Sensitization Of Primary Afferent Nociceptors Research Articles

Protein kinase C epsilon activation regulates proliferation, migration, and epithelial to mesenchymal-like transition in rat Schwann cells.

Protein kinase type C-ε (PKCε) plays an important role in the sensitization of primary afferent nociceptors, promoting mechanical hyperalgesia. In accordance, we showed that PKCε is present in sensory neurons of the peripheral nervous system (PNS), participating in the control of pain onset and chronification. Recently, it was found that PKCε is also implicated in the control of cell proliferation, promoting mitogenesis and metastatic invasion in some types of cancer. However, its role in the main glial cell of the PNS, the Schwann cells (SCs), was still not investigated. Rat primary SCs culture were treated with different pharmacologic approaches, including the PKCε agonist dicyclopropyl-linoleic acid (DCP-LA) 500 nM, the human recombinant brain derived neurotrophic factor (BDNF) 1 nM and the TrkB receptor antagonist cyclotraxin B 10 nM. The proliferation (by cell count), the migration (by scratch test and Boyden assay) as well as some markers of SCs differentiation and epithelial-mesenchymal transition (EMT) process (by qRT-PCR and western blot) were analyzed. Overall, we found that PKCε is constitutively expressed in SCs, where it is likely involved in the switch from the proliferative toward the differentiated state. Indeed, we demonstrated that PKCε activation regulates SCs proliferation, increases their migration, and the expression of some markers (e.g., glycoprotein P0 and the transcription factor Krox20) of SCs differentiation. Through an autocrine mechanism, BDNF activates TrkB receptor, and controls SCs proliferation via PKCε. Importantly, PKCε activation likely promoted a partial EMT process in SCs. PKCε mediates relevant actions in the neuronal and glial compartment of the PNS. In particular, we posit a novel function for PKCε in the transformation of SCs, assuming a role in the mechanisms controlling SCs' fate and plasticity.

Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons.

Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKCε, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKCε via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain.

Differential modulation of voltage-gated sodium channels by nerve growth factor in three major subsets of TrkA-expressing nociceptors.

Nerve growth factor is an inflammatory mediator that induces long-lasting hyperalgesia, which can partially be attributed to nerve growth factor-induced sensitization of primary afferent nociceptors. It was shown that nerve growth factor increases the excitability of polymodal C-fibre nociceptors by modulating tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium channels, but hitherto only little is known about the effects of nerve growth factor on sodium currents in other nociceptor subtypes that express the nerve growth factor receptor TrkA. We previously characterized two reporter mouse lines that allow the unequivocal identification of two important subclasses of TrkA-expressing nociceptors – i.e. neuropeptide Y receptor type 2 (NPY2R+ ) Aδ-fibre nociceptors that mediate pinprick pain and nicotinic acetylcholine receptor alpha-3 subunit (CHRNA3+ ) silent nociceptors, which are the most abundant TrkA+ nociceptors in visceral organs and deep somatic tissues. Here, we utilized these mouse lines to investigate the expression patterns and the possible nerve growth factor-dependent modulation of sodium channels in these neurons using whole-cell patch-clamp recordings and quantitative real-time polymerase chain reaction. We demonstrate that NPY2R+ nociceptors, CHRNA3+ ‘silent’ nociceptors and polymodal C-fibre nociceptors express different combinations of sodium channel α- and β-subunits and accordingly exhibit functionally different sodium currents. Moreover, we demonstrate that nerve growth factor produces robust hyperpolarizing shifts in the half-activation voltage of tetrodotoxin-resistant currents in NPY2R+ nociceptors and polymodal C-fibre nociceptors and also shifts the half-activation of tetrodotoxin-sensitive currents in polymodal C-fibre nociceptors. In silent nociceptors, however, nerve growth factor solely increases the current density of the tetrodotoxin-resistant current but does not alter other sodium channel properties. Considering the different peripheral target tissues and the previously reported roles in different forms of pain of the nociceptor subpopulations that were examined here, our results suggest that nerve growth factor differentially contributes to the development visceral and cutaneous pain hypersensitivity and highlights the importance of developing different therapeutic strategies for different forms of pain.

