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Notes: Abstract  We evaluated the effects of systemic administration of a low dose of naloxone in rats with bilateral lesions in the area of the locus coeruleus (LC) under conditions of unilateral inflammation, compared with those in sham-operated rats. In each group, rats received a single s.c. injection of carrageenan (6 mg in 0.15 ml saline), and effects of a low dose of naloxone (5 μg/kg, i.p.) on thermal nociception were examined at 4 h and 7 days following the induction of unilateral hindpaw inflammation. The antinociceptive effect was assessed by prolongation of the paw withdrawal latency (PWL) to noxious thermal stimuli. Prior to induction of inflammation, the low dose of naloxone had no significant effect on PWLs in either the sham-operated or the LC-lesioned rats. Four hours after carrageenan injection, the low dose of naloxone produced prolongation of PWLs in the sham-operated rats but failed to induce antinociception in the LC-lesioned rats. Antinociceptive effects were observed in both groups of rats 7 days after carrageenan injection. These results suggest that the LC is involved in naloxone-induced antinociception during the early phase of inflammation.

Notes: Abstract  Intradermal injection of capsaicin results in sensitization of spinothalamic tract cells to brushing and pressure applied to the cutaneous receptive field in anesthetized monkeys. A significant increase in background activity also occurs immediately after capsaicin injection that lasts for at least 2 h. A 40–50% decrease in the response to noxious heat stimuli is also observed following capsaicin injection. This study investigated the spinal role of second messengers by extracellularly recording from spinothalamic tract cells and delivering inhibitors of second messenger pathways to the spinal cord by microdialysis. Blockade of protein kinases with the general protein kinase inhibitor, H7 (5.0 mM, n = 6), reduced the sensitization of the cells to brush and pressure. Blockade of protein kinase C with NPC15437 (10.0 mM, n = 10) reduced the increased background activity and the increased responses to brush. Blockade of protein kinase A with H89 (0.01 mM, n = 9) was most effective. H89 reduced the background activity, the increased responses to brush and press, and reversed the decreased response to noxious heat stimuli. Blockade of G-proteins with the general G-protein inhibitor, GDP-β-S (1.0 mM, n = 9), reduced the background activity and the responses to brush and pressure without affecting the decreased response to heat. Thus, multiple intracellular messengers appear to be involved in the processing of central sensitization induced by activation of C-fibers following intradermal injection of capsaicin.

Notes: Summary Electrical stimulation of the sural, superficial peroneal and plantar nerves in anesthetized cats produces a sequence of potentials in the spinal cord lumbosacral enlargement. The distributions of the spinal cord dorsum negative intermediary potential (N1 wave) and of the associated field potential recorded in depth from the spinal gray matter were mapped. The N1 wave produced by the sural nerve was largest at the junction of the S1 and L7 segments, whereas that evoked by the other two nerves was maximum in L6 and L7. The field potentials recorded in depth also showed a differential distribution. The maximum negativity during phase 2, corresponding to the N1 cord dorsum potential, was found to lie laterally in the dorsal horn when the sural nerve was stimulated, but medially when the plantar nerve was activated. The superficial peroneal nerve produced its largest negative field potential in the central region of the dorsal horn. The negative field potentials from the sural and superficial peroneal nerves were not as well separated spatially from each other as they were from the potential evoked by the plantar nerve.

Notes: Summary The locations of the cell bodies of origin of a pathway ascending in the dorsal part of the lateral funiculus of the cat spinal cord were mapped. It is presumed that the pathway is the spino-cervical tract. The locations of the neurons were determined by recording the antidromic action potentials in the lumbosacral enlargement evoked by stimulation of their axons at the third cervical segment, and then histologically reconstructing the recording sites. The cells were found to be scattered throughout laminae 4–6 of the dorsal horn, although most were in laminae 4 and 5. The conduction velocities of the axons ranged from 7 to 90 m/sec (mean 44 m/sec). A somatotopic relationship was observed between the locations of the cells within the dorsal horn and the distributions of their peripheral receptive fields. This somatotopic organization was oriented with respect to rostrocaudal and dorso-ventral axes as determined for the adult hindlimb by reference to its fetal development. The axes become distorted during development, but are still recognizable in the adult. Cells receiving afferent input from skin derived from rostral portions of the limb, including the medial surface of the adult foot, are located rostrally in the cord. The caudal limb, which includes the lateral surface of the foot in the adult, is represented caudally in the spinal cord. The dorsal limb or extensor surface projects to the lateral part of the dorsal horn, while the ventral limb or flexor surface is represented medially.

