Nociceptive Receptive Fields Research Articles

Generalized expansion of nociceptive reflex receptive fields in chronic pain patients

Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25–75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38–0.54) and 0.33 (0.27–0.39), respectively (P=0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P<0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research.

Spatial encoding in spinal sensorimotor circuits differs in different wild type mice strains

BackgroundPrevious studies in the rat have shown that the spatial organisation of the receptive fields of nociceptive withdrawal reflex (NWR) system are functionally adapted through experience dependent mechanisms, termed somatosensory imprinting, during postnatal development. Here we wanted to clarify 1) if mice exhibit a similar spatial encoding of sensory input to NWR as previously found in the rat and 2) if mice strains with a poor learning capacity in various behavioural tests, associated with deficient long term potention, also exhibit poor adaptation of NWR.The organisation of the NWR system in two adult wild type mouse strains with normal long term potentiation (LTP) in hippocampus and two adult wild type mouse strains exhibiting deficiencies in corresponding LTP were used and compared to previous results in the rat. Receptive fields of reflexes in single hindlimb muscles were mapped with CO2 laser heat pulses.ResultsWhile the spatial organisation of the nociceptive receptive fields in mice with normal LTP were very similar to those in rats, the LTP impaired strains exhibited receptive fields of NWRs with aberrant sensitivity distributions. However, no difference was found in NWR thresholds or onset C-fibre latencies suggesting that the mechanisms determining general reflex sensitivity and somatosensory imprinting are different.ConclusionOur results thus confirm that sensory encoding in mice and rat NWR is similar, provided that mice strains with a good learning capability are studied and raise the possibility that LTP like mechanisms are involved in somatosensory imprinting.

The lateral ventromedial thalamic nucleus spreads nociceptive signals from the whole body surface to layer I of the frontal cortex

Neurons within the lateral ventromedial thalamic nucleus (VMl) convey selectively nociceptive information from all parts of the body. The present experiments were performed in rats and were designed to determine the organization of cortical projections from VMl neurons. In a first series of experiments, these cells were characterized electrophysiologically and individually labelled in a Golgi-like manner following juxtacellular electrophoresis of biotin-dextran. In a second experimental series, topical applications of the tracers fluorogold and tetramethylrhodamine-labelled dextran were placed into both the rostral-most and caudal areas of layer I of the dorsolateral frontal cortex, respectively. All VMl nociceptive neurons were fusiform and their full dendritic arborizations were bipolar, extending in the lateromedial axis. VMl cells are thus particularly well located to receive widespread nociceptive inputs via a brainstem link, viz. the medullary subnucleus reticularis dorsalis. VMl neurons driven by 'whole body' nociceptive receptive fields project to the rostral part of the layer I of the dorsolateral frontal cortex. These projections are widespread because double-labelling data showed a great number of VMl neurons labelled from both rostral and caudal dorsolateral cortices. The VMl comprises a homogeneous, organized subset of thalamic neurons that allow any signals of pain to modify cortical activity in a widespread manner, by interacting with the entire layer I of the dorsolateral neocortex.

Properties of an adult spinal sensorimotor circuit shaped through early postnatal experience.

During development, information about the three-dimensional shape and mechanical properties of the body is laid down in the synaptic connectivity of sensorimotor systems through adaptive mechanisms. This functional adaptation occurs through alteration of connection properties. Here, we characterize the differences between strong and weak connections in the nociceptive withdrawal reflex in adult decerebrate spinal rats, representing the preserved end product of the developmental adaptation process. Stronger excitatory reflex connections from the skin onto a muscle had relatively higher gain in their input-output relations, shorter onset latencies (up to approximately 150 ms) and lower trial-to-trial variability in relation to response amplitude (SD approximately mean(1/2)) than weaker pathways. Although inhibitory and excitatory nociceptive receptive fields of a muscle overlap to some degree, the results indicate that the inhibitory input is not a major determinant of the gain distribution within the excitatory receptive field and vice versa. The N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate (0.1-1 microg), applied topically on the spinal cord reduced the gain, whereas the response amplitude was mainly reduced by an absolute number by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist, 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (1-10 microg). The results indicate that NMDA receptors have a critical role in gain regulation in the nociceptive withdrawal reflex system. It is suggested that after normal postnatal experience-dependent adaptation, the number of connections from a given skin site onto the reflex encoding interneurons is a major determinant of the difference in gain.

