Dorsal root potentials and ventral root reflexes evoked by nonmyelinated fibers.

Electrical stimulation of C-fibers in the cat superficial peroneal nerve, with the A-fibers either conducting or blocked by cold, evoked dorsal root potentials having the same polarity as those evoked by A-fibers. Ventral root reflexes evoked by A-fibers were facilitated by a pure C-volley in the same or another nerve, but dorsal root potentials evoked by A-fibers were reduced by isolated dorsal root potentials from C-fibers. In the absence of anesthetics, single C-volleys produced brisk and prolonged reflex discharges in ventral roots.

Prostanoid-induced potentiation of the excitatory and sensitizing effects of bradykinin on articular mechanonociceptors in the rat ankle joint.

Responses of articular mechanonociceptors to intra-arterial injections of either bradykinin alone or in combination with prostaglandin E2, prostaglandin I2 or the selective I-type prostaglandin receptor agonist cicaprost were investigated electrophysiologically in anaesthetized rats. Bradykinin excited 76% of the mechanonociceptors studied and increased their responsiveness to repeated mechanical stimuli in 70% of units. Tachyphylaxis of these responses was evident in all cases. Injections of minimally effective doses of prostaglandin I2 or cicaprost excited the mechanonociceptors and increased their responsiveness to mechanical stimuli. Injections of prostaglandin E2 evoked only small increases in spontaneous discharge. Potentiation of bradykinin-evoked excitation was seen for combined injections of bradykinin with minimally effective or subthreshold doses of cicaprost in 86% of units, prostaglandin I2 in 40% of units and prostaglandin E2 in 56% of units. Combined injections of bradykinin and minimally effective or subthreshold doses of prostanoid agonist caused an increase in the responsiveness of mechanonociceptors to mechanical stimuli greater than that caused by either drug alone in 80% of units for cicaprost, 80% for prostaglandin I2 and 100% for prostaglandin E2. The relative potencies of prostaglandin I2, cicaprost and prostaglandin E2, suggest that prostanoid-induced excitation and sensitization of articular mechanonociceptors is mediated primarily by receptors for the naturally occurring prostanoid prostaglandin I2 (I-type P-receptors). Prostaglandin E2 may be important in potentiation of the sensitizing effects of bradykinin on mechanonociceptor responsiveness.

The effects of bradykinin and prostaglandin E1 on rat cutaneous afferent nerve activity.

1 The activity produced by intra-arterial bradykinin and prostaglandin E1 was investigated in multifibre strands dissected from the saphenous nerves of anaesthetized rats. 2 Bradykinin (0.5-10mug) alone produced little activity in nerve strands but produced considerable activity following a 10 min infusion, but not a single injection, of prostaglandin E1 (5-100 ng). 3 Prostaglandin E, alone produced a few large height spikes but following several injections of bradykinin smaller height spikes were also produced by prostaglandin E1. 4 It was concluded that the presence of a low concentration of prostaglandin E, is required for bradykinin to manifest its actions and that bradykinin and prostaglandin E1 are mutually potentiating in their effects on afferent nerve terminals.

Effects of paracetamol and aspirin on neural activity of joint mechanonociceptors in adjuvant arthritis.

1. The effects of paracetamol and lysine acetylsalicylate (L-AS) on high-threshold mechanonociceptors have been investigated by recording neural activity from the inflamed ankle joint in anaesthetized rats with mild adjuvant-induced monoarthritis. 2. Paracetamol (50 mg kg-1, i.v.) and L-AS (100 mg kg-1, i.v., equivalent to 50 mg kg-1 aspirin) both caused a maximal reduction of about 40% in mechanically-evoked discharge and of 30% in ongoing (spontaneous) activity by about 15 min after the injection: a second dose of either drug did not have any significant additional effect on discharge. 3. The prostanoid IP receptor agonist, cicaprost (0.1-0.5 micrograms), increased both mechanically-evoked and ongoing discharge to pre-paracetamol levels when injected close-arterially 30-50 min after paracetamol, whereas prostaglandin E2 (PGE2) was relatively ineffective at restoring activity. 4. The results suggest that prostacyclin (PGI2) contributes to the sensitization of high-threshold joint mechanonociceptors in adjuvant-induced monoarthritis, and that paracetamol and L-AS both act to reduce discharge by inhibiting the synthesis of prostacyclin in the joint capsule. 5. Paracetamol has a direct peripheral action affecting joint capsule mechanonociceptors in rat adjuvant-induced arthritis which is very similar to that of the soluble aspirin preparation, L-AS. These findings, together with the existing literature concerning the anti-arthritic effects of paracetamol, are relevant to the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

The effects of 5-HT on articular sensory receptors in normal and arthritic rats.