Notes: Abstract  Nitric oxide (NO) possibly plays an important role in the events resulting in hyperalgesia. Nitric oxide synthase (NOS) is a key enzyme in the production of NO. In this study, the relationship between NOS and hyperalgesia in a rat chronic arthritis model was tested. Chronic arthritis was induced by injection of incomplete Freund’s adjuvant into the knee joint cavity unilaterally. The paw withdrawal latency (PWL) to radiant heat was used to detect secondary thermal hyperalgesia induced by the arthritis. After 1 day the PWL of the arthritic hindpaw decreased and it reached its nadir at 3 days after induction of arthritis. The lumbar and cervical enlargement of the spinal cord were removed in different groups of animals 3, 7, 14, or 21 days after induction of arthritis, and frozen tissue sections were cut. Two series of sections were incubated with polyclonal antibodies to neuronal NOS (nNOS) or to inducible NOS (iNOS). nNOS was found to increase gradually in laminae I–III in the lumber but not in the cervical enlargement. The change became most obvious 14 days after induction of arthritis as compared to the control animals. Ependymal cells around the central canal of the lumbar enlargement were more densely stained by anti-iNOS after arthritis. A corresponding change was also found in the cervical enlargement. Computer-assisted image analysis revealed that the mean density of the affected areas in the treated group increased significantly compared with the control animals. This study suggests that the expression of both nNOS and iNOS increase following induction of chronic arthritis, which in turn would presumably lead to an increase in the production of NO. This process could be involved in mediation of the secondary thermal hyperalgesia induced by chronic arthritis.

Notes: Summary 1. Recordings were made from 16 ascending tract cells in the spinal cords of anaesthetized, spinalized cats before and after an acute arthritis was produced by injection of kaolin and carrageenan into the knee joint. 2. The responses tested routinely were to passive flexion of the knee, an innocuous movement. In some cases, responses to other movements were also tested, and changes in background discharge rates were monitored. 3. Control recordings for a period of 1 h or in 3 cases of 3 h indicated that the responses to flexion were reasonably stationary. 4. Four tract cells that initially showed little or no response to flexion of the knee joint developed large responses within 1 to 2 h after inflammation of the joint. 5. Another 9 cells were tested that had responses to flexion of the knee joint prior to inflammation. In 6 cases, inflammation produced enhanced static or transient responses. In 2 cases, the effect of flexion was initially inhibitory or variable, but after inflammation these cells showed large excitatory responses. In the other case, inflammation had no effect. Background discharges were increased by inflammation in 6 of these 9 cells. 6. The effect of inflammation of the knee joint was tested on 3 tract cells that had no clearly defined receptive field in the knee. In 1 case, a response developed to knee flexion after acute inflammation was produced. In the other 2 cases, there were initially responses to knee flexion, but these were unchanged by inflammation. 7. Two of the cells tested had bilateral receptive fields in or around the knee joints. Inflammation of one knee joint enhanced the responses to flexion of the same but not of the contralateral knee in one case but greatly increased the responses to flexion of both knees in the other case. 8. Injections of prostaglandin (PGE2) caused an enhancement of the responses to knee flexion beyond that caused by inflammation in 5 of 7 cases. One cell whose responses to flexion of the knee were unaffected by inflammation showed inhibitory responses to prostaglandin injections into the inflamed knee joint. 9. The effects of inflammation on the responses of ascending tract cells of the spinal cord appear to serve as a useful neural model of the events responsible for the development of arthritic pain.

