Descending Pain Inhibitory Pathways Research Articles

Electroacupuncture on Visceral Hyperalgesia - What Is Its Mechanism?

Electroacupuncture on Visceral Hyperalgesia - What Is Its Mechanism?

Presynaptic nicotinic acetylcholine receptors enhance GABAergic synaptic transmission in rat periaqueductal gray neurons

The periaqueductal gray (PAG) is a major component of the descending pain inhibitory pathway, which is related to central analgesia. In the present study, we have investigated the possible roles of presynaptic nicotinic acetylcholine receptors in GABAergic transmission onto PAG neurons. In acutely isolated rat PAG neurons, GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded by use of a whole-cell patch clamp technique. Acetylcholine (30 μM) transiently increased both the frequency and amplitude of GABAergic mIPSCs. However, acetylcholine did not affect the GABA-induced membrane currents. This facilitatory action of acetylcholine disappeared in the presence of mecamylamine, a nonselective nicotinic receptor antagonist, and mimicked by nicotine, a nicotinic receptor agonist. The nicotine-induced increase in mIPSC frequency was completely blocked by dihydro-β-erythroidine, a selective β2-containing nicotinic receptor antagonist, but not methyllycaconitine or α-bungarotoxin, selective α7 nicotinic receptor antagonists. The results suggest that acetylcholine or nicotine acts presynaptic β2-containing nicotinic receptors, presumably α4β2 nicotinic receptors, to enhance spontaneous GABA release onto PAG neurons. The nicotine-induced increase in mIPSC frequency was completely occluded in the presence of Cd 2+, a general voltage-dependent Ca 2+ channels blocker, and in the absence of extracellular Ca 2+ or Na +. The results suggest that presynaptic nicotinic receptors are less permeable to Ca 2+, and that the activation of these receptors depolarizes GABAergic nerve terminals. In conclusion, presynaptic nicotinic receptors would temporally regulate the excitability of PAG neurons being not overexcited and eventually contribute to the cholinergic modulation of output from the PAG.

Functional magnetic resonance imagery (fMRI) in fibromyalgia and the response to milnacipran

Functional imaging has been used to study response to pain in fibromyalgia patients. Functional magnetic resonance imagery (fMRI) which tracks local changes in blood flow has a higher spatial and temporal resolution than other techniques such as positron emission tomography (PET) or single-photon emission tomography (SPECT). fMRI studies in fibromyalgia patients suggest that similar levels of subjective pain result in similar central nervous system (CNS) activation in both fibromyalgia patients and controls. For a similar stimulus, however, fibromyalgia patients have a greater subjective sensation of pain. This increased sensitivity is accompanied with a decreased activity in brain regions implicated in the descending pain inhibitory pathways. The hypothesis that increased sensitivity to pain is due to decreased activity of the descending inhibitory pathways is supported by results with milnacipran. Fibromyalgia patients treated with the serotonin and noradrenaline reuptake inhibitor, milnacipran, exhibited a reduction in pain sensitivity and a parallel increase in activity in brain regions implicated in the descending pain inhibitory pathways compared to placebo-treated patients.

Mechanisms of analgesic action of pulsed radiofrequency on adjuvant-induced pain in the rat: Roles of descending adrenergic and serotonergic systems

Pulsed radiofrequency (PRF) has been reported to be effective in the treatment of several types of pain. The mechanism of action, however, is not well known. In a recent study, the antinociceptive effects of acute thermal pain were shown to be mediated via descending pain inhibitory pathways. In this study we observed an analgesic effect of PRF treatment in an adjuvant induced inflammatory pain model in rats. In this model, sciatic nerves were treated with PRF at 37° and 42°, which inhibited hyperalgesia in the inflammatory groups when compared to RF and sham treatment. This effect was attenuated after intrathecal administration of the alpha2-adrenoceptor antagonist yohimbine, the selective 5-HT3 serotonin receptor antagonist MDL72222, and the non-selective serotonin receptor antagonist methysergide. All three drugs were found to significantly inhibit the analgesic effect of PRF. The results suggest that the analgesic action of PRF involves the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways.

Mechanisms of Analgesic Action of Neurotropin on Chronic Pain in Adjuvant-Induced Arthritic Rat: Roles of Descending Noradrenergic and Serotonergic Systems

Neurotropin®, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug for treatment of chronic pain. In this study, we investigated the analgesic mechanisms of Neurotropin in the adjuvant-induced arthritic rat, a chronic pain model with inflammation. Neurotropin caused dose-dependent inhibition of hyperalgesia in the adjuvant-induced arthritic rat after single intravenous (10 – 100 NU/kg) and oral (30 – 200 NU/kg) administration. The analgesic effect of Neurotropin (intravenous 100 NU/kg and oral 200 NU/kg) was significantly inhibited by intrathecal injections of the α2-adrenoceptor antagonist yohimbine (30 nmol/animal) and the selective 5-HT3 serotonin receptor antagonist MDL72222 (30 nmol/animal), and slightly inhibited by the non-selective serotonin receptor antagonist methysergide (100 nmol/animal). The results suggest that the analgesic action of Neurotropin is at least in part due to the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways. Neurotropin may be useful for the clinical management of chronic pain diseases such as a rheumatoid arthritis and osteoarthritis.

