Biomedical subjects

S C Ahlgren

Publications and source records attributed to S C Ahlgren.

9 recordsLinked to original sources

PubMed1997

Effects of thyroid hormone on embryonic oligodendrocyte precursor cell development in vivo and in vitro.

The oligodendrocyte precursor cell divides a limited number of times before terminal differentiation. The timing of differentiation depends on both intracellular mechanisms and extracellular signals, including mitogens that stimulate proliferation and signals such as thyroid hormone (TH) and retinoic acid (RA) that help trigger the cells to stop dividing and differentiate. We show here that, both in vivo and in vitro, TH is required for the normal development of rodent optic nerve oligodendrocytes, although in its absence some oligodendrocyte development still occurs, perhaps promoted by signals from axons. We also demonstrate that TH from both mother and pup plays a part in oligodendrocyte development in vivo. Finally, we show that precursors in embryonic nerve cultures differ from those in postnatal cultures in two ways: they respond much better to TH than to RA, and they respond more slowly to TH, suggesting that oligodendrocyte precursor cells mature during their early development.

Animals↗

PubMed1997

C-fiber mechanical stimulus-response functions are different in inflammatory versus neuropathic hyperalgesia in the rat.

To compare changes in primary afferent nociceptors associated with inflammatory versus neuropathic hyperalgesia, we evaluated in rats the mechanical stimulus-response function of isolated C-fiber primary afferent nociceptors to 10-s stimuli of differing mechanical strengths; 36 fibers after prostaglandin E2, 28 fibers from streptozotocin-diabetic rats and 46 fibers from control, non-treated rats were examined. Intradermal injection of prostaglandin E2 decreased mechanical threshold of 19 of 35 (54%) C-fibers. C-fibers that demonstrated a decrease in the mechanical threshold after prostaglandin E2 also showed an increased response to suprathreshold stimuli. The increase in the number of action potentials in prostaglandin E2-treated C-fibers was greatest at lower magnitude stimulus intensities, i.e. near threshold; the response to higher magnitude stimulus intensities was unchanged from that in control animals. In contrast, an increase in the number of action potentials seen in C-fibers from streptozotocin-diabetic rats was not seen at low-magnitude stimulus intensities; rather, a pronounced increase in response was seen at high-magnitude stimulus intensities. The von Frey hair thresholds for C-fibers in streptozotocin-diabetic rats were not different from those in control C-fibers. These data suggest that the changes in mechanical stimulus-response function of C-fibers are different in inflammatory compared to neuropathic mechanical hyperalgesia. These differences may underlie some of the differences in clinical features between inflammatory and neuropathic hyperalgesias.

Animals↗

PubMed1996

Sensitization of C-fibres by prostaglandin E2 in the rat is inhibited by guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor peptide.

Behavioral studies have shown that mechanical hyperalgesia induced by intradermal injection of prostaglandin E2 is blocked by inhibitors of the cAMP second messenger system. Similarly, injection of prostaglandin E2 also induces a decrease in mechanical threshold and an increase in the number of action potentials elicited by test stimuli in most C-fibre nociceptors. This change is called sensitization. To further evaluate the degree of correlation between primary afferent sensitization and mechanical hyperalgesia, we conducted a study to evaluate the effect of agents known to block the cAMP second messenger system and behavioral manifestations of mechanical hyperalgesia following injection of prostaglandin E2. The agents tested were guanosine 5'-O-(2-thiodiphosphate), an inhibitor of stimulatory guanine nucleotide-binding regulatory proteins; 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase; and Walsh Inhibitor Peptide, an inhibitor of cAMP-dependent protein kinase. Single fibre electrophysiologic studies of 138 C-fibres, innervating the dorsum of the hind paw, was done in male Sprague-Dawley rats. The number of spikes evoked by a 10 s application of a threshold von Frey hair were determined before and after intradermal injection of test agents administered alone and in combination with prostaglandin E2. Injection of prostaglandin E2 with the test agent vehicle (saline or distilled water) resulted in a significant decrease in von Frey hair threshold and an increase in the number of spikes generated in response to threshold von Frey hairs. In contrast, co-injection of prostaglandin E2 with guanosine-5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine or Walsh inhibitor peptide did not result in a significant decrease in von Frey hair mechanical threshold or increase in the number of spikes generated to the threshold stimuli, compared with vehicle/prostaglandin E2. It is suggested that guanosine 5'-O-(2-thiodiphosphate), 2',5'-dideoxyadenosine and Walsh inhibitor protein inhibited prostaglandin E2 sensitization of primary afferent C-fibres by inhibiting a stimulatory guanine nucleotide-binding regulatory protein, adenylyl cyclase, and protein kinase A, respectively. These results support the hypothesis that primary afferent sensitization by prostaglandin E2 underlies prostaglandin E2-induced hyperalgesia.

