Robert F. Schmidt

Discharge characteristics of fine medial articular afferents at rest and during passive movements of inflamed knee joints

After induction of an experimental knee joint inflammation, the activity of single Group III and IV afferent units in the medial articular nerve of the cat was recorded at rest and during passive movements. The properties of these units were compared to those sampled from normal knee joints. The proportion of units displaying resting discharges was higher in the inflamed group. The frequency of discharges was also higher. The receptive fields were larger than those in the control units. Passive movements in the normal working range of the joint activated many more units in the inflamed joint than in the control sample. We conclude that joint inflammation sensitizes articular nociceptors to be active not only at rest, but also during normally innocuous joint movements.

Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene‐related peptide

1 The dura mater encephali of the rat was exposed and the blood flow around branches of the medial meningeal artery was monitored with a laser Doppler flowmeter. Changes in the meningeal blood flow (MBF) following electrical stimulation of the dura mater at a parasagittal site were registered. The effects of human calcitonin gene‐related peptide (h‐αCGRP) and the CGRP antagonist (h‐αCGRP8–37) on the MBF were tested.

Involvement of nitric oxide in the modulation of dural arterial blood flow in the rat

Nitric oxide (NO) has been proposed to be a key molecule in the pathogenesis of migraine pain and other headaches that are linked to vascular disorders. Several lines of evidence indicate that the meningeal vascularization is crucially involved in the generation of these headaches. In an experimental model in the rat a dominating role of calcitonin gene‐related peptide (CGRP) in causing neurogenic vasodilatation and increased blood flow has been shown. The aim of the present study was to clarify the role of NO in this model with regard to the meningeal blood flow. The blood flow in and around the medial meningeal artery (dural arterial flow) was recorded in the exposed parietal dura mater encephali of barbiturate anaesthetized rats using laser Doppler flowmetry. Local electrical stimulation of the dura mater (pulses of 0.5u2003ms delivered at 7.5–17.5u2003V and 5 or 10u2003Hz for 30u2003s) caused temporary increases in dural arterial flow for about 1u2003min that reached peaks of 1.6–2.6 times the basal flow. The effects of NO synthase (NOS) inhibitors on the basal flow and the electrically evoked increases in flow were examined. Systemic (i.v.) administration of Nω‐nitro‐L‐arginine methyl ester (L‐NAME) at cumulative doses of 10 and 50u2003mgu2003kg−1 lowered the basal flow to 87 and 72%, respectively, of the control and reduced the evoked increases in blood flow to 82 and 44% on an average. Both these effects could partly be reversed by 300u2003mgu2003kg−1 L‐arginine. The systemic arterial pressure was increased by L‐NAME at both doses. Injection of the stereoisomer D‐NAME at same doses did not change basal flow and evoked increases in flow. Topical application of L‐NAME (10−4–10−2u2003M) was effective only at the highest concentration, which caused lowering of the basal blood flow to 78% of the control; the evoked increases in flow were not changed. Topical application of 2‐amino‐5,6‐dihydro‐6‐methyl‐4H‐1,3‐thiazine (AMT), a specific inhibitor of the inducible NOS, at concentrations of 10−4–10−2u2003M lowered the basal flow to 89, 87.5 and 85%, respectively, but did not significantly change the evoked flow increases. Same concentrations of 7‐nitroindazole monosodium salt (7‐NINA), a specific inhibitor of the neuronal NOS, had no significant effects on basal flow and evoked increases in flow. It is concluded that NO is involved in the maintenance of the basal level of dural arterial blood flow as well as in the electrically evoked flow increases, which have been shown to be mainly mediated by CGRP released from dural afferent fibres. The most important source of NO is probably the endothelium of dural arterial vessels. The synergistic effect of NO and CGRP on the stimulated blood flow may be in part due to a NO mediated facilitation of the CGRP release.