Auriculotherapy stimulation for neuro-rehabilitation

The capability of reflex points on the external ear to alter neuromuscular and neuropathic disorders has been attributed to the descending pain inhibitory pathways of the central nervous system. The inverted fetus perspective of the somatotopic arrangement of auricular acupuncture points was first described in the 1950's by Dr. Paul Nogier of France, and has received scientific support from double blind studies examining auricular diagnosis of musculoskeletal and of coronary disorders. Acupuncture points on the ear and on the body have lower levels of electrical skin resistance than surrounding tissue. These electrodermal differences are apparently related to autonomic control of blood vessels rather than increased sweat gland activity. The heightened tenderness of reactive acupuncture points may be explained by the accumulation of noxious, subdermal substances. Electrical stimulation of specific points on the external ear leads to site specific neural responses in different regions of the brain. Behavioral analgesia produced by auricular acupuncture can be blocked by the opiate antagonist naloxone, indicating the role of endorphinergic systems in understanding the underlying mechanisms of auriculotherapy. The anatomical structures and electrical application of the auricle are described as they relate to the localization of master points, musculoskeletal points, internal organ points, and neuroendocrine points.

A preliminary report on pain thresholds in bulimia nervosa during a bulimic episode

Subjects with bulimia nervosa (BN) have been shown to exhibit abnormal satiety responses. Short-term satiety is largely mediated by afferent vagal activity. Activation of afferent vagal fibers has also been found to stimulate a descending pain inhibitory pathway that leads to elevation in somatosensory pain thresholds. Therefore, the study of pain thresholds in BN subjects may lead to a better understanding of afferent vagal function in this disorder. In this preliminary study, pressure pain thresholds were assessed in nine subjects with BN on 3 consecutive days during a binge-eating and vomiting (B/V) episode, during a normal meal, and after an overnight fast. A significant time versus condition effect was found with a significant change in the pain threshold in BN subjects under the B/V condition only. These data are consistent with the hypothesis that vagal afferent activation by a B/V episode also activates the descending pain inhibitory pathway.

Neurotropin induces antinociceptive effect by enhancing descending pain inhibitory systems involving 5-HT 3 and noradrenergic α2 receptors in spinal dorsal horn

Neurotropin, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug in Japan. Its analgesic effect has been demonstrated by reduced mechano-nociception in hyperalgesic rats exposed to SART-stress (a repeated cold stress) for 5 days. In order to clarify the mechanism of the analgesic effect of neurotropin at the spinal cord level, we examined the effects of several neurotransmitter receptor antagonists given by intrathecal (i.t.) injection on the antinociceptive effect of intraperitoneally (i.p.) injected neurotropin [100 and 200 Neurotropin Unit (NU)/kg]. The analgesic effect of neurotropin was significantly inhibited not only by methysergide (100 nmol Rat , i.t.), a non-selective antagonist against serotonin (5-HT), but also MDL 72222 (30 nmol Rat , i.t.), a selective 5-HT 3 antagonist, but not influenced by ketanserin (100 nmol Rat , i.t.), a 5-HT 2A antagonist. The antinociceptive effect of neurotropin (200 NU Kg , i.p.) was significantly inhibited also by yohimbine (30 nmol Rat , i.t.), a noradrenergic α 2 antagonist. However, the analgesic effect of neurotropin (100 and 200 NU Kg , i.p.) was not influenced by naloxone (30 nmol Rat , i.t.), an opioid antagonist. These results suggest that the mechanism of the antinociceptive effect of neurotropin is via enhancement of endogenous descending pain inhibitory pathways of the serotonergic and noradrenergic systems, especially involving 5-HT 3 and noradrenergic α 2 receptors in spinal dorsal horn in which these neurons terminate. No influence of opioid receptors at the spinal cord level is indicated.

The tolerance effect: its relevance to analgesia produced by physiotherapy interventions

Recent research has indicated that the analgesia provided by manual therapy may be caused not only through the improvement of pathomechanics of the affected structure, but also through the activity of descending pain inhibitory pathways. Analgesia associated with this descending neural circuitry has been classified as opioid or non-opioid in nature, and the pathways activated appear to be highly dependent on the parameters used to induce analgesia. A characteristic of opioid system activation is the development of tolerance to analgesia produced by both endogenous and exogenous mechanisms. This paper will review the possible mechanisms by which tolerance develops. A discussion of the literature pertaining to stimulation and stress-induced analgesia will indicate the possible relationship between tolerance and physiotherapy inverventions such as manual therapy, electrotherapy and exercise. Implications for physiotherapy research and practice will be discussed.

