dextrorphan and Inflammation

Hyperalgesia following unilateral complete Freund's adjuvant-induced inflammation was characterized by paw withdrawal latency to thermal stimulus. Paw withdrawal latencies were significantly shorter on the complete Freund's adjuvant-treated paw than on the contralateral paw of the complete Freund's adjuvant- and the sham-treated rats. Total cytosolic protein kinase C activity in the lumbar enlargement was unchanged on the sides of the spinal cord ipsi- and contra-lateral to the inflamed paw. Membrane-associated activities of protein kinase Calpha, protein kinase CbetaI and protein kinase Cgamma did not change significantly on the sides of the cord ipsi- and contra-lateral to the inflammation. However, membrane-associated activity of protein kinase CbetaII was increased in the cord section ipsilateral to the inflammation, suggesting that increased translocation/activation of protein kinase CbetaII is related to thermal hyperalgesia. Dextrorphan (an N-methyl-D-aspartate receptor antagonist), L-703,606 (an NK-1 receptor antagonist) and an antisense oligodeoxynucleotide for a selective knockdown of protein kinase Cbeta, reduced complete Freund's adjuvant-induced hyperalgesia, and reversed significant changes in the membrane activity of protein kinase CbetaII on the spinal cord section ipsilateral to the inflamed paw. Dextrorphan and protein kinase Cbeta antisense oligodeoxynucleotide were effective in reversing complete Freund's adjuvant-induced increase in the activity of protein kinase CbetaII ipsilateral to the inflammation at all the doses tested, but L-703,606 was effective only at the highest dose. Furthermore, in the presence of inflammatory stimulus, dextrorphan and L-703,606 did not alter the activities of membrane-associated protein kinase Calpha, protein kinase CbetaI, and protein kinase Cgamma in the section of the spinal cord ipsi- and contra-lateral to the inflammation. Protein kinase Cbeta antisense oligodeoxynucleotide had no significant effect on the membrane-associated activities of protein kinase Calpha and protein kinase Cgamma, but decreased the activities of both protein kinase CbetaI and protein kinase CbetaII and the expression of protein kinase Cbeta isozyme in the spinal cord. The data provide evidence that a common molecular event that converges to initiate and maintain hyperalgesia may include the translocation and activation of protein kinase CbetaII in the spinal dorsal horn.

Topics: Animals; Blotting, Western; Cell Membrane; Cytosol; Dextrorphan; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hot Temperature; Hyperalgesia; Immunoprecipitation; Inflammation; Infusion Pumps, Implantable; Isoenzymes; Male; Membranes; Posterior Horn Cells; Protein Kinase C; Protein Kinase C beta; Rats; Rats, Sprague-Dawley; Spinal Cord

1. The interaction between N-methyl-D-aspartate (NMDA) and NK1 tachykinin receptors was analyzed isobolographically in rats with inflammatory hyperalgesia induced by intraplantar injection of complete Freund's adjuvant-saline emulsion (CFA, 100 micrograms Mycobacterium tuberculosis). 2. Thermal hyperalgesia of the inflamed paw, determined by paw withdrawal response to a heat stimulus, was dose-dependently attenuated by intrathecal administration of an NMDA receptor antagonist, dextrorphan (2.5-40 micrograms, ED50 = 7.2 micrograms), and two NK1 tachykinin receptor antagonists, WIN 51,708 (0.01-200 micrograms, ED50 = 10.4 micrograms) or CP-96,345 (5-200 micrograms, ED50 = 82.1 micrograms). There was no effect of these agents on the nociceptive threshold of the non-inflamed paw. CP-96,344, an enantiomer of CP-96,345 that is inactive as an NK1 tachykinin receptor antagonist, slightly attenuated hyperalgesia at a dose of 200 micrograms. 3. Combinations of dextrorphan and WIN 51,708 were administered at fixed ratios (10%:90%; 41%:59%; 90%:10%). Isobolographic analysis revealed that the ED50s obtained from the three combination ratios were not significantly different from those that were expected from a simple additive effect. 4. Thus, an additive interaction was demonstrated between NMDA and NK1 tachykinin receptor systems at the spinal level. These results suggest that both NMDA and NK1 tachykinin receptors are activated in response to peripheral inflammation, but that they may contribute independently to development of hyperalgesia.

Topics: Androstanes; Animals; Benzimidazoles; Biphenyl Compounds; Dextrorphan; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Freund's Adjuvant; Hindlimb; Hyperalgesia; Inflammation; Male; Neurokinin-1 Receptor Antagonists; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The peripheral analgesic effects of opiates were evaluated in a rat model of inflammation. The experimental design excluded a potential central nervous system site of action for the observed analgesia. After the injection of carrageenan (CARRA) in the plantar surface of both hind paws, an opiate was injected into one paw and saline was injected into the other paw. The inflamed paws injected with the mu-agonist, fentanyl (0.3 micrograms) or the kappa-agonist, ethylketocyclazocine (10 micrograms) were significantly less hyperalgesic (P less than 0.001 and P less than 0.01, respectively) than were the contralateral inflamed paws injected with saline. At these doses, fentanyl and ethylketocyclazocine were devoid of systemic effects. Another mu-agonist, levorphanol (20, 40, 80, or 160 micrograms) and dextrorphan (160 micrograms), its dextrorotatory isomer, were used next to evaluate opioid specificity. Levorphanol produced a dose-related blockade of CARRA-induced hyperalgesia (P less than 0.005). In contrast, 160 micrograms of dextrorphan was inactive. These results demonstrate that local administration of opiates into an inflamed paw produces a dose-related, stereospecific analgesia restricted to the injected area.

Topics: Analgesics, Opioid; Animals; Carrageenan; Cyclazocine; Dextrorphan; Ethylketocyclazocine; Fentanyl; Hyperalgesia; Hyperesthesia; Inflammation; Levorphanol; Male; Peripheral Nerves; Rats; Receptors, Opioid