vofopitant and Pain

Although opioids can reduce stimulus-evoked efflux of Substance P (SP) from nociceptive primary afferents, the consequences of this reduction on spinal cord nociceptive processing has not been studied. Rather than assaying SP release, in the present study we examined the effect of opioids on two postsynaptic measures of SP release, Fos expression and neurokinin-1 (NK-1) receptor internalization, in the rat. The functional significance of the latter was first established in in vitro studies that showed that SP-induced Ca(2+) mobilization is highly correlated with the magnitude of SP-induced NK-1 receptor internalization in dorsal horn neurons. Using an in vivo analysis, we found that morphine had little effect on noxious stimulus-evoked internalization of the NK-1 receptor in lamina I neurons. However, internalization was reduced when we coadministered morphine with a dose of an NK-1 receptor antagonist that by itself was without effect. Thus, although opioids may modulate SP release, the residual release is sufficient to exert maximal effects on the target NK-1 receptors. Morphine significantly reduced noxious stimulus-induced Fos expression in lamina I, but the Fos inhibition was less pronounced in neurons that expressed the NK-1 receptor. Taken together, these results suggest that opioid analgesia predominantly involves postsynaptic inhibitory mechanisms and/or presynaptic control of non-SP-containing primary afferent nociceptors.

Topics: Analgesia, Epidural; Analgesics, Opioid; Animals; Cells, Cultured; Embryo, Mammalian; Male; Morphine; Neurokinin-1 Receptor Antagonists; Pain; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Signal Transduction; Spinal Cord; Substance P; Tetrazoles

The development and use of serotonin-1B/1D agonists to treat the acute attack of migraine has been a significant advance, but their vasoconstrictor effects have lead to a search for non-vasoconstrictor approaches to the management of the acute attack of migraine. One such suggested approach has been substance P (neurokinin-1) antagonists, since substance P is involved in mediating neurogenic plasma protein extravasation and has long been held to have a role in pain transmission. In this study, one such candidate compound, GR205171, a highly lipophilic potent neurokinin-1 antagonist, has been tested in a model of trigeminovascular nociception with considerable predictive value for anti-migraine activity. The superior sagittal sinus was isolated in the alpha-chloralose (60 mg/kg, i.p., and 20 mg/kg, i.v., supplemented every 2 h)-anaesthetized cat. The sinus was stimulated electrically (100 V, 250 micros duration, 0.3 Hz) and neurons in the dorsal C2 spinal cord monitored using electrophysiological methods. In separate experiments, the animals were prepared for stimulation and then maintained for 24 h before stimulation and perfusion for Fos immunohistochemistry. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.7 +/- 0.1 at a latency of 10.7 +/- 0.2 ms. Administration of GR205171 (100 microg/kg, i.v.) had no effect on probability of firing or latency. Stimulation of the sinus in separate cats resulted in increased expression over control levels in the superficial laminae of the trigeminal nucleus caudalis and C1/2 dorsal horns. GR205171 in the same dose had no effect upon Fos expression. Inhibition of substance P by the potent, selective and brain penetrant neurokinin-1 antagonist GR205171 had no effect upon either cell firing or Fos expression in the central trigeminal cells activated by stimulation of the superior sagittal sinus. These data and the published clinical data for other compounds suggest that neurokinin-1 blockade alone will not be an effective anti-migraine strategy. Further data will be required to assess whether neurokinin-1 antagonists will have any more general value in pain.

Topics: Afferent Pathways; Animals; Brain Mapping; Cats; Cranial Sinuses; Electric Stimulation; Neurokinin-1 Receptor Antagonists; Neurons; Nociceptors; Pain; Piperidines; Proto-Oncogene Proteins c-fos; Spinal Cord; Substance P; Synaptic Transmission; Tetrazoles; Trigeminal Nuclei

In adult rats response latencies to innocuous mechanical stimuli were found to be reduced and, in electrophysiological studies, the receptive fields of dorsal horn neurones were enlarged 7-14 days after chronic constriction injury of the sciatic nerve. The NK1 receptor antagonist GR205171 at 3 mg kg(-1) blocked responses to NK1 agonist evoked activity and reversed the mechanical hypersensitivity following nerve ligation in behavioural assays. GR205171 also reversed the receptive field expansion of spinal dorsal horn neurones caused by loose ligation of the sciatic nerve in an electrophysiological assay in anaesthetised rats. The less active enantiomer L-796,325 did not block NK1 agonist evoked activity at up to 10 mg kg(-1) and had no effect on behavioural or electrophysiological changes following nerve injury, indicating that the effects of GR205171 were attributable to selective NK1 receptor blockade. These data suggest that NK1 receptor antagonists may be useful for the treatment of certain types of neuropathic pain.

Topics: Analysis of Variance; Animals; Functional Laterality; Hyperalgesia; Isomerism; Male; Mice; Neurokinin-1 Receptor Antagonists; Neurons; Pain; Peripheral Nervous System Diseases; Piperidines; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord; Tetrazoles