Local administration of morphine decreases the extracellular level of GABA in the periaqueductal gray matter of freely moving rats

Opioids are generally believed to activate descending pain inhibitory pathways from the periaqueductal gray matter (PAG). Since opioids exert an inhibitory effect on neural excitability and transmitter release, an opioid-mediated inhibition of tonically active inhibitory γ-aminobutyric acid (GABA) neurons has been suggested to mediate this effect. The aim of the present microdialysis study was to investigate the effect of local administration of morphine on the extracellular GABA level in the PAG of awake rats. The recently developed and highly sensitive method of capillary electrophoresis with laser-induced fluorescence detection was used for GABA determination in microdialysate samples obtained from the PAG of freely moving rats. The basal GABA level was 54.5 ± 6.6 nM ( n = 8; mean ± SEM). Perfusion of the dialysis probe with morphine (100 μM) for 30 min significantly decreased the GABA level to 28.2 ± 4.2 nM ( n = 8; P < 0.05). The effect of morphine was reversed by coperfusion with naloxone (100 μM in the perfusion fluid). The present results thus provide direct experimental evidence for an opioid-induced inhibition of tonic GABA release in the PAG, which may in turn lead to a disinhibition of descending pain inhibitory pathways.

Repeated spinal cord stimulation decreases the extracellular level of γ-aminobutyric acid in the periaqueductal gray matter of freely moving rats

Most of the previous experimental studies on the antinociceptive effects of electrical spinal cord stimulation (SCS) have focused on short-lasting effects mainly depending on spinal mechanisms. However, patients treated with SCS for chronic pain often report pain relief exceeding the period of stimulation for several hours. The long lasting effect of SCS might not only involve spinal, but also supraspinal mechanisms. A supraspinal region of major importance for the coordination of descending pain inhibition is the periaqueductal grey matter (PAG). The aim of the present microdialysis study, performed in awake freely moving rats, was to investigate if repeated SCS (two 30 min periods separated by a 90 min resting period) alters the extracellular neurotransmitter concentrations in the ventrolateral PAG. In a first series of experiments significantly decreased (−30%; P < 0.05; n = 7) γ-aminobutyric acid (GABA) levels were detected immediately after the second SCS session. Neither the concentration of serotonin nor that of substance P-like immunoreactivity (SP-LI) was affected by SCS. The decrease of GABA after two SCS sessions was confirmed in a second series of experiments (−30%; P < 0.05; n = 7). No spontaneous decline of GABA was observed in sham-stimulated animals ( n = 6). The glutamate concentration was also determined in this latter series of experiments and a significant decrease (−23%; P < 0.05; n = 5) was observed after the second SCS session. As GABA-neurons in the PAG exert a tonic depressive effect on the activity in descending pain inhibitory pathways, a decreased extracellular GABA level in this region, as detected following repeated SCS, might indicate an increased pain inhibition.

The effect of GABA and its antagonists on midbrain periaqueductal gray neurons in the rat

Injection of GABA into the midbrain periaqueductal gray (PAG) activates medullary neurons that are involved in pain inhibition and potentiates morphine-induced analgesia. These observations suggest that GABAergic mechanisms in the PAG may modulate the descending pain inhibitory system that arises from this structure. In the present study, the effects of GABA and GABA antagonists on membrane properties and baseline activity of PAG neurons were examined using both in vitro and in vivo preparations. Application of bicuculline methiodide (BICM), at a dose that blocked the response to GABA, potently increased the baseline firing rate in 53% of cells recorded in vitro and 74% of cells recorded in the intact preparation. Application of BICM often yielded multiple or burst spiking episodes in both preparations. In 69% of cells the effect of BICM was diminished or totally abolished when the slice was perfused with high-magnesium, calcium-free, physiological saline solution. Intracellular recordings revealed that bicuculline caused depolarization of the membrane (70% of cells), increased the firing frequency (94% of cells) and increased the frequency of excitatory postsynaptic potentials (18% of cells). The effect of bicuculline on membrane resistance was not pronounced and in 64% of neurons it did not cause any measurable change in the resting membrane resistance. PAG neurons responsive to GABA and its antagonists were observed in all regions of the PAG. However, the highest number of neurons that responded to GABA and its antgonists was found in the medial and medioventral parts of the PAG. These results indicate that PAG may contain a tonically active GABAergic network that operates, at least in part, through GABA A receptors. This GABAergic system may modulate activity in descending pain inhibitory pathways emanating from PAG.

Pustative anxiolytics 8-OH-DPAT, buspirone and TVX Q 7821 are agonists at 5-HT 1A autoreceptors in the raphé nuclei

Pulsed radiofrequency (PRF) has been reported to be effective in the treatment of several types of pain. The mechanism of action, however, is not well known. In a recent study, the antinociceptive effects of acute thermal pain were shown to be mediated via descending pain inhibitory pathways. In this study we observed an analgesic effect of PRF treatment in an adjuvant induced inflammatory pain model in rats. In this model, sciatic nerves were treated with PRF at 37° and 42°, which inhibited hyperalgesia in the inflammatory groups when compared to RF and sham treatment. This effect was attenuated after intrathecal administration of the alpha2-adrenoceptor antagonist yohimbine, the selective 5-HT3 serotonin receptor antagonist MDL72222, and the non-selective serotonin receptor antagonist methysergide. All three drugs were found to significantly inhibit the analgesic effect of PRF. The results suggest that the analgesic action of PRF involves the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways.