Intra-articular injections of hyaluronan solutions of different elastoviscosity reduce nociceptive nerve activity in a model of osteoarthritic knee joint of the guinea pig.

OBJECTIVE: To study in guinea pigs knee joints the effects of intra-articular injection of HYADD 4-G (Fidia-Farmaceutici), a novel hyaluronan (HA)-derived elastoviscous material and of Hyalgan (Fidia-Farmaceutici), a HA product with very low viscoelasticity, on movement-evoked nociceptor impulse activity from normal and inflamed knee joints. DESIGN: Nociceptor impulse activity was recorded from single Adelta and C fibers of the medial articular nerve either under control conditions or after induction of an experimental knee joint osteoarthritis (OA) by partial medial menisectomy and transection of the anterior cruciate ligament (PMM-TACL). The stimuli consisted of standardized innocuous and noxious inward and outward rotations of the tibia against the femur of 50s duration, repeated every 5min for 1.5h. RESULTS: The number of movement-evoked impulses was significantly augmented 1 day and 1 week after PMM-TACL compared with intact knee joint. The enhanced impulse response to joint movements 1 week following surgery was attenuated by repeated intra-articular injection of HYADD 4-G and even more prominently by Hyalgan. CONCLUSIONS: HA products have a reducing action on joint nociceptor discharges that appears to depend predominantly on their role as an elastoviscous filter associated with their rheological properties, but also on a chemical effect on sensitized nociceptive terminals of inflamed joint tissues, possibly linked to the HA concentration.

Nociception and pain.

In recent years, progress in the treatment of pain has been strongly influenced by new insights into the mechanisms underlying pain and nociception. The following article briefly reviews some recent reports which make a significant contribution to our knowledge of the structure and function of nocisensors, the neuropeptides involved in the nociceptive system, and the spinal and supraspinal central mechanisms of nociception.

Somatostatin-like immunoreactivity in primary afferents of the medial articular nerve and colocalization with substance P in the cat.

The proportion of somatostatin-containing dorsal root ganglion cells innervating the knee joint of the cat via the medial articular nerve was determined by using retrograde labeling with fast blue and immunohistochemistry. Immunoreactivity was found in 8.6% of labeled cell bodies. In colchicine-treated ganglia, the proportion increased to 16.8%. Only small and intermediate-sized perikarya showed somatostatin-like immunoreactivity, indicating that this neuropeptide is synthesized predominantly in primary afferent units with unmyelinated sensory axons but may also be present in primary afferents with thinly myelinated sensory fibers. Colchicine treatment had no influence on the cell size distribution. Colocalization of somatostatin with substance P was determined by comparing the proportions of immunopositive dorsal root ganglion cells after incubation with antibodies against substance P or somatostatin or with a mixture of both. Substance P-like immunoreactivity was found in 18.1% (untreated ganglia) and 19.6% (colchicine treated ganglia) of the labeled neurons. After incubation with a mixed antibody solution, 18.2% of joint afferents in untreated and 19.9% of the cells in colchicine-treated ganglia were immunopositive. Comparing this result with the results obtained using somatostatin and substance P antibodies alone, one can calculate that both neuropeptides are colocalized in about 17% of the cat's knee joint afferents. About 3% of the neurons contain only substance P, whereas almost none of the neurons contain only somatostatin. Based on this fact, one can assume that both neuropeptides are coreleased in peripheral tissue as well as in the central nervous system.

Ultrastructural three-dimensional reconstruction of group III and group IV sensory nerve endings ("free nerve endings") in the knee joint capsule of the cat: evidence for multiple receptive sites.

The noncorpuscular endings ("free nerve endings") of thinly myelinated group III and nonmyelinated group IV afferent nerve fibers have been examined in the knee joint capsule of sympathectomized cats by transmission electron microscopy and three-dimensional reconstruction of series of semi- and ultrathin sections. The sensory ending is the most distal part of a group III or IV nerve fiber that consists only of the sensory axon and associated Schwann cells but lacks a myelin sheath and is not surrounded by perineurium. The sensory axon divides into several branches and forms a terminal tree. The branches run either as single fibers or within small Remak bundles in parallel to sensory axons of other endings; they spread along vessel walls and also extend into dense connective tissue. Each sensory axon consists of a series of spindle-shaped thick segments ("beads") connected by waist-like thin segments. Thus all axons of sensory endings have a string-of-beads appearance, which resembles that of efferent sympathetic nerve fibers. The beads of the sensory axon and the end bulb at its tip show the same ultrastructural features which are characteristic of receptive sites: an accumulation of mitochondria and glycogen particles and various vesicles in the axoplasm and "bare" areas of axolemma that are not covered by Schwann cell processes. Group III and group IV sensory endings differ in the length of their branches (up to 200 microM in group III vs. more than 300 microM in group IV), number of beads per 100 microM axon length (about seven vs. nine or ten), mean diameter of axons (0.9-1.5 microM vs. 0.3-0.6 microM), and the presence of a neurofilament core consisting of bundles of parallel microfilaments only in group III. In conclusion, we propose that the sensory part of noncorpuscular "free nerve endings" is formed by the entire terminal tree of group III or group IV nerve fibers and that the beads in the course of the sensory axon represent multiple receptive sites.