Common principles of sensory encoding in spinal reflex modules and cerebellar climbing fibres

An important step towards understanding the function of olivo-cerebellar climbing fibres must be to clarify what they signal. We suggest that climbing fibres projecting to paravermal cerebellum mediate highly integrated sensorimotor information derived from activity in spinal withdrawal reflex modules acting on single forelimb muscles. To test this hypothesis, cutaneous nociceptive receptive fields of spinal reflex modules were mapped and compared to those of climbing fibres. Quantitative methods were used both for mapping and for comparing receptive fields. The organization of muscle afferent input converging on individual climbing fibres was analysed in the light of results from receptive field comparisons. Individual cutaneous receptive fields in the two systems were readily matched. Matched pairs were highly similar with regard to detailed distributions of sensitivity: correlation coefficient r= 0.85; overlap of receptive field foci 72 % (average values). The olivary targets of muscle afferents from a given muscle were mainly climbing fibres with cutaneous receptive fields similar to that of the muscle itself, but to a lesser extent also other climbing fibres. In conclusion, paravermal climbing fibres apparently convey information integrating (i) cutaneous input to an individual spinal withdrawal reflex module, (ii) muscle afferent input from the output muscle of that module and (iii) muscle afferent input from muscles that constitute the output of functionally related modules. This suggests that an individual climbing fibre signals cutaneous sensory events reflecting activity of a single muscle conditional upon the functional state of the muscle itself and that of functionally related muscles.

The role of 5-hydroxytryptamine 1A and 5-hydroxytryptamine 1B receptors in modulating spinal nociceptive transmission in normal and carrageenan-injected rats

Single unit extracellular recordings from the dorsal horn neurons were obtained with glass micropipettes in pentobarbital-anesthetized rats. A total of 115 wide dynamic range (WDR) neurons were studied in 94 rats. In normal rats, the size of nociceptive receptive fields (RFs) of WDR neurons was approximately 123.3±8.21 mm 2 ( n=88). Following carrageenan-induced inflammation, the RFs were markedly enlarged (332.4±30.1 mm 2, n=27, P<0.001). The frequency of background activity of the WDR neurons in carrageenan-injected rats (11.3±2.1 imp/s, n=27) was greater than that in normal rats (7.1±0.8 imp/s, n=88, P<0.05). In 82% of WDR neurons in normal rats, there was a separation between the A- and C-responses. In contrast, in 67% of the neurons in carrageenan-injected rats, the response to suprathreshold electrical stimuli was a long train with no separation between the A- and C-responses. In carrageenan-injected rats, the magnitude and duration of the nociceptive responses were significantly increased compared to those in normal rats, and the average C-response threshold (7.7±1.1 mA, n=27) was lower than that in normal rats (10.4±0.7 mA, n=88, P<0.05). Intrathecal injection of the 5-hydroxytryptamine 1A (5-HT 1A) receptor agonist 8-hydroxy-DPAT hydroxybromide (8-OH-DPAT) (0.305, 1.525, 3.05, and 15.25 mM) dose-dependently increased Aδ- and C-responses and post-discharge in most of the WDR neurons. Following carrageenan-induced inflammation, the 8-OH-DPAT-induced facilitatory effect on Aδ- and C-responses and post-discharge was significantly enhanced ( P<0.05). Intrathecal injection of the 5-hydroxytryptamine 1B (5-HT 1B) receptor agonist CGS12066A (0.222, 1.11, 2.22, and 11.1 mM) dose-dependently enhanced the C-response and post-discharge without influencing the Aδ-response. In carrageenan-injected rats, CGS12066A not only enhanced the facilitatory effect on the C-response and post-discharge, but also facilitated the Aδ-response. Intrathecal injection of the 5-HT 1A receptor antagonist NAN-190 (0.2 mM) alone did not influence Aδ- and C-responses and post-discharge of WDR neurons in normal rats. When 0.2 mM NAN-190 was co-administered with 3.05 mM 8-OH-DPAT, the facilitatory effect of 8-OH-DPAT on Aδ- and C-responses and post-discharge was completely antagonized, whereas CGS12066A-induced facilitation on the C-response and post-discharge was not influenced by co-administration of 0.2 mM NAN-190 and CGS12066A. These data suggest that 5-HT 1A and 5-HT 1B receptor subtypes mediate the facilitatory effect of 5-HT on nociceptive processing in the spinal cord of rats. The excitability of dorsal horn WDR neurons and the sensitivity of the neurons to intrathecal 5-HT 1A and 5-HT 1B receptor agonists might increase following carrageenan-induced inflammation.