The long-lasting sensitization of primary afferent nociceptors induced by inflammation involves prostanoid and dopaminergic systems in mice

In recent years, evidence that sensitization of primary afferent nociceptors is an important event associated with chronic pain has been accumulating. The present study aimed to evaluate the participation of the prostaglandin and sympathetic components in the long-lasting sensitization of nociceptors induced by acute inflammation in mice. The intraplantar administration of carrageenan (100μg) enhanced the nociceptive response to a small dose of PGE2 (9ng/paw) or dopamine (3μg/paw) up to 30days later. This long-lasting sensitization is dependent on dopaminergic and prostanoid systems, since the pre-treatment with chlorpromazine (3μg/paw) or indomethacin (100μg/paw), but not local (6μg/paw) or systemic (6mg/kg) treatment with morphine, prevented its development. In agreement with this idea, the previous intraplantar administration of hyperalgesic doses of PGE2 or dopamine also induced long-lasting sensitization, which was fully prevented by pretreatment with EP4 and D1 antagonists, respectively. In summary, the present work described in mice a long-lasting sensitization of nociceptors, initiated by an acute inflammatory stimulation and dependent on dopaminergic and prostanoid systems. The present data represent new insights on the mechanisms of peripheral sensitization that could contribute to establish the basis of new therapeutic strategies for acute and chronic inflammatory pain.

Metallopeptidase inhibition potentiates bradykinin-induced hyperalgesia

The neuropeptide bradykinin (BK) sensitizes nociceptor activation following its release in response to inflammatory injury. Thereafter, the bioactivity of bradykinin is controlled by the enzymatic activities of circulating peptidases. One such enzyme, the metalloendopeptidase EC3.4.24.15 (EP24.15), is co-expressed with bradykinin receptors in primary afferent neurons. In this study, using approaches encompassing pharmacology, biochemistry, cell biology, and behavioral animal models, we identified a crucial role for EP24.15 and the closely related EP24.16 in modulating bradykinin-mediated hyperalgesia. Pharmacological analyses indicated that EP24.15 and EP24.16 inhibition significantly enhances bradykinin type-2 receptor activation by bradykinin in primary trigeminal ganglia cultures. In addition, bradykinin-induced sensitization of TRPV1 activation was increased in the presence of the EP24.15/16 inhibitor JA-2. Furthermore, behavioral analyses illustrated a significant dose–response relationship between JA-2 and bradykinin-mediated thermal hyperalgesia. These results indicate an important physiological role for the metallopeptidases EP24.15 and EP24.16 in regulating bradykinin-mediated sensitization of primary afferent nociceptors.Metalloendopeptidases EP24.15 and EP24.16 regulate inflammatory sensitization of primary afferent nociceptors by mediating bradykinin type-2 receptor activation by bradykinin.

Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions

The proinflammatory cytokine TNF-α has been shown to promote activation and sensitization of primary afferent nociceptors. The downstream signaling processes that play a role in promoting this neuronal response remain however controversial. Increased TNF-α plasma levels during migraine attacks suggest that local interaction between this cytokine and intracranial meningeal nociceptors plays a role in promoting the headache. Here, using in vivo single unit recording in the trigeminal ganglia of anesthetized rats, we show that meningeal TNF-α action promotes a delayed mechanical sensitization of meningeal nociceptors. Using immunohistochemistry, we provide evidence for non-neuronal localization of the TNF receptors TNFR1 to dural endothelial vascular cells and TNFR2 to dural resident macrophages as well as to some CGRP-expressing dural nerve fibers. We also demonstrate that meningeal vascular TNFR1 is co-localized with COX-1 while the perivascular TNFR2 is co-expressed with COX-2. We further report here for the first time that TNF-α evoked sensitization of meningeal nociceptors is dependent upon local action of cyclooxygenase (COX). Finally, we show that local application of TNF-α to the meninges evokes activation of the p38 MAP kinase in dural blood vessels that also express TNFR1 and that pharmacological blockade of p38 activation inhibits TNF-α evoked sensitization of meningeal nociceptors. Our study suggests that meningeal action of TNF-α could play an important role in the genesis of intracranial throbbing headaches such as migraine through a mechanism that involves at least part activation of non-neuronal TNFR1 and TNFR2 and downstream activation of meningeal non-neuronal COX and the p38 MAP kinase.