Fine sensory innervation of the knee joint capsule by group III and group IV nerve fibers in the cat.

Afferent group III and IV nerve fibers of the knee joint markedly differ in their responsiveness to mechanical stimulation, which may be reflected in the structure and location of their terminals. Therefore, in sympathectomized cats, the fine afferent innervation of the knee joint capsule was studied via ultrastructural three-dimensional reconstructions over distances of up to 300 microns. Small peripheral nerves and "free" (noncorpuscular) sensory nerve endings were found in a superficial layer of the outer fibrous part of the capsule, in the patellar retinaculum, and in the outer and inner surface layers of the medial collateral and patellar ligaments. Group III nerve fibers showed a proximal myelinated portion inside the nerve, an intermediate portion that lacks a myelin sheath and is only surrounded by perineurium, and a distal portion outside of the perineurium that forms the sensory ending proper. Group IV fibers showed only two distinct portions, an intraperineurial (proximal) and an extraperineurial (distal) portion without any further morphological differences. Outside of the perineurium, a network formed by Schwann cells ("Schwann cell reticulum") provides a pathway for the distal portion of the sensory axons. No distinct subgroups of the sensory terminal fibers could be defined according to the configuration of the Schwann cells and the nerve fiber terminals. Sensory terminals were located adjacent to different structures such as venous and lymphatic vessels, fat cells, and collagenous fibers. Distinct parts of the same terminal nerve fiber were found in close contact to a vessel wall; others were surrounded by dense collagenous tissue. Close to sensory endings, mast cells and mast cell-like cells were frequently found, indicating a functional relationship.

Three-dimensional reconstruction of scleral cold thermoreceptors of the cat eye.

Sensory endings that respond to local cooling were identified electrophysiologically in the cat's sclera. Functionally identified scleral thermal fibers were then used to analyze the structural characteristics of cold receptor endings. Four Adelta units sensitive to controlled cooling of their scleral receptive fields were recorded. The receptive areas were mapped, demarcated with pins and examined electron microscopically using extensive three-dimensional reconstructions. The supporting tissue within the receptive areas of cold units consisted of dense collageneous tissue with a small number of blood vessels that were either veins or capillaries. Adelta nerve fibers were found within these tissue blocks presumably corresponding with cold sensitive fibers. Small nerves and single nerve fibers devoid of a perineurium were found in all parts of the tissue, only occasionally passing a blood vessel. The terminal portions showed axonal swellings all along the unmyelinated segment filled with mitochondria, glycogen particles, and some vesicles. About 30% of the terminal axonal membrane is not covered by Schwann cells. In the unmyelinated distal portion, the mitochondrial content ranged from 0.012 to 0.038 microm(3) mitochondrial volume per microm(2) nerve fiber membrane. In comparison with sensory endings in the cat's knee joint, cold receptors in the cat sclera showed many similarities in their three-dimensional structure with polymodal nociceptor endings of the knee joint but contain less mitochondria. This suggests that cold sensory endings do not require specialized cellular processes for the transduction of cold stimuli, as is the case for multimodal transduction and sensitization in the terminal portion of polymodal nociceptors.

Activation of normal and inflamed fine articular afferent units by serotonin.

In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 micrograms 5-HT excited about 43% of group III (CV: 2.5-20 m/sec) and 73% of group IV units (CV: less than 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: greater than 16 m/sec) and group II units (CV: greater than 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages.

Effects of acetylsalicylic acid and indomethacin on single groups III and IV sensory units from acutely inflamed joints.