Notes: Summary 1.Responses were recorded from 160 ascending tract cells in segments L4 to L6 of the spinal cord in chloralose anaesthetized, spinalized cats. The tract cells were identified by antidromic activation following stimulation of pathways in the lateral and ventral funiculi at the level of the spinal cord transection at the thoracolumbar junction. Axonal conduction velocities ranged from 9 to 114 m/s. 2. A sample of 152 of the neurones examined could be subdivided according to the distribution of their receptive fields into 49 cells activated just from receptors located in skin (“s” cells), 17 neurones excited by receptors in deep tissues (“d” cells), 15 units with a convergent input from receptors in skin and deep tissues (“sd” cells), and 25 neurones with a convergent input from the knee joint and either skin (“sj” cells), deep tissues (“dj” cells) or both (“sdj” cells). No receptive fields could be demonstrated for the remaining 46 neurones. 3. “S” and “sj” cells were found almost exclusively in the dorsal horn, whereas many “d”, “sd”, “sdj” and “dj” units were in the ventral horn. Almost all of the cells that lacked receptive fields were in the ventral horn or intermediate grey. 4. Ninety-one of 158 cells (56%) demonstrated no background activity. Of these, 43 cells (27%) lacked receptive fields. Many of the silent neurones were in the ventral horn, but some were in the dorsal horn. Of 25 cells having knee joint input, 18 (72%) had background activity. 5. All of the neurones that had a receptive field in the knee joint also had a convergent input from receptors in other tissues. In 3 cases, there was a receptive field in the skin over the foot (“sj” cells). For 16 cells, receptive fields included not only the knee joint but also skin and deep tissue (“sdj” cells). Usually, the cutaneous receptive field was near the knee joint, but sometimes it was remote, such as on the foot. The deep receptive fields were chiefly in the muscles of the thigh and/or leg. For 6 “dj” cells, the receptive fields included not only the knee joint but also deep fields like those of “sdj” cells. 6. Cutaneous receptive fields were classified as “low threshold” (cells excited best by innocuous intensities of mechanical stimulation), “wide dynamic range” (cells activated by weak mechanical stimuli, but the best responses were to noxious stimuli) or high threshold (innocuous stimuli had little effect, but noxious mechanical stimuli produced a vigorous discharge). Similarly, stimulation of the knee joint with weak mechanical stimuli could excite some neurones, while others could be activated by weak or strong articular stimuli but were excited best by noxious stimuli, and still other neurones were activated by knee joint stimuli only if the intensity was noxious. 7. In several instances, contralateral receptive fields were noted. These were generally in deep tissue or in the knee joint. 8. It was concluded that many of the responses to articular stimulation of the spinal cord ascending tract cells examined in this study could have been mediated by the fine afferent fibres that supply the knee joint. Although further work will be required to determine which particular ascending tracts transmit nociceptive information concerning the knee joint, it can be proposed that many of the responses demonstrated here were likely to play a role in either joint pain of in triggering responses associated with joint pain.

Notes: Abstract  The effects of a protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), on the activity and periaqueductal gray (PAG)-induced inhibition of rat dorsal horn neurons of the lumbar spinal cord were tested. A microdialysis fiber was placed through the dorsal horn for the purpose of local application of pharmacological agents. Extracellular single-unit recordings from dorsal horn neurons were made near the microdialysis fiber. TPA was tested on nociceptive dorsal horn cells. There was a significant increase in the background activity and responses to ”brush”, with no changes in responses to pressure and pinch stimuli. TPA also significantly blocked the PAG-induced inhibition of responses to brush, press, and pinch. These effects were eliminated by coadministration of the PKC inhibitor NPC-15437. The solvent, which contained dimethyl sulfoxide, was also tested for its effect on the responses to peripheral mechanical stimuli and PAG-induced inhibition of the dorsal horn neurons. There were no significant changes. This experiment suggests that activation of the PKC second messenger system might increase the activity of dorsal horn neurons and their responses to peripheral stimuli; in addition, the phorbol ester attenuated the PAG-induced descending inhibition of the dorsal horn neuron activity.

Notes: Abstract  Substance P, acting through neurokinin I receptors, is involved in the processing of nociceptive information in the spinal cord. Sensitization of spinothalamic tract neurons occurs to low-intensity stimuli following capsaicin injection. The current study tested the effects of the novel neurokinin 1 receptor antagonist, SDZ NKT 343, on the sensitization of spinothalamic tract cells by capsaicin in monkeys. Spinothalamic tract cells from the lumbar enlargement with receptive fields in the hindpaw were isolated and recorded before and after intradermal injection of capsaicin. The background activity and responses to brushing, pressing and pinching the skin were assessed. Thirty minutes after capsaicin injection there was an increase in background activity and responses to brush and pressure applied to the receptive field. Infusion of SDZ NKT 343 (for 30–45 min) significantly reversed the increased response to brushing without affecting the increased background activity or the increased response to pressure. Thus, blockade of neurokinin 1 receptors reduces the sensitized responses to innocuous mechanical stimuli but not to noxious mechanical stimuli.

Notes: [Auszug] Adult cats were used, either decerebrated at a just pre-collicular level or anaesthetized lightly with pentobarbital sodium. The cerebellum was removed by suction. Axons projecting rostrally from neurones of the reticular formation in the brain stem were stimulated antidromically by means of a ...