Sensory Disturbances in Complex Regional Pain Syndrome: Clinical Observations, Autonomic Interactions, and Possible Mechanisms

To review mechanisms that might contribute to sensory disturbances and sympathetically-maintained pain in complex regional pain syndrome (CRPS). CRPS is associated with a range of sensory and autonomic abnormalities. In a subpopulation of patients, sympathetic nervous system arousal and intradermal injection of adrenergic agonists intensify pain. Mechanisms responsible for sensory abnormalities in CRPS include sensitization of primary afferent nociceptors and spinothalamic tract neurons, disinhibition of central nociceptive neurons, and reorganization of thalamo-cortical somatosensory maps. Proposed mechanisms of sympathetically-maintained pain include adrenergic excitation of sensitized nociceptors in the CRPS-affected limb, and interaction between processes within the central nervous system that modulate nociception and emotional responses. Central mechanisms could involve adrenergic facilitation of nociceptive transmission in the dorsal horn or thalamus, and/or depletion of bulbo-spinal opioids or tolerance to their effects. Sympathetic neural activity might contribute to pain and sensory disturbances in CRPS by feeding into nociceptive circuits at the site of injury or elsewhere in the CRPS-affected limb, within the dorsal horn, or via thalamo-cortical projections.

Sensitization of Primary Afferent Nociceptors Induced by Intradermal Capsaicin Involves the Peripheral Release of Calcitonin Gene-Related Peptide Driven by Dorsal Root Reflexes

Neuropeptides released from axons of primary afferent nociceptive neurons are the key elements for the incidence of neurogenic inflammation and their release is associated with dorsal root reflexes (DRRs). However, whether the release is due to the triggering of DRRs and plays a role in inflammation-induced pain still remain to be determined. The present study assessed the role of calcitonin gene-related peptide (CGRP) in sensitization of primary afferent nociceptors induced by activation of transient receptor potential vanilloid-1 (TRPV(1)) after intradermal injection of capsaicin and determined if this release is due to activation of primary afferent neurons antidromically by triggering of DRRs. Under dorsal root intact conditions, primary afferent nociceptive fibers recorded in anesthetized rats could be sensitized by capsaicin injection, as shown by an increase in afferent responses and lowering of the response threshold to mechanical stimuli. After DRRs were removed by dorsal rhizotomy, the capsaicin-evoked sensitization was significantly reduced. In dorsal root intact rats, peripheral pretreatment with a CGRP receptor antagonist could dose-dependently reduce the capsaicin-induced sensitization. Peripheral post-treatment with CGRP could dose-dependently restore the capsaicin-induced sensitization under dorsal rhizotomized conditions. Capsaicin injection evoked increases in numbers of single and double labeled TRPV(1) and CGRP neurons in ipsilateral dorsal root ganglia (DRG). After dorsal rhizotomy, these evoked expressions were significantly inhibited. These data indicate that the DRR-mediated neurogenic inflammation enhances sensitization of primary afferent nociceptors induced by capsaicin injection. The underlying mechanism involves antidromic activation of DRG neurons via upregulation of TRPV(1) receptors whereby CGRP is released peripherally.

Nociceptor sensitization to mechanical and thermal stimuli in pig skin in vivo

Primary hyperalgesia to mechanical and thermal stimuli are major clinical symptoms of inflammatory pain and can be induced experimentally by ultraviolet-B (UV-B) irradiation in humans. We set-up a pig model in order to have more options for pharmacological intervention on primary hyperalgesia. Pig skin was irradiated with a dose one- to threefold higher than the minimum erythema dose (MED) and investigated for mechanical and heat responsiveness 24 and 48 h post UV-B treatment. C-fiber activation upon mechanical and thermal stimulation was assessed indirectly by extent of the axon reflex erythema (flare) measured by laser Doppler imaging. Mechanical stimulation with von Frey filaments (100 mN) induced flare responses in UV-B treated skin at 24 and 48 h, but no effect was measured in normal untreated skin. Increased mechanical stimulation (600 mN) elicited a small flare response in normal skin in an area of 1.8 cm 2 on average that was extending about 2.5 cm 2 in the UV-B irradiated sites. Thermal stimuli provoked in normal pig skin flare areas of approximately 2 cm 2 (45 °C, 10 s) and 4.5 cm 2 (47 °C, 10 s) which increased to about 3.5 cm 2 (45 °C) and 5.5 cm 2 (47 °C) following UV-B irradiation at 24 and 48 h. No significant differences of mechanically or thermally induced hypersensitivity were seen between 24 and 48 h after irradiation. We conclude that UV-B induced mechanical and heat sensitization of primary afferent nociceptors can be assessed in pig skin, providing a new human-like model of primary hyperalgesia. Sensitization of primarily mechano-insensitive (silent) nociceptors, which are underlying the flare response in humans, most probably contributes to the observation presented here.

Involvement of Peripheral Purinoceptors in Sympathetic Modulation of Capsaicin-Induced Sensitization of Primary Afferent Fibers

Purinoceptors are distributed in primary afferent terminals, where transmission of nociceptive information is modulated by these receptors. In the present study, we evaluated whether the activation or blockade of purinoceptors of subtypes P2X and P2Y in the periphery affected the sensitization of primary afferents induced by intradermal injection of capsaicin (CAP) and examined their role in sympathetic modulation of sensitization of primary nociceptive afferents. Afferent activity was recorded from single Adelta- and C-primary afferent fibers in the tibial nerve in anesthetized rats. Peripheral pretreatment with alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP), a P2X-selective receptor agonist, could potentiate the CAP-induced enhancement of responses of Adelta- and C-primary afferent nociceptive fibers to mechanical stimuli in sympathetically intact rats. After sympathetic denervation, the enhanced responses of both Adelta- and C-fibers after CAP injection were dramatically reduced. However, this reduction could be restored when P2X receptors were activated by alpha,beta-meATP. A blockade of P2X receptors by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid could significantly reduce the CAP-induced sensitization of Adelta- and C-fibers. Pretreatment with uridine 5'-triphosphate, a P2Y-selective receptor agonist, did not significantly affect or restore the CAP-induced sensitization of Adelta- and C-fibers under sympathetically intact or sympathectomized conditions. Our study supports the view that ATP plays a role in modulation of primary afferent nociceptor sensitivity mainly by P2X receptors. Combined with our previous study, our data also provide further evidence that the sensitization of primary afferent nociceptors is subject to sympathetic modulation by activation of P2X as well as alpha(1)-adrenergic receptors.

Sympathetic modulation of afferent activity in primary afferent nociceptors following intradermal capsaicin injection in rats

Excitation and sensitization of transient receptor potential vanilloid receptor 1 (TRPV1) by the action of capsaicin (CAP) are established to be a major mechanism by which primary afferent nociceptors are activated and sensitized. TRPV1 receptors are located on small diameter neurons of dorsal root ganglia (DRG) with Adelta and C primary afferent nociceptive axons. Sympathetic post-ganglionic efferents are involved in the modulation of nociceptive transmission. The data presented here were collected in our ongoing study “Sympathetic modulation of acute neurogenic inflammation” to determine if sensitization of primary afferent nociceptors by activating TRPV1 receptors following intradermal injection of CAP is sympathetically modulated.

Sympathetic influence on capsaicin-evoked enhancement of dorsal root reflexes in rats.

A series of experiments by our group suggest that the initiation and development of neurogenic inflammation in rats are mainly mediated by dorsal root reflexes (DRRs), which are conducted centrifugally from the spinal dorsal horn in primary afferent nocieptors. In this study, DRRs were recorded in anesthetized rats from single afferent fibers in the proximal ends of cut dorsal root filaments at the L4-L6 level and tested for responses to intradermal injection of capsaicin. Sympathectomy combined with pharmacological manipulations were employed to determine if the capsaicin-evoked enhancement of DRRs was subject to sympathetic modulation. DRRs could be recorded from both myelinated (Abeta and Adelta) and unmyelinated (C) afferent fibers. After capsaicin was injected intradermally into the plantar foot, a significant enhancement of DRRs was seen in C- and Adelta-fibers but not in Abeta-fibers. This enhancement of DRRs evoked by capsaicin injection was almost completely prevented by sympathectomy. However, if peripheral alpha1-adrenoceptors were activated by intra-arterial injection of phenylephrine, the enhancement of DRRs evoked by capsaicin could be restored, whereas no such restoration was seen following pretreatment with an alpha2-adrenoceptor agonist, UK14,304. Under sympathetically intact conditions, the enhanced DRRs following capsaicin injection could be blocked by administration of terazosin, an alpha1-adrenoceptor antagonist, but not by administration of yohimbine, an alpha2-adrenoceptor antagonist. These results provide further evidence that the DRR-mediated neurogenic inflammation depends in part on intact sympathetic efferents acting on peripheral alpha1-adrenoceptors, which augment the sensitization of primary afferent nociceptors induced by capsaicin injection, helping trigger DRRs that produce vasodilation.

Hyperalgesia induced by peripheral inflammation is mediated by protein kinase C betaII isozyme in the rat spinal cord.

We have addressed the molecular mechanism(s) of hyperalgesia, which depends on increased excitability of dorsal horn neurons and on sensitization of primary afferent nociceptors, during peripheral inflammation. Following unilateral adjuvant-induced inflammation in the rat hind paw, time-course changes in behavioral hyperalgesia and functional activities of Ca2+/phospholipid-dependent protein kinase C isozymes were examined. Inflammation was characterized by increase in paw diameter, and behavioral hyperalgesia was quantified as paw withdrawal latency from a radiant heat source. Behavioral hyperalgesia on the injected paw was significantly increased. This was accompanied by a significant increase in total functional membrane-associated protein kinase C activity, whereas total cytosolic protein kinase C activity was unchanged on the sides of the lumbar spinal cord both contralateral and ipsilateral to the inflammation. Importantly, on the side of lumbar cord ipsilateral to the inflamed paw, the activity of membrane-associated protein kinase CbetaII was increased following the same time-course as the paw withdrawal latency decrease, suggesting an increased translocation of protein kinase Cbetall to the membrane related to behavioral hyperalgesia. A defined mixture of purified gangliosides, which inhibits intracellular protein kinase C translocation and activation, decreased inflammation-induced paw withdrawal latency, and specifically decreased the activity of membrane-associated protein kinase Cbetall on the side of the spinal cord ipsilateral to the inflammation. Quantitative immunohistochemical analyses demonstrated intensified protein kinase CbetaII-like immunoreactivity on the side of the spinal cord ipsilateral to the inflammation. Time-course for increases in the activity of membrane-associated protein kinase CbetaII, and in intensity of protein kinase CbetaII-immunoreactivity, paralleled inflammation-mediated changes in paw withdrawal latency and paw diameter. Our findings indicate an apparent involvement of protein kinase CbetaII isozyme specifically in the molecular mechanism(s) of thermal hyperalgesia.

Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin.

Evidence suggests that nerve growth factor (NGF) is an important mediator in inflammatory pain states: NGF levels increase in inflamed tissue, and neutralization of endogenous NGF prevents the hyperalgesia which normally develops during inflammation of the skin. Here we asked whether NGF contributes to sensitization of primary afferent nociceptors, which are an important component of pain and hyperalgesia in inflamed tissue. An in vitro skin nerve preparation of the rat was used to directly record the receptive properties of thin myelinated (Adelta) and unmyelinated (C) nociceptors innervating normal hairy skin, carrageenan-inflamed skin and carrageenan-inflamed skin where endogenous NGF had been neutralized by application of a trkA-IgG (tyrosine kinase Aimmunoglobulin G) fusion molecule. Following carrageenan inflammation, there was a marked increase in the proportion of nociceptors which displayed ongoing activity (50% of nociceptors developed spontaneous activity compared to 4% of nociceptors innervating normal uninflamed skin), and this was reflected in a significant increase in the average ongoing discharge activity. Spontaneously active fibres were sensitized to heat and displayed a more than twofold increase in their discharge to a standard noxious heat stimulus. Furthermore, the number of nociceptors responding to the algesic mediator bradykinin increased significantly from 28% to 58%. By contrast, the mechanical threshold of nociceptive afferents did not change during inflammation. When the NGF-neutralizing molecule trkA-IgG was coadministered with carrageenan at the onset of the inflammation, primary afferent nociceptors did not sensitize and displayed essentially normal response properties, although the inflammation as evidenced by tissue oedema developed normally. We therefore conclude that NGF is a crucial component for the sensitization of primary afferent nociceptors associated with tissue inflammation.

Descending facilitatory influences from the rostral medial medulla mediate secondary, but not primary hyperalgesia in the rat

Prolonged nociceptive input following peripheral injury results in hyperalgesia (enhanced response to a noxious stimulus), which is thought to occur as a consequence of sensitization of primary afferent nociceptors and enhanced excitability of spinal dorsal horn nociceptive neurons (central sensitization). [21] Since there is often an expansion of hyperalgesia to tissue adjacent, and even distant from the site of injury (secondary hyperalgesia), it is thought that this phenomenon primarily involves mechanisms of central modulation/plasticity. [2, 3, 7, 10, 22] In contrast, hyperalgesia observed at the site of tissue injury (primary hyperalgesia) involves peripheral mechanisms.

Involvement of cyclic AMP and cyclic GMP systems in the mechanism of sensitization of primary afferent nociceptors

Involvement of cyclic AMP and cyclic GMP systems in the mechanism of sensitization of primary afferent nociceptors

Pain and hyperalgesia after intradermal injection of bradykinin in humans

Pain and hyperalgesia, the perceptual campanions of tissue injury and inflammation, are thought to be in part attributable to the sensitization of primary afferent nociceptors by endogenously released chemicals, such as bradykinin. Bradykinin (0.1 to 10 nmol in 10 microliters) evoked a dose-dependent pain, hyperalgesia to heat stimuli, and wheal and flare when injected in a double-blind manner into the volar forearm intradermally. Though hyperalgesia to mechanical stimuli is a conspicuous feature of inflammatory pain, none was measurable for any of the bradykinin doses in response to graded nylon monofilament probes. A second injection of bradykinin (5- or 30-minute intervals) at the same site produced markedly less pain and hyperalgesia to heat stimuli, indicating that the algesic and hyperalgesic effects of bradykinin undergo tachyphylaxis. These findings suggest that bradykinin alone cannot account for all aspects of the hyperalgesia that occurs after inflammation.

Production of Hyperalgesic Prostaglandins by Sympathetic Postganglionic Neurons

Prostaglandin E2 and prostacyclin (prostaglandin I2) produce hyperalgesia in animals and humans. Because there is evidence that prostaglandins contribute to pain maintained by sympathetic nervous system activity, we evaluated whether sympathetic postganglionic neurons synthesize these hyperalgesic prostaglandins, and whether production of prostaglandins by these neurons can contribute to sensitization of primary afferent nociceptors. Intradermal injection of arachidonic acid but not linoleic acid, in the rat hindpaw, produces a decrease in mechanical nociceptive threshold. This hyperalgesic effect is prevented by indomethacin, an inhibitor of prostaglandin synthesis or by prior surgical removal of the lumbar sympathetic chain. To test the hypothesis that sympathetic postganglionic neurons are the source of prostaglandins, we measured production of prostaglandin E2 and 6-keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin) by homogenates of adult rat sympathetic postganglionic neurons from superior cervical ganglia. These homogenates produced significant amounts of prostaglandin E2 and 6-keto-prostaglandin F1 alpha, and most of this production is eliminated by neonatal administration of 6-hydroxydopamine which selectively destroys sympathetic postganglionic neurons. These results demonstrate that sympathetic postganglionic neurons produce prostaglandins, and supports further the hypothesis that the release of prostaglandins from sympathetic postganglionic neurons contributes to the hyperalgesia associated with sympathetically maintained pain.

Responses of primate SI cortical neurons to noxious stimuli.

Recordings were made from single SI cortical neurons in the anesthetized macaque monkey. Each isolated cortical neuron was tested for responses to a standard series of mechanical stimuli. The stimuli included brushing the skin, pressure, and pinch. The majority of cortical neurons responded with the greatest discharge frequency to brushing the receptive field, but neurons were found in areas 3b and 1 that responded maximally to pinching the receptive field. A total of 68 cortical nociceptive neurons were examined in 10 animals. Cortical neurons that responded maximally to pinching the skin were also tested for responses to graded noxious heat pulses (from 35 to 43, 45, 47, and 50 degrees C). If the neuron failed to respond or only responded to 50 degrees C, the receptive field was also heated to temperatures of 53 and 55 degrees C. Fifty-six of the total population of nociceptive neurons were tested for responses to the complete series of noxious heat pulses: 46 (80%) exhibited a progressive increase in the discharge frequency as a function of stimulus intensity, and the spontaneous activity of two (4%) was inhibited. One population of cortical nociceptive neurons possessed restricted, contralateral receptive fields. These cells encoded the intensity of noxious mechanical and thermal stimulation. Sensitization of primary afferent nociceptors was reflected in the responses of SI cortical nociceptive neurons when the ascending series of noxious thermal stimulation was repeated. The population of cortical nociceptive neurons with restricted receptive fields exhibited no adaptation in the response during noxious heat pulses of 47 and 50 degrees C. At higher temperatures the response often continued to increase during the stimulus. The other population of cortical nociceptive neurons was found to have restricted, low-threshold receptive fields on the contralateral hindlimb and, in addition, could be activated only by intense pinching or noxious thermal stimuli delivered on any portion of the body. The stimulus-response functions obtained from noxious thermal stimulation of the contralateral hindlimb were not different from cortical nociceptive neurons with small receptive fields. However, nociceptive neurons with large receptive fields exhibited a consistent adaptation during a noxious heat pulse of 47 and 50 degrees C. Based on the response characteristics of these two populations of cortical nociceptive neurons, we conclude that neurons with small receptive fields possess the ability to provide information about the localization, the intensity, and the temporal attributes of a noxious stimulus.4+.