Central Nociceptive Pathways Research Articles

The role of calcitonin gene-related peptide in the pathogenesis of primary headache

The activity of neurons in the spinal trigeminal nucleus (STN) is thought to reflect the activity of central trigeminal nociceptive pathways that underlie facial pain and headache in man. About 40% of human trigeminal neurons contain the neuropeptide calcitonin gene-related peptide (CGRP), which is released from these primary afferents upon activation. The CGRP levels in the jugular venous blood are elevated during migraine attacks and cluster headache, and the time course of CGRP plasma levels parallels headache intensity. The functional relevance of mechanisms downstream of CGRP has been demonstrated by headache generation following CGRP infusion and the successful treatment of spontaneous migraine by a CGRP receptor antagonist. The functional relevance of CGRP in the pathophysiology of headache is further supported by animal experiments in which a CGRP receptor antagonist reduced nociceptive signaling in the STN.

Altered central excitability and analgesic treatment in patients with restless legs syndrome

Sir, Stiasny-Kolster et al . (2004) found enhanced sensitivity to pinprick stimuli in patients with restless legs syndrome (RLS) compared with healthy controls. Interestingly, no dynamic mechanical hyperalgesia to light tactile stimuli (allodynia) was observed. The authors concluded there might be a close relationship of RLS and pain modulation disorders with altered excitability of central nociceptive pathways as seen in patients with neuropathic pain. Recent clinical data support their conclusion: in a sample of 243 consecutive patients with affective and anxiety disorders, 52 out of 65 patients with RLS also suffered from chronic recurrent pain (Leutgeb et …

Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture

Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture

Does Mg 2+ deficiency induce a long-term sensitization of the central nociceptive pathways?

In rats, a Mg 2+-deficient diet, which in a few days dramatically decreased the Mg 2+ concentration in plasma, cerebrospinal fluid (CSF) and spinal cord, was accompanied by a significant lowering of the nociceptive threshold. After reloading, the Mg 2+ concentration was rapidly normalized in both spinal cord and CSF. In parallel, the neurological disturbances induced by Mg 2+ deficiency vanished in less that 24 h, but the reversal of the hyperalgesia was delayed for up to 11 to 20 days. In this model, repeated doses of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist, given at start of the Mg 2+-depleted diet, prevented hyperalgesia, suggesting the involvement of NMDA receptor channels. The delayed recovery of a normal pain threshold argues for long-term sensitization of the nociceptive pathways.

Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome

Although individuals with fibromyalgia syndrome (FMS) consistently report wide-spread pain, clear evidence of structural abnormalities or other sources of chronic stimulation of pain afferents in the involved body areas is lacking. Without convincing evidence for peripheral tissue abnormalities in FMS patients, it seems likely that a central pathophysiological process is at least partly responsible for FMS, as is the case for many chronic pain conditions. Therefore, the present study sought to obtain psychophysical evidence for the possibility that input to central nociceptive pathways is abnormally processed in individuals with long standing FMS. In particular, temporal summation of pain (wind-up) was assessed, using series of repetitive thermal stimulation of the glabrous skin of the hands. Although wind-up was evoked both in control and FMS subjects, clear differences were observed. The perceived magnitude of the sensory response to the first stimulus within a series was greater for FMS subjects compared to controls, as was the amount of temporal summation within a series. Within series of stimuli, FMS subjects reported increases in sensory magnitude to painful levels for interstimulus intervals of 2–5 s, but pain was evoked infrequently at intervals greater than 2 s for control subjects. Following the last stimulus in a series, after-sensations were greater in magnitude, lasted longer and were more frequently painful in FMS subjects. These results have multiple implications for the general characterization of pain in FMS and for an understanding of the underlying pathophysiological basis.

Chronic Pain is Associated with Increased TrkA Immunoreactivity in Spinoreticular Neurons

Repetitive noxious stimulation leads to permanent adaptive changes of central pathways involved in the genesis and integration of nociception. Several classes of neurotrophic factors that affect brain plasticity are also involved in the regulation of sensory functions in adulthood. To investigate a putative role of nerve growth factor (NGF) in central plasticity linked to chronic pain, modifications in immunoreactivity (IR) for the high-affinity NGF receptor, TrkA, were studied at spinal levels in a rat model of inflammatory chronic pain, adjuvant-induced arthritis (AIA). We report a specific increase in the number of TrkA-IR profiles in laminae V-VI at lumbar levels L3 and L4 in arthritic rats. Tract tracing using FluoroGold injections in the ventrobasal complex of the thalamus and in the brainstem showed that these increased TrkA-IR profiles are spinoreticular neurons. Dual labeling with calcitonin gene-related peptide or substance P showed that TrkA-IR neurons were mainly located in projection fields of small- to medium-sized primary afferent fibers, which convey nociceptive inputs. These results suggest that TrkA-containing neurons of the spinal dorsal horn participate in the first central relay of transmission of nociceptive information to supraspinal centers. Enhanced numbers of TrkA-IR neurons during AIA strongly support the hypothesis of a participation of NGF in adaptive mechanisms of central nociceptive pathways observed in chronic pain states.

8 The NMDA-antagonist ketamine for prevention and treatment of acute and chronic post-operative pain

Summary The data reviewed here show that ketamine in sub-anaesthetic doses has analgesic properties that is related to the blockade of central NMDA receptors. Ketamine may become an effective pre-emptive analgesic by reducing the central sensitization to pain caused by increased activity in nociceptive primary afferents. Central sensitization to pain is dependent on the activation of NMDA receptors, and the action of ketamine is related to the blockade of central NMDA receptors. Psychotomimetic side effects is a major disadvantage with ketamine. Therefore, the compound should be co-administered with other drugs that may have additive effects so that the dose of ketamine can be reduced, like opioids or local anaesthetics, or drugs that reduce the psychotomimetic side effects, like benzodiazepines. Ketamine also reduces the different components associated with chronic pathological pain, including continuous, intermittent and evoked pain. Chronic pathological pain is dependent on altered functional activity in central nociceptive pathways, including neuronal hyperexcitability and hyperactivity. In these patients the central sensitization to pain has not been reversed in the normal way after an acute trauma. Evidence is given that ketamine may down-regulate this neuronal hyperactivity and thereby relieve pathological pain. However, a major objection against ketamine is the frequency of side effects. Therefore, the role of NMDA-receptor antagonists in the treatment of chronic pain, is dependent on the development of new and more selective NMDA-receptor blockers with few side effects. Furthermore, the co-administration of NMDA-receptor antagonists with other neurochemicals such as opioids, neuropeptides, and possibly local anaesthetics, might increase the analgesic efficacy.

Nicotinic acetylcholine receptors on capsaicin-sensitive nerves.

To study the density of nicotinic acetylcholine receptors on primary afferents and central nociceptive pathways, [3H](-)-nicotine binding was conducted in the cerebral cortex and spinal cord including dorsal roots and ganglia (DRG), of control rats and rats desensitized by neonatal capsaicin treatment. [3H](-)-nicotine binding in capsaicin-treated rats was reduced in cerebral cortex by 35% and spinal cord+DRG by 46% (p < 0.05). Functionally, both iontophoretically applied acetylcholine- and capsaicin-evoked flares (measured by laser Doppler flowmetry) were reduced in capsaicin-treated animals (p < 0.05); similarly, electrical stimulation-evoked flares were significantly lower in the same group, compared with controls (p < 0.05). These data provide direct evidence that many neuronal nicotinic acetylcholine receptors are associated with capsaicin-sensitive peptidergic neurones, including primary afferents, DRG and central nociceptive pathways.

