Opioid analgesics with restricted access to the central nervous system represent a new approach to the treatment of severe pain with an improved safety profile. The objective of this study was to investigate the peripheral and central components of the antinociceptive actions of the 6-amino acid conjugates (glycine, alanine, and phenylalanine) of 14-O-methyloxymorphone. Their antinociceptive activities were compared with those of the centrally penetrating mu-opioid agonists morphine, fentanyl, and 14-O-methyloxymorphone. In the tail-flick test in rats, the 6-amino acid conjugates were 45- to 1170-fold more potent than morphine after i.c.v. administration and 19- to 209-fold after s.c. administration. They showed potencies similar to fentanyl after s.c. administration and were more potent after i.c.v. application. The time course of action was different between s.c. and i.c.v. administration, with significant long-lasting effects after i.c.v. administration. Systemic administration of the peripherally selective opioid antagonist naloxone methiodide antagonized the effects after s.c. but not after i.c.v. administration in the tail-flick test. Subcutaneous 6-amino acid derivatives also elicited antihyper-analgesic effects in the formalin test in rats, which were reversed by systemically administered naloxone methiodide. Although morphine exerts its analgesic effects by central and peripheral mechanisms, the investigated new opioids interact primarily with peripheral opioid receptors after s.c. administration. The present data indicate that the 6-amino acid conjugates of 14-O-methyloxymorphone have limited access to the central nervous system and can mediate antinociception at peripheral sites. Also, they might find clinical application when the central actions of opioids are unwanted.

Although nitrate therapy, used in the treatment of cardiovascular disorders, is frequently associated with side‐effects, mainly headaches, the summaries of product characteristics of nitrate‐containing medicines do not report detailed description of headaches and even do not highlight the possibility of nitrate‐induced migraine. Two different types of nitrate‐induced headaches have been described: (i) immediate headaches that develop within the first hour of the application, are mild or medium severity without characteristic symptoms for migraine, and ease spontaneously; and (ii) delayed, moderate or severe migraine‐type headaches (occurring mainly in subjects with personal or family history of migraine), that develop 3–6 h after the intake of nitrates, with debilitating, long‐lasting symptoms including nausea, vomiting, photo‐ and/or phono‐phobia. These two types of headaches are remarkably different, not only in their timing and symptoms, but also in the persons who are at risk. Recent studies provide evidence that the two headache types are caused by different mechanisms: immediate headaches are connected to vasodilation caused by nitric oxide (NO) release, while migraines are triggered by other actions such as the release of calcitonin gene‐related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S‐nitrosylation. Migraines usually need anti‐attack medication, such as triptans, but these drugs are contraindicated in most medical conditions that are treated using nitrates. In conclusion, these data recommend the correction of summaries of nitrate product characteristics, and also suggest a need to develop new types of anti‐migraine drugs, effective in migraine attacks, that could be used in patients with risk for angina pectoris.

When the opioid agonist morphine is given chronically and systemically to mice by pellet implantation for 3 days, the animals develop substantial tolerance to the antinociceptive effect of a test dose of morphine given systemically. When the test dose is administered to the spinal cord, however, very little tolerance is observed. We tested six strains of mice differing in the degree to which they develop systemic tolerance to morphine and found that none of them developed significant tolerance to spinal morphine. However, most of these strains did develop substantial spinal tolerance to antinociception induced by the selective μ-agonist [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO) and by the selective δ-agonist [d-Pen²,d-Pen⁵]-enkephalin (DPDPE). Moreover, in naı̈ve animals, the antinociceptive effect of both DAMGO and DPDPE was blocked byd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH₂, a selective μ-antagonist, indicating that both agonists mediate antinociception in the spinal cord through μ-receptors. In addition to directly mediating antinociception, however, DPDPE potentiated the antinociceptive activity of DAMGO in the spinal cord of naı̈ve animals, and this antinociception was blocked by the δ-antagonist H-TyrTicPsi[CH₂NH]Phe-Thr-OH (TIPPψ), indicating mediation through δ-receptors. In contrast, in tolerant animals, TIPPψ enhanced the antinociception of DAMGO. These results thus demonstrate not only that μ- and δ-opioid receptors interact in naı̈ve animals, but that the nature of this interaction changes during tolerance, from a potentiation to an inhibition. The lack of tolerance to spinal morphine may result from the ability of morphine to act as a partial antagonist at δ-receptors.