerve injured paw) had no effect on morphine analgesia. The doses of opioid receptor antagonists used, injected i.v., in the contralateral paw, or alone in the nerve injured paw had no significant effect. These results suggest that the peripheral effect of systemic morphine in this model of neuropathic pain could be mediated not only by mu- but also by kappa-opioid receptors.
The effects of peptidase inhibitors on the antinociceptive induced by intrathecally (i.t.) administered by dynorphin A and dynorphin B in the mouse formalin test were examined. When administered i.t. 5 min before the injection of 0.5% formalin solution into the dorsal surface of a hindpaw, dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) produced a dose-dependent and significant reduction of the paw-licking response. Dynorphin A (2 nmol) and dynorphin B (8 nmol)-induced antinociception disappeared completely within 90 min and 60 min, respectively. p-Hydroxymercuribenzoate, a cysteine proteinase inhibitor, and phosphoramidon, and endopeptidase 24.11 inhibitor simultaneously administered with dynorphin A or dynorphin B. Significantly prolonged antinociception induced by both dynorphins. However, captopril, and angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine proteinase inhibitor phenylmethanesulfonyl fluoride, were active. Dynorphin converting enzyme(s) transform dynorphin-related peptides to [Leu5]enkephalin and [Leu5]enkephalin-Arg6. Neither [Leu5]enkephalin nor [Leu5]enkephalin-Arg6, even at high dose (10 nmol), produced any antinociceptive effect. However, [Leu5[enkephalin-Arg6, but not [Leu5]enkephalin, produced a significant antinociceptive effect when co-administered with phosphoramidon. Therefore, the prolongation of the antinociception induced by both dynorphins in the presence of phosphoramidon, may be due to inhibition of [Leu5]enkephalin-Arg6 degradation. The present results indicate that dynorphin-converting enzyme(s) may be important enzyme(s) responsible for terminating dynorphin-A- and dynorphin-B-induced antinociception at the spinal cord level in mice.