Biomedical subjects

E Brodin

Publications and source records attributed to E Brodin.

At least 19 recordsLinked to original sources

PubMed2001

Delayed stress-induced increase in tissue level of cholecystokinin in rat prefrontal cortex: modulation by microdialysis probe implantation and systemic ketamine.

In the brain, the neuropeptide cholecystokinin (CCK) appears to be involved in the mediation of stress responses. Here we provide new evidence that mild stress induces long-term changes in CCK-like immunoreactivity (CCK-LI) in the prefrontal cortex (PFC). The changes in CCK-LI show a biphasic pattern, with a decrease 20 min after and an increase 8 h after mild stress. These changes seem to be region specific. Measurement of CCK mRNA in prefrontal cortex neurons 4 or 8 h after the stress stimulus did not reveal changes in mRNA levels, suggesting that afferent CCK-containing neuron terminals may be more affected than local cortical CCK-ergic neurons. Furthermore, treatment with the glutamate NMDA receptor antagonist ketamine, led to more pronounced decreases in CCK-LI observed within 20 min after mild stress and counteracted the stress induced increase in cortical CCK-LI levels observed at 8 h. Implantation of a microdialysis probe in the PFC affected the response to mild stress, with no significant decrease in the CCK-LI level 20 min after, and attenuated reactivity to stress 8 h after the saline injection. Our results indicate that a mild stressful stimulus such as an intraperitoneal saline injection may have long-lasting effects on CCK-ergic transmission in the PFC. The use of microdialysis to study stress induced in vivo CCK-LI release in awake animals may, however, be significantly compromised by the impact of the microdialysis probe implantation on CCK-ergic mechanisms in the PFC. In addition, we hypothesize that subanesthetic doses of the psychotomimetic drug ketamine interfere with CCK-ergic mechanisms in the PFC during stress.

Animals↗

PubMed2001

Changes in spinal cholecystokinin release after peripheral axotomy.

The gene expression of cholecystokinin (CCK), a neuropeptide with anti-opioid properties, has been reported to be upregulated in some primary sensory neurons after a peripheral nerve lesion. We have recently demonstrated that the upregulation of CCK mRNA is not accompanied by an increased potassium-evoked release CCK-like immunoreactivity (CCK-LI) 2-4 weeks after a complete transection of the sciatic nerve. The potassium-evoked release of CCK-LI at earlier and later time points has, however, not been studied. The aim of the present in vivo microdialysis study was to monitor how the basal and stimulated extracellular level of CCK in the dorsal horn of the spinal cord is affected at various time points after a complete transection of the sciatic nerve (axotomy). During the first week after transection of the sciatic nerve a tendency towards an elevation of the potassium-induced (100 mM in the perfusion fluid) release of spinal CCK-LI was observed. In contrast, no potassium-induced release of CCK-LI could be detected 2-3 weeks and 2 months after axotomy. No significant effect was observed on the basal extracellular levels of CCK-LI in the dorsal horn. The present study provides further support for the notion that the adaptive changes in the dorsal horn 2 weeks and later after a deafferentiation injury do not include an increased release of CCK.

Animals↗

PubMed2001

Involvement of spinal N-methyl-D-aspartate receptors in capsaicin-induced in vivo release of substance P in the rat dorsal horn.

The aim of the present in vivo microdialysis study was to determine the possible contribution of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors to capsaicin-induced release of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat. Perfusion of a microdialysis probe with capsaicin (50 or 100 microM) induced a significant eight-fold increase of the extracellular SP-LI level. The capsaicin (50 microM)-evoked release of SP-LI was blocked by spinal administration of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (D-APV; 5 mM), but not by the AMPA/KA antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione disodium (NBQX; 0.5 mM). In contrast, the SP-LI release induced by 100 microM capsaicin could not be prevented by D-APV (10 mM) or NBQX (0.5 mM). The data suggest that the spinal SP-LI release induced by a moderate concentration of capsaicin is in part dependent on the release of glutamate acting on NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed2001

Physical activity, muscle performance and quality of life in patients treated with chronic peritoneal dialysis.

