Acid-catalyzed addition of methanol to 1 occurs by rupture of the internal carbon-carbon bond of the cyclopropane to give 2 with both retention and inversion at the site of electrophilic attack (4:5, 1.3:1.0). Nucleophilic attack occurs with inversion without relaxation of the corner-and edgeprotonated cyclopropanes to a secondary cation.

Although dynorphin A-(1-17) has been characterized in vitro as a high efficacy kappa-opioid receptor agonist, functional studies of dynorphin A-(1-17) following central or systemic administration indicate the involvement of both opioid and non-opioid components. The aim of this study was to investigate whether local administration of dynorphin-related analogs can attenuate capsaicin (8-methyl-N-vanillyl-6-nonenamide)-induced nociception and what type of opioid receptor mediates the local action of dynorphin A-(1-17) in monkeys. Capsaicin (100 microg) was used to evoke a nociceptive response, thermal allodynia, which was manifested as a reduced tail-withdrawal latency in normally innocuous 46 degrees C warm water. Co-administration of dynorphin A-(1-17) (0.3-10 microg) with capsaicin in the tail dose-dependently inhibited thermal allodynia; however, both non-opioid fragments dynorphin A-(2-17) (10-300 microg) and dynorphin A-(2-13) (10-300 microg) were ineffective. Local antiallodynia of dynorphin A-(1-17) was antagonized by a small dose (100 microg) of an opioid receptor antagonist, quadazocine, applied s.c. in the tail. Pretreatment with a selective kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), s.c. 320 microg in the tail also reversed local antiallodynia of dynorphin A-(1-17). Both locally effective doses of antagonists, when applied s.c. in the back, did not antagonize local dynorphin A-(1-17), indicating that peripheral kappa-opioid receptors selectively mediated the local action of dynorphin A-(1-17) in the tail. In addition, a much larger dose of dynorphin A-(1-17) (1000 microg), when administered s. c. in the back or i.m. in the thigh, did not cause sedative or diuretic effects. These results suggest that in vivo opioid actions of dynorphin-related peptides can be differentiated locally in this procedure. They also indicate that local application of peptidic ligands may be a useful medication for localized pain.

A recent review calls attention to the discrepant results resulting from studies that have examined the nociceptive or antinociceptive properties of orphanin-FQ/nociceptin (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-ArgLys-Leu-Ala-Asn-Gln; OFQ/N), the heptadecapeptide isolated from rat (nociceptin) and pig (orphanin FQ) brain that binds with high affinity to the opioid 'orphan' receptor (a seven transmembrane protein with sequence homology to opioid receptors), but exhibits only low affinity binding with conventional opioid ligands. Some of the discrepancy might result from differences in species, test, route of administration or time-course. We undertook a comprehensive examination of the effects of spinal (i.t.) or supraspinal (i.c.v.) administration of OFQ/N in mice and rats. Mice treated with OFQ/N either i.t. or i.c.v. demonstrated no significant nociceptive effect in the hot plate, warm-water or radiant heat tail-flick tests (except for the highest and most sedative dose of 10 nmol i.c.v. in the mouse warm-water tail-flick test). Pretreatment with the opioid antagonist naloxone or with peptidase inhibitors did not enhance the nociceptive effects of OFQ/N peptide in the warm-water tail-flick test. The motor activity in mice administered OFQ/N i.c.v. decreased significantly compared to controls. Rats administered i.c.v. or i.t. OFQ/N displayed no significant difference from vehicle-treated animals in similar noxious stimulus tests and OFQ/N-treated rats did not exhibit allodynia in a paw-withdrawal test. Overall, OFQ/N was ineffective in significantly altering response to noxious stimuli, regardless of whether the peptide was given at supraspinal or spinal sites in mice or in rats. In addition, i.c.v. or i.t. application of antisense or mismatch ODN to the orphan receptor did not modify tail-flick latency in either mice or rats, arguing against a tonic nociceptive tone mediated via the OFQ/N receptor.

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