In cats with an acute experimental inflammation in the right knee joint the effects of acetylsalicylic acid (ASA) and indomethacin on the discharge properties of single fine myelinated and unmyelinated articular afferent units were tested. The knee joint was inflamed by injection of kaolin and carrageenan into the joint cavity some hours before the recording period. Before drug application the single afferent fibres showed resting activity and responses to movements of the joint within its working range which is common for units from the inflamed knee. Resting activity was reduced significantly in most units within 0.5 h after the intravenous injection of the drugs. Within the observation time of about 1-2 h there was no recovery. In a few units a transient increase of resting activity was observed immediately after the injection of a drug. After the initial observation period of 1-2 h the responses to movements were tested. They were reduced in all units except one myelinated afferent. Also during this testing period the resting discharges did not recover. Intra-arterial injection of prostaglandin E2 in low doses close to the joint temporarily nullified the depressing effects of aspirin and indomethacin. Resting activity and movement evoked responses were increased up to the level before the treatment with analgesic drugs. The effects of prostaglandin E2 lasted for several minutes to more than 1 h. The depression of resting and evoked activity in single afferent articular units from inflamed joints is discussed in relation to the analgesic properties of aspirin and indomethacin.

Elastoviscous substances with analgesic effects on joint pain reduce stretch-activated ion channel activity in vitro.

Activation by noxious mechanical stimuli of sensory nerve fibres that signal joint pain takes place through stretch-activated ion channels, which open in response to increased membrane tension. It has been suggested that the analgesic effect of hyaluronan solutions used for intra-articular treatment of joint pain in humans are mediated by a reduction of the sensitivity of mechanosensory ion channels of nociceptive nerve terminals. We have investigated whether cross-linked hyaluronan solutions (hylans) of different elastoviscosities modify the response characteristics of stretch-activated ion channels of Xenopus laevis oocytes. Patch-clamp recordings on intact oocytes and in excised membrane patches (outside-out and inside-out configurations) were performed in Barth's solution (control condition) and after exposure to hylans of different elastoviscosities. For mechanical stimulation, monitored suction was applied through the microelectrode and the activity of stretch-activated channels was recorded. The activity of stretch-activated channels was significantly reduced in the presence of high elastoviscous hylan A (0.8% polymer content, molecular weight 6M) and of a mixture of hylan A (90% by weight) and hylan B (10% by weight), 0.9% total polymer content, a clinically used hylan product. In contrast, solutions of hylan A with the same chemical composition but reduced elastoviscosity (0.8% polymer content, molecular weight 96000) were found ineffective. It is concluded that stretch-activated channels have a decreased mechanical sensitivity in the presence of elastoviscous solutions of hylan, but not in the presence of non-elastoviscous solutions of hylan of the same concentration. These data suggest that the analgesic effects of intra-articular injections of elastoviscous solutions of hylans are due to a reduction of the sensitivity to mechanical forces of stretch-activated channels present in the membrane of joint mechanonociceptors.

Substance P- and calcitonin gene-related peptide immunoreactivity in primary afferent neurons of the cat's knee joint.

The distribution of substance P and calcitonin gene-related peptide was determined in primary afferent neurons of the medial and posterior articular nerve of the cat's knee joint. Perikarya of articular afferents were visualized by retrograde labelling with the fluorescent dye Fast Blue which was applied at the transected end of the peripheral nerves. Substance P was found in about 17% of labelled medial articular afferents and in about 16% of labelled posterior articular afferents, respectively, whereas calcitonin gene-related peptide was present in about 35 and 32% of the medial and posterior articular nerve cells, respectively. Taking into account that these neuropeptides are known to be co-localized, probably not more than one-third of the joint afferents contain substance P and/or calcitonin gene-related peptide. Quantification of cell diameters revealed that substance P was found only in small- or intermediate-sized perikarya (less than 50 microns) indicating that this peptide is predominantly found in unmyelinated neurons. Calcitonin gene-related peptide was present mainly in small- and intermediate- but also in some large-sized neurons (greater than 50 microns) providing evidence that this peptide is found in unmyelinated and to a lesser extent in myelinated neurons. This is consistent with previous studies that show that substance P and calcitonin gene-related peptide are present primarily in unmyelinated and thinly myelinated primary afferents. When the portion of substance P-positive neurons of the medial articular nerve is compared to the number of articular afferents displaying a nociceptive function as determined in earlier electrophysiological studies, it can be calculated that at most 30% of the nociceptive-specific articular afferents contain this neuropeptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Inflammatory mediators and nociception in the joint: excitation and sensitization of slowly conducting afferent fibers of cat's knee by prostaglandin I2.