1. The effects of intra arterial (i.a.) injections of 5-hydroxytryptamine (5-HT, 1-100 micrograms) on the discharge of (a) identified articular high threshold mechanoreceptors and (b) unidentified chemosensitive receptors in the ankle joint have been studied electrophysiologically in anaesthetized normal and arthritic rats. Recordings were made from a fine branch of the medial plantar nerve. 2. 5-HT increased the mechanical responsiveness of high threshold nociceptive mechanoreceptors with C and A delta fibre afferents in both normal and adjuvant-arthritic rats. Receptors in arthritic joints were more sensitive to 5-HT than were those from normal joints. 3. 5-HT produced a complex response from both types of articular receptors following i.a. injection. Two separate components were identified: (a) a fast transient burst of activity was obtained within 10 s of this injection in 66% of units from normal animals and 45% from arthritics, followed by (b) a delayed slow longer-lasting excitation seen in 62% of the units examined from normals and 77% of units from arthritic rats. 4. Increased mechanoreceptor responsiveness produced by 5-HT was reduced or abolished by the 5-HT3 receptor antagonists studied (MDL 72222, ICS 205-930, or GR 38032F, in single doses of 100 micrograms kg-1, i.a.). 5. Fast excitation showed marked tachyphylaxis and was antagonized by MDL 72222, ICS 205-930 or GR 38032F. It was unaffected by ketanserin (100 micrograms kg-1, i.a.). Delayed excitation was reduced or abolished by ketanserin but was unaffected by the 5-HT3-receptor antagonists. 6. Administration of MDL 72222, ICS 205-930 or GR 38032F caused short lasting (< 5 min) reductions in background activity from both types of unit recorded in arthritic rats, as well as in normal rats in which activity had increased following administration of 5-HT. Ketanserin caused similar reductions in background activity in chemosensitive units, but had no effect on mechanoreceptors. 7. At least two types of receptor are involved in the actions of 5-HT on articular sensory receptors with fine afferent fibres. Increased mechano-responsiveness involves a 5-HT3-receptor as does fast excitation. Delayed excitation probably involves a 5-HT2-receptor. Endogenous 5-HT appears not to play a crucial role in sensitization of high threshold mechanoreceptors in this model of chronic inflammation and arthritis, although its local release may potentiate the actions of other inflammatory mediators on sensory receptors in the ankle joint.

Dorsal root potentials in the cat: effects of bicuculline.

Bicuculline (0.2 1 mg/kg) administered intravenously depressed dorsal root potentials (DRPs) evoked by stimulation of mixed, pure muscle or pure cutaneous nerves which was clearly concurrent with enhanced background potentials in intact cat. Administration of sodium pentobarbitone (15-30 mg/kg i.v.) reduced the ability of bicuculline to enhance background potentials and to depress evoked DRPs. In spinalized preparations, bicuculline depression of evoked DRPs by bicuculline in intact cat may not result from its action at axo-axonic GABAergic synapses alone and occlusion may also play a part. However, the role of gamma-aminobutyric acid (GABA) in primary afferent depolarization is confirmed in the spinalized preparations.

An alpha 2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones.

Extracellular recordings were made of 59 neurones with long, ascending projections (spinocervical tract (SCT) and dorsal column postsynaptic (DCPS) neurones) in the lumbar dorsal horn of anaesthetized and paralyzed cats. All showed prominent excitatory responses to innocuous stimuli, applied to their cutaneous receptive fields on the ipsilateral hindlimb. The majority of the population investigated (83%) was multireceptive, being activated by noxious as well as innocuous cutaneous stimuli. Drug effects were examined on a regular cycle of responses to these cutaneous stimuli and also to DL-homocysteic acid (DLH). In 49 multireceptive SCT and DCPS neurones, ionophoretically-applied L-noradrenaline (NA) produced a potent selective inhibition of the nociceptive responses (to heat or pinch) in 40 out of 44 SCT and 3 out of 5 DCPS neurones, with no statistically significant change in the responses to innocuous brush or DLH, or in spontaneous activity. NA had no effect on the majority of cells (8 out of 11) that responded only to innocuous stimuli. In 19 SCT neurones that showed NA-selectivity, the alpha 2-selective agonists clonidine (in 12 out of 15) and metaraminol (in 2 out of 3) mimicked this selective effect, whereas, the alpha 1 agonist, phenylephrine and the beta agonist, isoprenaline did not. Furthermore, the alpha 2 antagonists, yohimbine and idazoxan (RX781094), either reversed or reduced the potency of the NA-elicited inhibition of nociceptive responses in all 7 SCT neurones tested. These results are discussed in relation to other evidence for spinal antinociceptive effects of noradrenergic systems acting at a spinal level and the possible involvement of an alpha 2 receptor in such effects.