Animals↗

PubMed1994

Catecholamine-induced mechanical sensitization of cutaneous nociceptors in the rat.

C-Fiber mechanoheat (C-MH) nociceptors from the saphenous nerve were studied, in control rats and in rats that underwent surgical sympathectomy. Intradermal injection, alone, of either norepinephrine (NE) or the calcium ionophore, A23187, did not affect mechanical threshold. The combination of A23187 and NE, however, significantly decreased mechanical threshold. In the presence of the alpha 2-adrenergic antagonist, yohimbine, or the cyclooxygenase inhibitor, indomethacin, C-MHs were not sensitized by the combination of NE + A23187. One week after surgical sympathectomy, the number of C-MHs sensitized by NE + A23187 was significantly reduced. In summary, NE appears to sensitize nociceptors indirectly. These data are compatible with the suggestion that a sympathetic postganglionic neuron-dependent release of prostaglandins mediates the sensitization. NE appears to act at an alpha 2-adrenergic receptor, only in the presence of an increased intracellular Ca2+.

Action Potentials↗

PubMed1994

Walking evokes a distinctive pattern of Fos-like immunoreactivity in the caudal brainstem and spinal cord of the rat.

We have evaluated the pattern of c-fos expression induced in the rat spinal cord, caudal brainstem and cerebellum by a behavior that is associated with non-noxious inputs transmitted over large-diameter primary afferent fibers, namely walking for 1 h on a rotating rod. Walking on the rotating rod induced a large increase in the number of Fos-like immunoreactive neurons in regions of the cervical and lumbar spinal cord gray matter that contain neurons that respond to non-noxious stimuli: the inner part of the substantia gelatinosa (lamina IIi), the nucleus proprius and the medial parts of laminae V and VI. We also observed considerable labeling in lamina VII and in ventral horn motoneurons. We did not record an increased number of Fos-like immunoreactive neurons in lamina I, in the outer substantia gelatinosa (lamina IIo), or in the lateral, reticulated portion of lamina V, regions that contain neurons predominantly responsive to noxious stimulation. Unilateral sensory deafferentation of the forelimb, by multiple dorsal rhizotomies, significantly decreased the number of Fos-like immunoreactive neurons in the ipsilateral spinal cord, suggesting that afferent input contributed to the walking-induced pattern of labeling. In rats that walked on the Rota-Rod, we also recorded increased labeling in the dorsal column nuclei. Unilateral cervical deafferentation reduced the labeling in the cuneate nucleus; this reduction was paralleled by decreased cytochrome oxidase activity. Finally, we found that there was a significant increase in the number of Fos-like immunoreactive neurons in the cerebellum of rats that walked on the Rota-Rod. Northern blot analysis revealed that the increase in Fos-like immunoreactivity was associated with an increase in c-fos messenger RNA. The pattern of labeling observed in the rats that walked on the Rota-Rod was distinct from that observed when rats are exposed to a noxious stimulus [Presley et al. (1990) J. Neurosci. 10, 323-335]. This result reinforces the conclusion that by monitoring the evoked expression of the c-fos proto-oncogene, it is possible to identify unique populations of neurons that are specifically related to the modality of the stimulus or to behaviour occurring during the stimulus presentation.

Animals↗

PubMed1994

Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat.

1. We have previously demonstrated that although rats with streptozotocin-induced diabetes (STZ-D) have decreased behavioral mechanical nociceptive thresholds (hyperalgesia), their C-fiber primary afferent mechanical (von Frey hair) thresholds are not altered. Instead, when stimulated with a standardized sustained suprathreshold mechanical stimulus, C-fibers from STZ-D rats were found to have an increased number of spikes (hyperexcitability). We suggested that this C-fiber hyperexcitability contributes to the behavioral hyperalgesia and that agents that reverse the hyperalgesia may act by decreasing this hyperexcitability. Because protein kinase C activity contributes to C-fiber afferent excitability, we examined the effect of agents that inhibit protein kinases on behavioral mechanical nociceptive thresholds and on the response of C-fiber afferents to sustained mechanical stimulation. 2. The effects of intradermal injection of two protein kinase inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC(19-36)], on behavioral mechanical nociceptive thresholds were determined using the Randall-Selitto paw-withdrawal device. These agents increased the mechanical nociceptive threshold of STZ-D rats in a dose-dependent manner but did not alter nociceptive threshold in control rats. 3. The same agents were tested for their effects on single C-fiber mechanical thresholds and excitability in response to suprathreshold (445 g) mechanical stimulation. Intradermal injection of staurosporine or PKC(19-36) significantly reduced the response of C-fibers from STZ-D rats to sustained suprathreshold mechanical stimulation but did not alter the response of C-fibers from control rats to the same stimulation. Neither agent altered mechanical threshold in C-fibers from either STZ-D or control rats. 4. In this study we found that both the mechanical behavioral hyperalgesia and the C-fiber hyperexcitability to mechanical stimuli seen in STZ-D rats are reduced by agents that inhibit protein kinase C. This evidence supports our hypothesis that C-fiber hyperexcitability, in part mediated by PKC activity, contributes to hyperalgesia in this model of diabetic neuropathy.

