enkephalin--ala(2)-mephe(4)-gly(5)- and Edema

Stimulation of the saphenous nerve in the anaesthetised rat results in cutaneous neurogenic oedema formation. We have examined the effect of a tachykinin NK1 and a bradykinin B2 antagonist, and a mu-opioid agonist on plasma extravasation observed in response to two differing nerve stimulating parameters (10 V, 1 ms, 2 Hz and 25 V, 2 ms, 10 Hz). The NK1 antagonist SR140333 abolished oedema, supporting the theory that an NK1 agonist is a primary mediator of neurogenic oedema. The B2 antagonist HOE 140 had no effect, indicating a lack of involvement of B2 receptors in this response. The pre-junctionally acting mu-opioid agonist DAMGO significantly inhibited oedema formation at the 10 V, 1 ms, 2 Hz (P < 0.001), but not the 25 V, 2 ms, 10 Hz stimulation parameters. Thus a post-junctionally acting NK1 antagonist inhibited neurogenic oedema formation induced by both stimulation parameters, whilst a pre-junctionally acting mu-opioid agonist acted only at 10 V, 1 ms, 2 Hz parameters. These findings could be of interest with respect to therapeutic approaches of pathophysiological conditions which involve a neurogenic component.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Edema; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Extravasation of Diagnostic and Therapeutic Materials; Male; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Peptide Fragments; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Receptors, Neurokinin-1; Receptors, Opioid, mu; Substance P; Time Factors

Dynorphin A (DYN) peptides, administered into the central nervous system, have produced inconsistent analgesic actions in tests using thermal stimuli. This study examined antinociceptive effects of intravenous and intraplantar DYN-(2-17) against noxious pressure in rats with Freund's adjuvant-induced unilateral hindpaw inflammation. The effects of DYN-(2-17) were compared to those of the opioid agonists morphine. (D-Ala2,N-Methyl-Phe4,Gly-ol5)-enkephalin (DAMGO) and DYN-(1-17). Intravenous DYN-(2-17) (0.188-10 mg/kg) produced dose-dependent elevations of paw pressure thresholds in inflamed and in non-inflamed paws. These effects were similar in magnitude to those of subcutaneous morphine (2 mg/kg), at doses of 0.375-1.5 mg/kg they were significantly greater on the inflamed (right) than on the non-inflamed (left) paw, and they were not reversible by intravenous naloxone (1-10 mg/kg). Intraplantar Dyn-(2-17)(0.001-0.3 mg) was ineffective, whereas both intraplantar DYN-(1-17)(0.15-0.3 mg) and DAMGO (0.008-0.016 mg) produced dose-dependent and naloxone-reversible elevations of paw pressure thresholds. The intraplantar injection of both Dyn peptides produced a transient increase in the volume of non-inflamed paws. These findings suggest that intravenous DYN-(2-17) produces possibly centrally mediated, non-opioid antinociceptive effects against noxious pressure. At certain doses these effects are more potent in inflamed than in non-inflamed paws. In contrast to the opioid peptides DYN-(1-17) and DAMGO, DYN-(2-17) does not appear to have no peripheral antinociceptive actions.

Topics: Analgesics; Analgesics, Opioid; Animals; Dynorphins; Edema; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Foot; Inflammation; Male; Nociceptors; Peptide Fragments; Rats; Rats, Wistar

We have examined the effect of the micro-opioid analgesic buprenorphine on osteoclastic bone resorption in vitro and in the rat adjuvant arthritis model. In the bone slice assay buprenorphine inhibited osteoclastic bone resorption with an IC50 of 1 microM. This effect was not mimicked by the micro-opioid agonist ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin and was not prevented by the micro-opioid antagonist naloxone. Since other agents that inhibit osteoclastic bone resorption, such as bisphosphonates and calcitonin prevent bone erosion in the rat adjuvant arthritis model, we also examined the effect of buprenorphine in this model. Surprisingly, buprenorphine exacerbated inflammation measured by paw volume and increased joint destruction assessed by X-ray scores, in the injected paws and particularly in the non-injected paws. These studies also show that attempts to ameliorate animal suffering in this chronic model by using centrally acting analgesics such as buprenorphine may lead to complications in interpreting screening results obtained with novel, potential anti-arthritic compounds.

Topics: Analgesics; Analgesics, Opioid; Animals; Arthritis, Experimental; Arthrography; Bone Resorption; Buprenorphine; Cells, Cultured; Disease Models, Animal; Edema; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Femur; Lethal Dose 50; Naloxone; Narcotic Antagonists; Osteoclasts; Rats

The antinociceptive effect of the octapeptide vapreotide, an analog of somatostatin, was studied after systemic injection in normal mice using the hot plate and abdominal stretching assays, and in normal rats using the paw pressure analgesiometric assay. Vapreotide was ineffective at 1 microgram/kg s.c. in the hot plate test in mice, but 30 min after injection it induced an antinociceptive effect at s.c. injected doses of 8, 64, 512 and 4096 micrograms/kg, with an ED50 of 213 +/- 5 micrograms/kg. For the three highest doses this effect persisted 24 hr after the injection (maximal increase: +80 +/- 23% for 512 micrograms/kg) and disappeared at 48 hr. In the phenylbenzoquinone stretching test, in mice, the ED50 was 186 +/- 6 micrograms/kg (maximal decrease: -63 +/- 5%); the effect persisted 24 hr only for the same two highest doses. Using the paw pressure test, in rats, a dose-dependent increase in paw withdrawal and vocalization thresholds was observed for 21 and 24 hr, respectively, after s.c. injections of 16, 64 and 512 micrograms/kg. Global scores obtained for vocalization thresholds were significantly increased (vs. paw withdrawal thresholds) for 64 and 512 micrograms/kg. Carrageenan-induced nociception in rats was reduced for 21 hr by 64 and 512 micrograms/kg s.c.; scores of the contralateral noninflamed paw were also increased. Vapreotide administered locally in the inflamed paw was inactive. No change in edema volume was obtained after systemic injection of vapreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Analgesics; Animals; Brain; Disease Models, Animal; Edema; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; In Vitro Techniques; Inflammation; Male; Membranes; Mice; Molecular Sequence Data; Morphine; Motor Activity; Naloxone; Necrosis; Nociceptors; Octreotide; Pain Measurement; Rats; Rats, Sprague-Dawley; Somatostatin; Spinal Cord; Time Factors; Tritium