OBJECTIVE: Today's medical treatment of patients with end-stage renal failure has increased their opportunities for an active lifestyle. The aim of this study was to describe the muscle performance, level of physical activity, independence in activities of daily living and quality of life in patients treated with chronic peritoneal dialysis. MATERIAL AND METHODS: The study investigated 33 patients (30-81 years old) treated with chronic peritoneal dialysis. The results were compared with an age-matched healthy reference group. Muscle mass was determined by measuring total body potassium, while maximal grip strength was measured with an electric force transducer. The ability to perform heel-lifts, walking speed and level of physical activity were also assessed, along with the extent to which patients were independent in activities of daily living (ADL) and satisfied with their health. RESULTS: Total body potassium was 97 +/- 11.6% of normal and correlated positively with the maximal grip strength (r = 0.658, p < 0.0002) and the maximal walking speed (r = 0.558, p < 0.0027). Maximal grip strength was 70% of the reference, the ability to perform heel-lifts was 49% of the reference, the walking speed was 85% the reference and the level of physical activity was 56% of expected. The patients were independent in ADL to a great extent and 52% of the patients were satisfied with their health. CONCLUSION: The peritoneal dialysis patients had a relatively good quality of life and were largely independent in ADL Further studies are needed to investigate whether it is possible to improve muscle performance and the level of physical activity with exercise and muscle training in these patients.

Activities of Daily Living↗

PubMed2000

Peripheral axotomy increases cholecystokinin release in the rat anterior cingulate cortex.

The anterior cingulate cortex (ACC) is a limbic region with a high density of cholecystokinin (CCK) immunoreactivity, that has been suggested to be of importance for the affective and emotional component of pain. In the present microdialysis study, performed in the awake rat, we demonstrate a bilateral 4- to 6-fold increase of the potassium-induced release of CCK-like immunoreactivity (CCK-LI) in the ACC 2-3 weeks after a unilateral transection of the sciatic nerve (axotomy), an animal model of phantom limb or deafferentiation pain. Considering the implication of CCK in pain modulation and anxiety, we suggest that an altered activity of CCK containing neurons in the ACC may be of importance for the affective component of certain pain conditions.

Animals↗

PubMed1999

Measurement of cholecystokinin release in vivo in the rat spinal dorsal horn.

The microdialysis technique, used to monitor extracellular levels of transmitter substances in the central nervous system of laboratory animals as a reflection of transmitter release, is based on the ability of neurotransmitters to diffuse in the extracellular fluid from the site of release and to cross a semipermeable dialysis membrane. Even though the surgical procedure is not very complicated, the detection of released substances in the recovered dialysate may be difficult. Especially, the measurement of neuropeptide release is limited by the low extracellular concentration and of low recovery as compared to, for example, monoamines. Thus, for example, cholecystokinin (CCK), which is the most abundant neuropeptide in the central nervous system, is found at concentrations that are several orders of magnitude lower than those of classical transmitters. Therefore a highly sensitive detection method is of utmost importance. In the dorsal horn of the spinal cord CCK is found mainly in interneurons and in terminals of descending fibers. CCK seems to be involved in nociceptive transmission and CCK attenuates morphine-induced antinociception. We here describe in vivo microdialysis in the lumbar dorsal horn of the rat with subsequent quantification of the level of CCK-like immunoreactivity (-LI) by a highly sensitive radioimmunoassay.

Afferent Pathways↗

PubMed1999

Pharmacological characterization of morphine-induced in vivo release of cholecystokinin in rat dorsal horn: effects of ion channel blockers.

Previous studies indicate that an increased release of cholecystokinin (CCK) in response to morphine administration may counteract opioid-induced analgesia at the spinal level. In the present study we used in vivo microdialysis to demonstrate that systemic administration of antinociceptive doses of morphine (1-5 mg/kg, s.c.) induces a dose-dependent and naloxone-reversible release of CCK-like immunoreactivity (CCK-LI) in the dorsal horn of the spinal cord. A similar response could also be observed following perfusion of the dialysis probe for 60 min with 100 microM but not with 1 microM morphine. The CCK-LI release induced by morphine (5 mg/kg, s.c.) was found to be calcium-dependent and tetrodotoxin-sensitive (1 microM in the perfusion medium). Topical application of either the L-type calcium channel blocker verapamil (50 microg) or the N-type calcium channel blocker omega-conotoxin GVIA (0.4 microg) onto the dorsal spinal cord completely prevented the CCK-LI release induced by morphine (5 mg/kg, s.c.). Our data indicate that activation of L- and N-type calcium channels is of importance for morphine-induced CCK release, even though the precise site of action of morphine in the dorsal horn remains unclear. The present findings also suggest a mechanism for the potentiation of opioid analgesia by L- and N-type calcium channel blocking agents.

Analgesics, Opioid↗

PubMed1998

Electrical stimulation of the prefrontal cortex increases cholecystokinin, glutamate, and dopamine release in the nucleus accumbens: an in vivo microdialysis study in freely moving rats.