Painful Neuropathy

In neuropathic pain states, dynamic mechanical allodynia is mediated by large diameter A beta-fibers. We test whether ongoing peripheral C-nociceptor input is necessary to maintain central changes hypothetically responsible for A beta-mediated allodynia. A patient with long-standing diabetes mellitus demonstrated generalized signs of painless diabetic small fiber polyneuropathy. Following mechanical trauma, the patient additionally developed a typical neuropathic pain syndrome at the arm. Despite substantial impairment of cutaneous small fiber function, he complained of severe dynamic mechanical allodynia confined to a forearm skin area. Marstock test revealed a considerably increased cold perception threshold within the allodynic area and on the contralateral side. The patient could not perceive any warm sensation on either side. Histamine iontophoresis was not followed by any itch or pain sensations within the allodynic area or contralaterally. Nociceptive C-fiber axon reflex reactions were substantially impaired within the allodynic skin or contralaterally. Standard neurophysiological testing and quantitative vibrametry showed only mild impairment of large diameter sensory and motor fiber function at the arms. Cardiovascular reflex tests showed almost no heart rate variation indicating impairment of vagal small fiber function. (a) Cutaneous nociceptive C-fibers do not signal dynamic mechanical allodynia. This symptom may hypothetically be due to secondary changes in the central nervous system processing that might strengthen the synaptic ties between A beta-fibers and central nociceptive pathways, or due to peripheral multiplication of primary afferent low threshold mechanoreceptor input. (b) Ongoing nociceptive C-fiber input is not necessary to maintain either hypothetical mechanism. (c) Hypothetical secondary central hyperexcitability might work autonomously without any nociceptive C-fiber input for a long time or even indefinitely in some neuropathic patients.

Causalgia—reflex sympathetic dystrophy—sympathetically maintained pain: Myth and reality

Causalgia, reflex sympathetic dystrophy, and sympathetically maintained pain (SMP) are a complex group of disorders, with symptoms of spontaneous/stimulus-induced pain and vasomotor, sudomotor or skeletomotor dysfunction of the involved area. Sympatholysis has been recommended for diagnosis/classification and treatment of these patients. Lack of adequate placebo control makes the physiologic response to this intervention unclear. Sensitization of wide dynamic range (WDR) neurons in the central nociceptive pathway has been proposed as a key element in pathophysiologic mechanisms of these disorders. Low threshold mechanoreceptors and nociceptors have been implicated as the primary afferents transmitting signals to or maintaining sensitization of WDR neurons in SMP. Vasomotor disturbances may result from antidromic vasodilatation, vasoparalytic dilatation, normal somatosympathetic reflexes, and denervation supersensitivity. There is conflicting information regarding the use of phentolamine and clonidine in these pain syndromes. Treatment of these patients remains a challenge given the many potential underlying mechanisms.

Deafferentation Pain Syndromes

Neuropathic pain is a major clinical problem and is often a source of persistent suffering and disability for patients with deafferenting injuries. In addition to the emotional burden of this persistent pain, patients' lives are frequently disrupted socially and financially. Understanding of the mechanisms that underlie neuropathic pain is poor, although there is evidence for widespread changes within the peripheral and central somatosensory nervous systems of such patients. In addition, treatment for neuropathic pain is often ineffective. Some degree of symptom control is often possible, however, through a multidisciplinary approach. This approach includes medications, physical treatments, and behavioral modifications. The limited understanding we have of the mechanisms of neuropathic pain is a strong reason to actively pursue further research into the pathophysiology of these conditions. Continued clinical and basic investigations into neuropathic pain also provide the best chance of finding treatments that are effective.

Vascular Headaches and Cerebral Circulation: An Overview

A complex network of neurotransmission systems underlies the control of the cerebral circulation. Classical neurotransmitters, vasoactive peptides and receptors have been found in cerebral arteries. Central and peripheral structures are also probably involved in the neurogenic control of the cerebral circulation. Vascular and neurotransmission changes reported in vascular headaches suggest that an alteration of the neurogenic control of the brain circulation may be implicated in vascular headaches. In particular, locus coeruleus, which may control the intracerebral adrenergic pathway, can induce vascular changes similar to those of migraine. Moreover, the trigeminal ganglion, which may induce the release of substance P, can change the extracranial and intracranial vasodilator activity. The vascular theory of migraine, proposed by Wolff, is re-evaluated on the grounds of a possible mediation of the vascular responses by neurotransmitters. It is hypothesized that a deficient modulation by enkephalins may cause alterations of locus coeruleus and/or trigeminal ganglion. The problem of pain in vascular headaches is also considered: whether it is of vascular origin or whether it is due to a dysfunction of the central nociceptive pathway. Knowledge of the neurogenic control of the cerebral circulation may be useful in understanding some pathogenetic mechanisms of vascular headaches.