Developmental Tuning in a Spinal Nociceptive System: Effects of Neonatal Spinalization

Recent studies indicate a modular organization of the nociceptive withdrawal reflex system. Each module has a characteristic receptive field, closely matching the withdrawal movement caused by its effector muscle. In the rat, the strength of the sensory input to each module is tuned during the first postnatal weeks, i.e., erroneous spinal connections are depressed, and adequate connections are strengthened. To clarify if this tuning is dependent on supraspinal structures, the effect of a complete neonatal spinal cord transection on the postnatal tuning of withdrawal reflexes was studied. The nociceptive receptive fields of single hindlimb muscles and compound withdrawal reflexes were examined in decerebrate unanesthetized and awake rats, respectively. Noxious thermal CO(2) laser stimulation was used to evoke reflex responses. Neonatal spinal cord transection resulted in a disrupted reflex organization in the adult rat, resembling that previously found in neonatal rats. The receptive fields of single hindlimb muscles exhibited abnormal distribution of sensitivity not matching the withdrawal action of the effector muscles. Likewise, the composite nocifensive movements, as documented in the awake rat, often resulted in erroneous movements toward the stimulus. It is concluded that withdrawal reflexes do not become functionally adapted in rats spinalized at birth. These findings suggest a critical role for supraspinal systems in the postnatal tuning of spinal nociceptive systems.

Characterization of spinal somatosensory neurons having receptive fields in lumbar tissues of cats

In pentobarbital anesthetized cats, extracellular unitary recordings were made from neurons in the extreme lateral dorsal horn of spinal segments L4–5. All 118 units reported had receptive fields in deep somatic tissues and/or skin of the lumbar region, hip and/or proximal leg. Neurons were functionally characterized according to their responses to non-noxious and noxious mechanical stimuli and to injections of algogens. Most neurons (92%) were either wide-dynamic range (WDR) or nociceptive specific (NS), and most of these had very large nociceptive receptive fields in the back/hip/leg that included both skin and deep somatic tissues innervated through both the dorsal (back/hip) and ventral (leg/ventral spine) rami. Most (72%) were ‘hyperconvergent’ in that they were responsive to stimulation of many different somatic tissues including skin, muscles, facet joint capsules, ligaments, and periosteum. Some units were tested and found also to be activated by noxious stimulation of spinal dura and ventral annulus fibrosis and ventral longitudinal ligament. Twelve of 22 neurons tested were found to have ascending axons extending beyond Th10. The nocireceptive neurons (NS and WDR) in the population tested are suitable for processing information about tissue damage in deep somatic tissues in the back, hip and proximal leg. The apparent relative paucity of such neurons and their very large hyperconvergent receptive fields suggest that sensations served by these neurons, such as low back and referred leg pain, would be neither well localized nor attributable to pathology in a specific tissue. These deductions, based on physiological characteristics in cats, are consistent with clinical reports from humans who experience pain as a consequence of spinal or paraspinal injuries.