PGI2-induced activation and sensitization of articular mechanonociceptors.

The effects of PGE2 PGI2 and the stable PGI2 analogue cicaprost on the afferent discharge of ankle joint mechanonociceptors were studied in the anaesthetized rat. Close-arterial injection of PGI2 (0.01-0.1 micrograms) or cicaprost (0.05-5 micrograms) caused both sensitization to mechanical stimulation and excitation of the majority of mechanonociceptors, whereas PGE2 (0.03-3 micrograms) had only weak effects on a small number of nociceptive units. These results suggest the existence of specific PGI2 sensitive receptors (IP receptors) on rat sensory afferent nerves, and support the hypothesis that in the rat endogenous PGI2 plays an important role in the lowering of nociceptive thresholds in inflamed joints.

The anatomy and fine structure of the echidna Tachyglossus aculeatus snout with respect to its different trigeminal sensory receptors including the electroreceptors.

The gross anatomy and nerve supply of the bill of echidna (Tachyglossus aculeatus) is described in relation to its function as an outstanding sensory organ. The sensory innervation of the skin of the echidna snout was investigated by means of frontal serial sections, after decalcification of the specimens. A comprehensive light and electron microscopic description of the location and fine structure of cutaneous sensory receptors of the trigeminal system was made by this means. The encapsulated and non-encapsulated Ruffini receptors, the types of other free receptors in the connective tissue and the Merkel cell receptor do not differ morphologically from those of higher mammals, whereas the pacinian-like corpuscle shows a unique organization of its outer core. This is composed of large perineural cells containing a unique reticulum of parallel-orientated endoplasmic membranes. Lamellated corpuscles, seen in isolation or in association with push rods, are numerous in the snout and in the tip of the tongue of echidna. Push rod receptor organs occur in the hairless skin of the bill with a very dense array at its rostral end and in the pseudopalatal ridges. Gland duct receptors are restricted to the skin adjacent to the nostrils and the mouth opening, including the pseudopalatal plates. Only about one quarter of the total number of 400 seromucous glands receive a sensory innervation of their intraepidermal duct segment. Within each innervated gland two types of receptor terminals are identified. The distributions of the different receptor types are mapped for different regions of the skin, the mucous membrane of the nasal and oral vestibule and the tip of the tongue. The fine structure of nerve terminals is discussed from a comparative anatomical point of view, and some speculations are made about possible transduction processes that underlie the known electrophysiological properties. The sensory organs such as the "push rod" and "gland duct receptor", and most of their sensory terminals, are less differentiated in echidna snout than in the platypus (Ornithorhynchus anatinus) bill.

The afferent innervation of the face of sheep and goats.

The sensory innervation of the maxillary hairy skin and buccal mucous membrane was studied in anaesthetised sheep and goats. An electrophysiological technique isolated 47 single afferent units from the infraorbital nerve under chloralose or halothane anaesthesia. Mechanoreceptors of hairy skin were located in association with the following features: sinus hairs (n = 9); central primary hairs (n = 18); clear marginal hairs (n = 7) and skin-not-hair (n = 3). Units responded to hair tip displacement of 35 to 50 microm. Afferent units were also located in the mucous membrane of the cheek either associated with conical papillae (n = 8), or unassociated with papillae (n = 1). Receptor responses associated with hairs were classified as rapidly adapting (n = 18) and slowly adapting (n = 18) mechanoreceptor responses during sustained hair deflection. Seven mechanoreceptors of hairy skin and mucous membrane were excited by a fall in surface temperature. Two specific cold thermoreceptors were found: one in hairy skin and one in the mucous membrane. These units had phasic discharges during abrupt thermal depression and static discharges at constant surface temperatures. All afferent units had myelinated axons as indicated by their conduction velocities (range 20 to 57 m sec-1, mean 34 m sec-1). It is concluded that the mechanoreceptors identified had similarities with those of other mammalian species and some distinct differences. An interesting feature of mechanoreceptors in the buccal mucosa was their cold sensitivity. They therefore shared characteristics with mechanoreceptors in the penile mucosa of the ram and tongue of the sheep.