Effects of the 5-HT1 receptor agonists sumatriptan and CP 93,129 on dural arterial flow in the rat

The blood flow in and around the medial meningeal artery (dural arterial flow) was recorded in the exposed parietal dura mater encephali of the anesthetized rat using laser Doppler flowmetry. Local electrical stimulation of the dura mater (pulses of 0.5 ms delivered at 7.5-17.5 V and 5 or 10 Hz for 30 s) caused temporary increases in dural arterial flow. The effects of the 5-HT1 receptor agonists sumatriptan and CP 93,129 on the basal flow and the electrically evoked increases in flow were examined. Topical administration of undiluted sumatriptan (12 mg/ml) lowered the basal and the evoked flow by 20% on average. Systemic (i.v.) administration of sumatriptan (0.24, 0.72 and 3.6 mumol/kg) caused a short-lasting reduction of the evoked flow increases only at the higher doses while the basal flow was not significantly altered. Systemic administration of CP 93, 129 (0.46 and 4.6 mumol/kg) caused no significant changes of the basal and the evoked flow. At a dose of 23 mumol/kg CP 93,129 lowered the basal flow by 20% and the evoked flow by 30% for 20 min. The systemic arterial pressure was not significantly altered by sumatriptan and CP 93,129 within the whole range of doses. It is suggested that sumatriptan and CP 93,129 at high doses exert inhibitory effects on those fine afferent nerve fibers which release the calcitonin gene-related peptide, since this neuropeptide mediates the evoked increases in dural arterial flow.

Gentle mechanical skin stimulation inhibits the somatocardiac sympathetic: C-reflex elicited by excitation of unmyelinated C-afferent fibers

The effects of gentle mechanical skin stimulation on reflex discharges in cardiac sympathetic nerve evoked by somatic afferent stimulation were studied in anesthetized rats. Mass discharges were recorded from cardiac sympathetic efferent nerve while somatocardiac sympathetic A‐ and C‐reflexes were elicited by single electrical stimuli to myelinated A‐ and unmyelinated C‐afferent fibers of the tibial nerve. Continuous touch was applied to inner thigh skin with a force of 0.12 N for 10 min periods by a soft elastomer “brush” (1.1 cm in diameter with 417 microcones). When touch was applied ipsilateral to the stimulated tibial nerve, the C‐reflex was inhibited by up to 40% of its pre‐touch amplitude, whereas the A‐reflex was unaffected. Inhibition of the C‐reflex started during the touch period and lasted for 15 min after cessation of touching. Contralateral touch did not inhibit the C‐reflex. The opioid receptor antagonist naloxone attenuated the C‐reflex inhibition, but did not abolish it. The C‐reflex inhibition was abolished after severing cutaneous nerves innervating inner thigh. We recorded unitary afferent activity from thigh branches of the saphenous nerve and found fibers excited by touch were low‐threshold mechanoreceptive Aβ, Aδ and C fibers that have rapidly or slowly adapting properties. In all units tested, average discharge rates during touch period were less than 4 Hz. The results suggest that touch‐induced excitation of low threshold cutaneous mechanoreceptive fibers inhibits nociceptive transmission conveyed by C‐primary‐afferents, via the release of both opioid and non‐opioid inhibitory mediators.

Spinal Termination of Primary Afferents of the Cat’s Knee Joint

Afferent inflow via the articular nerves of the cat’s knee trans-synaptically excites neurons in superficial and deep layers of the spinal cord (cf. Schaible et al, 1986, 1987a, b). In order to map histologically the afferent input from the knee to the spinal cord we have now investigated the spinal projection of afferent fibres of the medial and posterior articular nerves (MAN and PAN) using transganglionic transport of horseradish peroxidase.

The cutaneous afferents contributing to inhibitions of the sympathetic reflex elicited by excitation of unmyelinated C-afferent fibers in anesthetized rats

BMAL1 is rhythmically phosphorylated in the suprachiasmatic nucleus (SCN), the mammalian central pacemaker. CK2 activity pattern correlates with the circadian (circasemidian) pattern of cytoplasmic BMAL1 phosphorylation and subsequent nuclear accumulation. Gene silencing of CK2 or mutation of the highly conserved CK2-phosphorylation site in BMAL, Ser90, result in impaired nuclear BMAL1 accumulation and disruption of clock function. Notably, phosphorylation at Ser90 follows a rhythmic pattern. These findings reveal that circadian kinase CK2 is an essential regulator of the mammalian circadian system.