Alkaloids↗

PubMed1993

Mechanical hyperalgesia in streptozotocin-diabetic rats is not sympathetically maintained.

It has been suggested that the mechanism underlying the pain that occurs in patients with diabetic neuropathy may be similar to that mediating sympathetically maintained pain (SMP), such as occurs in patients with reflex sympathetic dystrophy. To evaluate this suggestion we have examined a model of diabetes mellitus, the streptozotocin-diabetic (STZ-D) rat, for features characteristic of SMP. We demonstrate that the decrease in nociceptive threshold observed in the STZ-D rat is not attenuated by chemical sympathectomy nor exacerbated by intradermal injection of norepinephrine (NE). In addition, the NE content is markedly decreased in the skin of the STZ-D rat. These results suggest that altered nociceptive thresholds associated with diabetic neuropathy are not sympathetically maintained.

Animals↗

PubMed1993

Mechanical hyperalgesia in streptozotocin-diabetic rats.

Recent evidence strongly suggests that the hyperalgesia induced by agents acting directly on the primary afferent is mediated by stimulatory G-proteins and the cAMP second messenger system. In this study, we used the Randall-Selitto paw-pressure device to study hyperalgesia that develops in the streptozotocin-diabetic rat. Subcutaneous injection of streptozotocin in male Sprague-Dawley rats induced hyperglycemia and glucosuria detectable within 24 h of injection. A decrease in mechanical nociceptive threshold in the hindpaw was detected after one week. Intradermal injection of indomethacin, a cyclooxygenase inhibitor, had no significant effect on nociceptive threshold; and prostaglandin E2, which produces hyperalgesia by a direct action on the primary afferent, decreased nociceptive threshold similarly in streptozotocin-diabetic and control rats. Guanosine 5'-O-(2-thiodiphosphate), which blocks stimulatory G-proteins, attenuated the prostaglandin E2-hyperalgesia in both streptozotocin-diabetic and control rats, but had no effect on baseline nociceptive threshold in either group. Intradermal injection of either 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, or phosphodiesterase, which degrades cAMP, increased mechanical nociceptive threshold in streptozotocin-diabetic rats whilst not affecting mechanical nociceptive threshold in the control rats. Intradermal injection of 8-bromo cAMP, a membrane-permeable analog of cAMP, produced hyperalgesia of significantly greater magnitude in the streptozotocin-diabetic rats than the control rats. Intradermal injection of N6-cyclopentyl adenosine, an A1-type adenosine agonist, which can activate an inhibitory G-protein and decrease cAMP production, also increased nociceptive thresholds in streptozotocin-diabetic rats. This effect was blocked by pertussis toxin.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat.

1. This study examined sensory neurons in the saphenous nerve of rats treated with streptozotocin to induce diabetes (STZ-D). Several physiological properties of sensory neurons were not significantly different in STZ-D compared with control (CON) rats, including percentage and rate of spontaneous activity seen in the whole nerve and mechanical and thermal thresholds of individual C-fibers. 2. The response of STZ-D and CON C-fibers to a sustained (1 min) mechanical stimulus of threshold force was similar. However, during the 5 min immediately after removal of this stimulus, there was a much greater afterdischarge in STZ-D rats (STZ-D: n = 35; 14.6 +/- 5.1 action potentials/5 min, mean +/- SE; CON: n = 34; 3.9 +/- 0.7 action potentials/5 min). The number of action potentials during a sustained (1 min) suprathreshold mechanical (445 g) stimulus was also significantly greater in the C-fibers from STZ-D rats (STZ-D: n = 44; 149.7 +/- 18.4 action potentials; CON: n = 45; 84.7 +/- 12.2 action potentials). The afterdischarge during the 5 min immediately after removal of the sustained suprathreshold stimulus was also greater in C-fibers from STZ-D rats (STZ-D: 38.7 +/- 13.1 action potentials/5 min; CON: 9.3 +/- 2.3 action potentials/5 min). 3. There was a significant difference between C-fibers from STZ-D and CON rats with respect to the distribution among certain sensory classes.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