The effects of prostaglandin I2 on the discharge properties of fine articular afferents (group III and group IV fibers) in the cat were examined by extracellular recordings from single units dissected from the medial articular nerve of the knee joint. Prostaglandin I2 was applied intra-arterially close to the joint in doses of 0.3-30 micrograms per 0.3 ml bolus injection, and its effects on the spontaneous activity as well as on discharges evoked by mechanical and chemical stimulation (bradykinin) were monitored. Prostaglandin E2 was also applied and the effects of prostaglandins I2 and E2 on particular units were compared. An excitatory effect of prostaglandin I2 was observed in 49% of 37 group III and in 37% of 27 group IV units. A sensitization to passive movements of the joint occurred in 71% of 31 group III and 48% of 21 group IV units. Sixty-seven per cent of 32 units (groups III and IV) were both excited and sensitized by prostaglandin I2 to movements of 27% were sensitized but not excited. In 64% of 11 group III and 63% of eight group IV units studied the responses to bradykinin were enhanced by prostaglandin I2. Prostaglandin E2 had qualitatively similar effects as prostaglandin I2 but excited and sensitized a lower proportion of articular afferents. Forty-one per cent of the units were sensitive to both prostaglandins but 26% of the fibers were only sensitive to prostaglandin I2. None of the units was exclusively sensitive to prostaglandin E2. In general, the excitatory and sensitizing effects of prostaglandin E2 had a longer duration than those exerted by prostaglandin I2. We conclude that prostaglandin I2 increases the sensitivity to mechanical stimuli as well as to chemical stimulation by bradykinin in the majority of articular group III and group IV fibers. Moreover, in a large proportion of articular afferents, prostaglandin I2 had an excitatory effect. Thus, prostaglandin I2 may be an inflammatory mediator which is important for inflammation-evoked activity in slowly conducting afferents and it may participate in the development of arthritic hyperalgesia and pain.

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-alpha CGRP) and the CGRP antagonist (h-alpha CGRP8-37) on the MBF were tested. 2. Electrical stimulation with rectangular pulses of 0.5 ms, 10-20 V, 5-10 Hz and a duration of 30 s caused an increase of the MBF in 14 out of 16 rats tested. The increases were dependent on stimulus strength and frequency. 3. The increase in MBF was inhibited in a dose-dependent manner by topical application of 0.1 ml of h-alpha CGRP8-37 at concentrations of 10(-7) - 10(-5) M. The highest dose abolished the increase in MBF. 4. Topical administration of 0.1 ml of h-alpha CGRP at a concentration of 10(-4) M increased the basal MBF by 15% on average. 5. It is suggested that the increase in MBF following electrical stimulation of the dura mater is mediated by the release of CGRP. The contribution of the dural afferent and sympathetic and parasympathetic efferent nerve fibres to this response are discussed.

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

1. 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. 2. 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 0.5 ms delivered at 7.5 - 17.5 V and 5 or 10 Hz for 30 s) caused temporary increases in dural arterial flow for about 1 min 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. 3. Systemic (i. v.) administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) at cumulative doses of 10 and 50 mg kg(-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 300 mg kg(-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. 4. 4. Topical application of L-NAME (10(-4) - 10(-2) M) 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(-2) M 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. 5. 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.

No evidence for bradykinin B1 receptors in rat dorsal root ganglion neurons.

Bradykinin receptors are believed to contribute to hyperalgesia under conditions of neuropathic pain. Using calcium imaging we investigated responses to B1 and B2 agonists on isolated rat dorsal root ganglion neurons. No response to the B1 agonist was detected, whereas 12% of neurons responded to the B2 agonist. Northern blot analysis confirmed the lack of B1 receptor expression in dorsal root ganglia, as B1 mRNA was neither detected under normal conditions nor after nerve injury. In the calcium imaging experiments, agonists were applied with an elevated superfusion flow rate to avoid tachyphylaxis to the drug. Normal external solution applied at this flow rate constituted a mechanical stimulus causing a response in some neurons. Thus, in comparable set-ups mechanosensitivity has first to be tested to avoid masking effects.

Depending on the mode of application morphine enhances or depresses somatocardiac sympathetic A- and C-reflexes in anesthetized rats.

The effects of morphine on the reflex discharges in sympathetic efferents recorded from branches of the inferior cardiac nerve (ICN) were studied in rats anesthetized with alpha-chloralose and urethane. Somatocardiac sympathetic A- and C-reflexes were elicited by single shock electrical stimulation of myelinated (A) and unmyelinated (C) afferent fibers of the tibial nerve, respectively. Application of morphine either into the femoral vein or into the subarachnoid space of the cisterna magna enhanced both the A- and C-reflexes in a dose-dependent manner, while application of morphine into the intrathecal space of the lumbar spinal cord selectively inhibited C-reflexes. All effects of morphine were antagonized by naloxone. Application of morphine via the internal carotid artery to central nervous structures above the brainstem had no effect on the somatocardiac sympathetic reflexes. It is concluded that in the anesthetized rat morphine in a dose-dependent and naloxone-reversible manner (1) depresses spinal transmission of C-afferent activity, whereas (2) at the brainstem it enhances the transmission of somatocardiac sympathetic A- and C-reflexes.

