Antinociceptive effects of R(-)- and S(+)-flurbiprofen on rat spinal dorsal horn neurons rendered hyperexcitable by an acute knee joint inflammation.

The antinociceptive effects of the S(+)-enantiomer of flurbiprofen (potent inhibitor of cyclooxygenase) and the R(-)-enantiomer (500 times less potent) were investigated in the spinal cord of 20 anesthetized rats. In lumbar segments, 20 wide-dynamic-range dorsal horn neurons with knee joint input were recorded extracellularly. After induction of an acute inflammation in the knee joint by kaolin and carrageenan, the neurons developed hyperexcitability consisting of enhanced responses to stimuli applied to the inflamed knee and the noninflamed ankle and an expansion of receptive fields. Intravenous administration of R(-)-flurbiprofen (1-9 mg/kg) and S(+)-flurbiprofen (0.3-9 mg/kg) at 5.5 to 8.5 h after kaolin, dose dependently reduced the neurons' responses to pressure applied to the inflamed knee (18 of 18 neurons) and the noninflamed ankle (17 of 17 neurons) and paw (8 of 8 neurons). R(-)-flurbiprofen decreased the receptive field size in 8 of 16 neurons, S(+)-flurbiprofen in 10 of 16 neurons. The suppressive effects started 3 to 6 min and reached a maximum 9 to 15 min after i.v. administration. S(+)-flurbiprofen was more potent than the R(-)-enantiomer. When injected directly into the knee joint, S(+)-flurbiprofen (50 and 80 micrograms), but not the R(-)-enantiomer (100 and 180 micrograms) reduced the hyperexcitability in 12 of 12 neurons. These results suggest a central site of antinociceptive action for R(-)-flurbiprofen and S(+)-flurbiprofen and an additional peripheral site for S(+)-flurbiprofen. The doses used in these experiments did not produce any sedative effects in rats subjected to behavioral testing.

Involvement of substance P and neurokinin-1 receptors in the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint.

1. In anesthetized rats we studied the involvement of substance P and neurokinin-1 receptors in the generation and maintenance of hyperexcitability in spinal cord neurons, which develops in the course of an acute experimental inflammation in the knee. In all experiments one nociceptive neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the injections of kaolin and carrageenan into the knee joint. In 18 experiments either the specific antagonist at the neurokinin-1 receptor ionophoretically close to the neuron or intravenously during the injections of kaolin and carrageenan and in three periods of 15 min in the 95 min postkaolin (initial period of inflammation) to test their effects on the development of hyperexcitability. CP96,345 and CP96,344 were also administered after full development of inflammation to study their effects in hyperexcitable neurons. CP96,345 was ejected at currents that reduced or completely suppressed the effects of ionophoretically administered substance P but not those of neurokinin A, the agonist at neurokinin-2 receptors. 2. After the injections of kaolin and carrageenan into the knee joint, untreated control neurons (n = 8) developed hyperexcitability consisting of enhanced responses to noxious stimuli applied to the injected knee and the noninjected ankle, of an enhancement or induction of the responses to innocuous pressure applied to the joints and of an expansion of the receptive field. In eight neurons treated with ionophoretic administration of CP96,345 during the induction and initial period of inflammation, the development of hyperexcitability was not completely prevented but significantly attenuated. In comparison with the changes in the control neurons, the development of hyperexcitability was markedly reduced from the 2nd h up to 5 h postkaolin, but it was barely affected by CP96,345 within the 1st h postkaolin. Intravenous administration of CP96,345 in the initial period of inflammation produced a similar reduction of the development of hyperexcitability in another four neurons. The ionophoretic application of CP96,344 during and after induction of inflammation did not apparently impair the development of hyperexcitability (n = 6 neurons). 3. After development of inflammation and hyperexcitability, both the responses to innocuous and noxious pressure applied to the inflamed knee joint were reduced by the ionophoretic (n = 16 neurons) and intravenous administration (n = 9 neurons) of CP96,345 (tested 4.5-8 h postkaolin). Similarly, the responses to innocuous and noxious pressure applied to the noninflamed ankle were reduced by CP96,345 after inflammation had developed in the knee joint.(ABSTRACT TRUNCATED AT 400 WORDS)

The involvement of substance P and neurokinin-1 receptors in the responses of rat dorsal horn neurons to noxious but not to innocuous mechanical stimuli applied to the knee joint.

In 29 anesthetized rats, the involvement of substance P and neurokinin-1 receptors in the spinal processing of mechanosensory innocuous and noxious information from the knee and ankle joint was investigated. In 21 rats, multibarrel electrodes were used to record from 46 spinal cord neurons with afferent input from the knee joint and to administer agonists and antagonists by microinophoresis. In 35 of 46 nociceptive neurons, substance P (ejected at 20-120 nA) caused an excitation and/or an increase in responses to innocuous and noxious pressure applied to the knee and ankle. These effects were reduced by ionophoretic application of the specific neurokinin-1 receptor antagonist CP96,345 (ejected at 25-80 nA) but not by CP96,344, its inactive enantiomer. CP96,345 dose-dependently reduced the responses to noxious pressure applied to the knee joint in 28/28 substance P-sensitive neurons but not those to innocuous pressure in 23/23 substance P-sensitive wide dynamic range neurons. CP96,345 did not affect responses to pressure in substance P-insensitive neurons and the inactive enantiomer CP96,344 had no effect in any of the neurons tested. Using microprobes coated with antibody to substance P, intraspinal release of immunoreactive substance P was found to be evoked by noxious pressure applied to the knee but not by innocuous pressure in 8 rats. Both sets of data suggest a role for substance P and neurokinin-1 receptors in the neuronal mechanisms in the spinal cord related to nociception and pain in the normal joint.