Functional organization of the nociceptive withdrawal reflexes

The spatial organization of the cutaneous input to hindlimb withdrawal reflexes was studied in spinalized, decerebrated, unanesthetized rats. Reflex activity in plantar flexors of the digits, pronators of the foot, dorsiflexors of the digits, and/or the ankle and flexors of the knee was recorded with electromyographic techniques for up to 12 h after spinalization. Graded mechanical (pinch) and thermal stimulation (CO2 laser) of the skin were used. Reflexes were absent ("spinal shock") during approximately 10-20 min after spinalization. The reflex thresholds for pinch and CO2 laser stimulation then decreased considerably during the following 5-8 h. After this time, even mild pressure (less than 0.1 N/mm2) on the skin was sufficient to evoke a reflex in most muscles. During the period from about 0.5-3 h after spinalization, the nociceptive receptive field of each muscle usually corresponded to the area of the skin withdrawn by the muscle. Maximal responses were evoked from the area of the receptive field maximally withdrawn. During this period, responses to innocuous pinch were evoked mainly from the most sensitive area of the receptive fields. Concomitant with the decrease in reflex thresholds, the nociceptive receptive fields expanded for all muscles, often to include areas of the skin not withdrawn by the muscles. For most muscles, reflexes on tactile stimuli were eventually elicited from the entire receptive fields. The receptive fields for thermonociceptive and mechanonociceptive inputs were similar in most muscles. The interossei muscles were exceptional in that they responded very weakly to thermal stimulation. It is concluded that there are neuronal networks in the spinal cord that translate cutaneous nociceptive and tactile input into a withdrawal. However, the control exerted by descending pathways is necessary to maintain a functionally adequate excitability in these reflex pathways and an appropriate size for their receptive fields.

The postsynaptic dorsal column pathway mediates cutaneous nociceptive information to cerebellar climbing fibres in the cat.

1. The location in the spinal cord of the pathway mediating cutaneous nociceptive C fibre input to climbing fibres projecting to the forelimb area of the C3 zone in the cerebellar anterior lobe was investigated in pentobarbitone-anaesthetized cats. Lesions of the spinal cord at the segmental level of C3 sparing the dorsal funiculi (DF preparation) or lesions of the ipsilateral and part of the contralateral dorsal funiculi were made. 2. In the DF preparation, the cutaneous input to climbing fibres projecting to the C3 zone was the same as in cats with an intact spinal cord. Also, the topography of tactile and nociceptive receptive fields and the distribution of A- and C fibre-evoked climbing fibre field potentials was similar to that in cats with an intact spinal cord. 3. In cats with an initially intact spinal cord the cutaneous nociceptive C fibre input and the topographically well organized tactile input to the C3 climbing fibres disappeared following a lesion of the ipsilateral and part of the contralateral dorsal funiculi. Following this lesion the receptive fields of the climbing fibres became indistinct and only irregular responses were evoked on skin stimulation. 4. It is concluded that the cutaneous nociceptive C fibre input from the forelimb to climbing fibres projecting to the C3 zone is mediated by the ipsilateral dorsal funiculus. Since cutaneous C fibres terminate exclusively in the spinal cord close to their entrance zone the postsynaptic dorsal column pathway must be part of this spino-olivocerebellar pathway.

Topography and nociceptive receptive fields of climbing fibres projecting to the cerebellar anterior lobe in the cat.

1. The cutaneous receptive fields of 225 climbing fibres projecting to the forelimb area of the C3 zone in the cerebellar anterior lobe were mapped in the pentobarbitone-anaesthetized cat. Responses in climbing fibres were recorded as complex spikes in Purkinje cells. 2. A detailed topographical organization of the nociceptive climbing fibre input to the C3 zone was found. In the medial C3 zone climbing fibres with receptive fields covering proximal and/or lateral parts of the forelimb projected most medially. Climbing fibres with receptive fields located more medially on the forelimb projected successively more laterally. The sequence of receptive fields found in the lateral C3 zone was roughly the reverse of that in the medial C3 zone. Climbing fibres with receptive fields restricted to the digits projected preferentially to the caudal part of the forelimb area, whereas those with receptive fields covering both proximal and ventral areas of the forearm projected to more rostral parts. 3. The representation of the forelimb was uneven. Receptive fields with a focus on the digits or along the lateral side of the forearm dominated. 4. The proximal borders of the receptive fields were located close to joints. The area from which maximal responses were evoked was usually located eccentrically within the receptive field. Based on spatial characteristics the receptive fields could be divided into eight classes, which in turn were tentatively divided into subclasses. Similar subclasses of receptive fields were found in different cats. This classification was further supported by the results of a quantitative analysis of eighty-nine climbing fibres. The receptive fields of these climbing fibres were mapped with standardized noxious stimulation. 5. Climbing fibres terminating within sagittal strips (width, 100-300 microns; length, greater than 1 mm) had receptive fields which belonged to the same subclass. There were commonly abrupt changes in receptive fields between such microzones. Most classes of receptive fields were found in both the medial and the lateral parts of the C3 zone. However, receptive fields with a focus on the ventral side of either the metacarpals, the wrist or the forearm were found only in the medial part of the C3 zone. Furthermore, the class of receptive fields restricted to the lateral side of the upper arm and shoulder was only found in the lateral part of the C3 zone. 6. In the discussion, it is proposed that climbing fibres projecting to each microzone carry information from spinal multireceptive reflex arcs acting on a single muscle or a group of synergistic muscles.(ABSTRACT TRUNCATED AT 400 WORDS)

Stimulation of cranial vessels excites nociceptive neurones in several thalamic nuclei of the cat

Extracellular recordings were made in the thalamus of cats anaesthetized with chloralose and urethane following electrical, mechanical and chemical stimulation of the superior sagittal sinus or middle meningeal artery. Facial receptive fields were looked for using electrical and mechanical stimuli. The locations of fifty-six cells were verified histologically. Twenty six cells were located in the ventroposteromedial nucleus (VPM) and six in its ventral periphery (VPMvp). All units in VPM had facial receptive fields, usually involving the first trigeminal division. Cells with nociceptive receptive fields or responding to the craniovascular application of bradykinin were often found in the periphery or "shell" region of VPM. Other craniovascular nociceptive cells were found in VPMvp, in the posterior group and in the intralaminar complex. This study shows that craniovascular afferents in the cat project to several thalamic nuclei and implicate VPM especially in craniovascular nociception.

Mustard oil excites but does not inhibit nociceptive dorsal horn neurones in the rat: a presumed effect on A-delta fibres.

1. Mustard oil was applied topically in concentrations of 10-20% to the excitatory and inhibitory nociceptive receptive fields in glabrous and hairy skin of the anesthetized rat while recording the activity of nociceptive dorsal horn neurones. The noxious stimulus was radiant heat which is known to activate C-fibres in glabrous and hairy skin. 2. Mustard oil had little effect when applied to glabrous skin and this was attributed to poor penetration of the skin. 3. Mustard oil excited cells in the dorsal horn which were excited by noxious heat in the receptive field on hairy skin. 4. Mustard oil excited cells in the dorsal horn which were inhibited by noxious heat in the receptive field on hairy skin. 5. Inhibitory effects of mustard oil were never seen, even when applied to receptive fields in which noxious heating caused inhibition. 6. The excitatory effects of mustard oil on cells inhibited by noxious heating of the skin are attributed to the reported activation of A-delta fibres which probably masked any C-fibre activation.