Imipramine-fentanyl antinociception in a rabbit tooth pulp model

Antinociception of imipramine (I) and its effect in combination with fentanyl (F) was evaluated in rabbits using electrically-induced lick chew responses via tooth pulp stimulation as the model of nociception. Acute i.v. injections of I elicited a graded dose response comparable to i.v. morphine (M) with I ED 50 = 4.35 mg/kg (2.31-8.14, 95% CL) and M ED 50 = 1.81 mg/kg (1.11-3.90), with no differences in the slopes between the two curves. The lethal dose of I was 10 mg/kg. An i.v. dose of I twice the ED 50 elicited an antinociceptive effect of more than 50% maximum possible effect (MPE) for 90 minutes with peak effect of 82% MPE occurring at 15 minutes. These effects of I were not reversed by a morphine-reversal dose of naloxone (0.1 mg/kg i.v.) but were reversed with a ten fold dose of naloxone. F ED 50 values (mcg/kg) were lowered from 11.35 to 2.70, 0.74 and 0.33 with increasing pretreatment doses of I (1.0, 2.1 and 3.2 mg/kg). These magnitudes of potency increases of F were 4.2, 15.3 and 34.4 fold respectively. A single i.v. ED 50 dose of I extended the time to 50% MPE of an ED 90 dose of F from 26 minutes to 77 minutes; of a 2 X ED 50 dose of F from 17 minutes to 28 minutes. Data points for three different combinations of I and F fell significantly within the synergistic field of an ED 50 isobologram and a polynomial equation described the curve best fitting the data points. F alone (i.v. ED 50 dose) increased the PaCO2 values to 74% above controls and three different combinations with I showed no increases in PaCO2 values above controls. I alone did not significantly cause any change in PaCO2 values from controls.     

Feeling by sight or seeing by touch?

We have addressed the role of occipital and somatosensory cortex in a tactile discrimination task. Sight-ed and congenitally blind subjects rated the roughness and distance spacing for a series of raised dot patterns. When judging roughness, intermediate dot spacings were perceived as being the most rough, while distance judgments generated a linear relation. Low-frequency rTMS applied to somatosensory cortex disrupted roughness without affecting distance judgments, while rTMS to occipital cortex disrupted distance but not roughness judgments. We also tested an early blind patient with bilateral occipital cortex damage. Her performance on the roughness determination task was normal; however, she was greatly impaired with distance judgments. The findings suggest a double-dissociation effect in which roughness and distance are primarily processed in somatosensory and occipital cortex, respectively. The differential effect of rTMS on task performance and corroborative clinical evidence suggest that occipital cortex is engaged in tactile tasks requiring fine spatial discrimination.     

Speech Rhythms and Multiplexed Oscillatory Sensory Coding in the Human Brain

Cortical oscillations are likely candidates for segmentation and coding of continuous speech. Here, we monitored continuous speech processing with magnetoencephalography (MEG) to unravel the principles of speech segmentation and coding. We demonstrate that speech entrains the phase of low-frequency (delta, theta) and the amplitude of high-frequency (gamma) oscillations in the auditory cortex. Phase entrainment is stronger in the right and amplitude entrainment is stronger in the left auditory cortex. Furthermore, edges in the speech envelope phase reset auditory cortex oscillations thereby enhancing their entrainment to speech. This mechanism adapts to the changing physical features of the speech envelope and enables efficient, stimulus-specific speech sampling. Finally, we show that within the auditory cortex, coupling between delta, theta, and gamma oscillations increases following speech edges. Importantly, all couplings (i.e., brain-speech and also within the cortex) attenuate for backward-presented speech, suggesting top-down control. We conclude that segmentation and coding of speech relies on a nested hierarchy of entrained cortical oscillations.     

The effect of 5,6-dihydroxytryptamine on post-decapitation convulsions

Previous data (1) have shown that L-DOPA increases the duration of the clonic phase of post-decapitation convulsions (PDC) in mice. It was suggested that this effect is produced by depleting 5-hydroxytryptamine (5-HT) in the inhibitory bulbospinal pathways and thus enhancing reflex activity in the spinal cord. If this were true then L-DOPA administration should not influence clonic PDC in animals whose 5-HT pathways were destroyed. We therefore tested the effects of L-DOPA on mice 3 weeks after pretreatment with the 5-HT neurotoxin, 5,6-dihydroxytryptamine (5, 6-DHT) (50 μg/kg, intracerebroventricularly). All mice were given the peripheral decarboxylase inhibitor, Ro 4-4602. 5,6-DHT halved the brain 5-HT levels and significantly increased the duration of clonic PDC. The administration of L-DOPA (320 mg/kg i.p.) to 5,6 DHT treated mice did not produce any further significant increases in duration. The administration of 5-hydroxytryptophan (5-HTP) (100 mg/kg, i.v.) to 5,6-DHT treated mice, however, increased 5-HT to above control levels and reduced convulsions to control levels. Administration of both 5-HTP and L-DOPA to 5,6-DHT treated mice resulted in 5-HT levels and convulsion times which were also not significantly different from the controls. These data give additional indication that intact 5-HT nerve terminals are necessary for L-DOPA to prolong the duration of clonic PDC.     

The role of dopamine and serotonin in the prolongation of post-decapitation convulsions in mice.

L-DOPA (320 mg/kg, i.p.) increased the duration of the clonic phase of post-decapitation convulsions (PDC) by 60% in mice pretreated with the peripheral decarboxylase inhibitor, Ro 4-4602 (50 mg/kg, i.p.). Assays of brains at the time of decapitation showed a 300% increase in dopamine (DM), an 80% reduction in serotonin (5-HT) and no change in norepinephrine (NE) levels. The effect of L-DOPA on PDC was not blocked by haloperidol (0.5 – 5.0 mg/kg), a blocker of DM receptors, nor by diethyldithiocarbamate (400 mg/kg) an inhibitor of NE synthesis. Parachlorophenylalanine (300 mg/kg × 3 days) produced an 80% reduction in 5-HT and a prolongation of PDC similar to that observed after L-DOPA. Prolongation of PDC was also seen after the 5-HT antagonists methysergide (5 mg/kg) and cinanserin (10 mg/kg), but not after cyproheptadine (10 mg/kg). The 5-HT precursor, 5-hydroxytryptophan (100 mg/kg), produced no change in PDC when used alone but inhibited L-DOPA's prolongation of PDC. The results suggest that L-DOPA acts by depleting 5-HT in bulbospinal pathways and thus enhancing reflex activity in the spinal cord.     

Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130.

Leukemia inhibitory factor (LIF) is a cytokine with a broad range of activities that in many cases parallel those of interleukin-6 (IL-6) although LIF and IL-6 appear to be structurally unrelated. A cDNA clone encoding the human LIF receptor was isolated by expression screening of a human placental cDNA library. The LIF receptor is related to the gp130 'signal-transducing' component of the IL-6 receptor and to the G-CSF receptor, with the transmembrane and cytoplasmic regions of the LIF receptor and gp130 being most closely related. This relationship suggests a common signal transduction pathway for the two receptors and may help to explain similar biological effects of the two ligands. Murine cDNAs encoding soluble LIF receptors were isolated by cross-hybridization and share 70% amino acid sequence identity to the human sequence.