An intact nerve preparation for monitoring inputs from single joint afferent fibres.

A preparation is described that permits the monitoring of activity from individual joint afferent nerve fibres in an intact peripheral nerve of the cat. The joint nerve used was the medial articular nerve (MAN) that supplies the medial and anteromedial aspects of the knee joint. This nerve is sufficiently fine that if freed from nearby tissue over a length of 2-5 cm and placed over a platinum hook electrode it is possible to identify and monitor, from the intact nerve, the impulse activity from each group II joint afferent fibre activated by mechanical stimulation of the joint capsule. The signal-to-noise ratio exceeds 5:1 and in most cases was approximately 10:1. With this preparation it is now possible to examine the central actions and security of transmission at central synaptic targets for single, identified group II joint afferent fibres.

Neurokinin A-like immunoreactivity in articular afferents of the cat.

Dorsal root ganglion cells with axons innervating the cat's knee joint via the medial articular nerve were retrogradely labelled with Fast blue. Neurokinin A-like immunoreactivity was found in 4.5 +/- 1.1% (mean +/- S.D. of 5 nerves and 695 cells) of the articular afferents. Colchicine treatment of the ganglia increased the percentage of immunopositive cells to 8.5 +/- 0.7% (mean +/- S.D. of 6 nerves and 554 cells) after 3-22 h. The diameter distribution of the immunopositive somata ranged from 20 to 50 microns with a maximum at 26-30 microns. Comparing the proportions of neurokinin A-immunopositive cells with those of substance P, it can be calculated on the basis of mRNA encoding that neurokinin A is synthetized in about half of the substance P-containing primary articular afferents.

Activation of fine articular afferent units by bradykinin.

The responses of single fine articular afferent units to close intra-arterial injection of KCl and bradykinin were recorded from filaments of the saphenous nerve of the cat's right hindlimb. All units included in this study were sensitive to local mechanical probing of the medial and anteromedial aspects of the knee joint. The units were identified by conduction velocity as belonging either to group III (2.5-20 m/s, 17 units) or group IV (less than 2.5 m/s, 23 units). Prior to bradykinin administration the responses of all units to passive limb movements were recorded in order to classify the units as belonging to one of the following 4 categories: activated by non-noxious movements; weakly activated by non-noxious movements; activated only by noxious movements; not activated by movements. Bolus injections of KCl were used to test the accessibility of the units via the blood vessels. Such injections elicited a rapid burst of impulses at short latencies of less than 1 s. If this discharge did not occur, no test with bradykinin was carried out. There was no difference in latency and time course between such discharges in group III and group IV units. With only 3 exceptions the 40 units excited by KCl were also activated by bradykinin which was applied in doses from 0.026 to 26 micrograms. Higher doses were not used. For most group III and IV units the minimal effective dose of bradykinin for a clear excitation was usually either 0.26 or 2.6 micrograms. In both groups of units the bradykinin-evoked discharge generally had a uniform latency and a time course with a total duration well under 1 min. In the course of repetitive injections at intervals of 3-5 min, the latency of the evoked discharge increased gradually and its magnitude became successively smaller. This tachyphylaxis was usually very pronounced, regardless of whether low or high doses of bradykinin were administered. No differences in the bradykinin sensitivity were found between units with very low to very high thresholds to local mechanical stimulation (tested with von Frey hairs) and between units belonging to the 4 different categories of response behavior to passive innocuous and noxious joint movements. These results indicate that the sensitivity to bradykinin is shared by all fine articular afferent units, regardless of their thresholds to local mechanical stimulation and joint movement and, hence, their functional role in signaling innocuous or noxious mechanical events at the knee joint.(ABSTRACT TRUNCATED AT 400 WORDS)

Capsaicin inhibits responses of fine afferents from the knee joint of the cat to mechanical and chemical stimuli.

In adult anaesthetized cats we studied the effects of capsaicin on the responses of single slowly conducting afferents of the knee joint to mechanical and chemical stimuli (bradykinin). An intra-arterial bolus injection of capsaicin into the joint reduced or abolished the responses to passive movements of the joint in 8 of 19 afferents and the responses to intra-arterially administered bradykinin in 10 of 11 units. Capsaicin was usually effective at 10(-4) to 10(-3) M. The inhibition was predominantly observed in nociceptive afferents, whereas most low threshold units were not desensitized.

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.