In vivo microdialysis, radioimmunoassay, and HPLC with electrochemical or fluorometric detection were used to investigate the release of cholecystokinin (CCK), glutamate (Glu), and dopamine (DA) in nucleus accumbens septi (NAS) as a function of ipsilateral electrical stimulation of medial prefrontal cortex (mPFC). CCK was progressively elevated by mPFC stimulation at 50-200 Hz. Stimulation-induced CCK release was intensity-dependent at 250-700 microA. NAS Glu and DA levels were each elevated by stimulation at 25-400 Hz; the dopamine metabolites DOPAC and homovanillic acid were increased by stimulation at 100-400 Hz. When rats were trained to lever press for mPFC stimulation, the stimulation induced similar elevations of each of the three transmitters to those seen with experimenter-administered stimulation. Perfusion of 1 mM kynurenic acid (Kyn) into either the ventral tegmental area (VTA) or NAS blocked lever pressing for mPFC stimulation. VTA, but not NAS, perfusion of Kyn significantly attenuated the increases in NAS DA levels induced by mPFC stimulation. Kyn did not affect NAS CCK or Glu levels when perfused into either the VTA or NAS. The present results are consistent with histochemical evidence and provide the first in vivo evidence for the existence of a releasable pool of CCK in the NAS originating from the mPFC. Although dopamine is the transmitter most closely linked to reward function, it was CCK that showed frequency-dependent differences in release corresponding most closely to rewarding efficacy of the stimulation. Although not essential for the reward signal itself, coreleased CCK may modulate the impact of the glutamatergic action in this behavior.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Peripheral axotomy influences the in vivo release of cholecystokinin in the spinal cord dorsal horn-possible involvement of cholecystokinin-B receptors.

An increased expression of cholecystokinin (CCK) messenger RNA (mRNA) as well as CCK-B receptor mRNA in dorsal root ganglion (DRG) cells following peripheral axotomy has previously been demonstrated. In the present in vivo microdialysis study, the effect of unilateral sciatic nerve section on basal and potassium-induced release of CCK-like (CCK-LI) immunoreactivity in the rat dorsal horn was investigated. We also compared the effects of the CCK-B receptor antagonist CI988 on basal and potassium-stimulated CCK-LI release in intact animals and in chronically axotomized rats. Perfusion of the microdialysis probe with KCl (100 mM) induced a more than 6-fold increase of the extracellular level of CCK-LI in control animals. In contrast, following unilateral sciatic nerve section the same KCl stimulation failed to evoke a release of CCK-LI ipsilaterally. However, after systemic administration of CI988 (1 mg kg-1, i.v.), 100 mM KCl induced a significant increase of the extracellular CCK-LI level in axotomized rats, similar to that observed in control animals. In control animals no effect of CI988 on KCl-stimulated CCK-LI release could be detected. CI988 by itself had no influence on the extracellular CCK-LI level in either nerve injured or control animals. The present data suggest that axotomy reduces the release of CCK-like immunoreactivity in the spinal cord by a mechanism involving the CCK-B receptor binding site.

Animals↗

PubMed1998

Differential release of cholecystokinin by morphine in rat spinal cord.

The analgesic efficacy of opioids is reduced in neuropathic pain states and increased in inflammation. Since the neuropeptide cholecystokinin (CCK) plays a role in the modulation of opiate-induced analgesia, the morphine-mediated release of CCK in the spinal cord of rats was compared with in vivo microdialysis in normals and different pain models. The effect of systemic and intrathecal (i.t.) morphine on the extracellular level of CCK was analyzed in the spinal cord dorsal horn of halothane-anaesthetized normal rats as well as during peripheral neuropathy and inflammation. No difference was found in basal CCK level among groups. However, morphine significantly increased extracellular CCK concentration after both systemic and spinal application in intact as well as axotomized rats and this effect was naloxone-reversible in non-lesioned animals. Similar results were seen in axotomized rats. In contrast, morphine did not induce CCK release during carrageenan-induced inflammation. These data provide evidence that the ability of opiates to release CCK under different pain states may play a key role in their analgesic efficacy.

Analgesics, Opioid↗

PubMed1998

Substance P and related peptides in porcine cortex: whole tissue and nuclear localization.

A large portion of the knowledge that has been gathered on the distribution of neuropeptides in neural tissues is based on findings obtained with immunocytochemistry and radioimmunoassay. However, these methods give limited structural information about the peptides being studied. Using porcine cortex as a model tissue, we combined immunoaffinity chromatography with reversed-phase high-performance liquid chromatography, radioimmunoassay, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). We determined the molecular nature of the peptides contributing to the substance P-like immunoreactivity measured in extracts of whole tissue and cell nuclei. In addition to substance P(1-11), other peptides were extracted using this protocol. The presence of SP(1-11) was confirmed through post-source decay analysis. These results illustrate the usefulness of MALDI-TOF-MS in the characterization of neuropeptides from biological tissues.

Amino Acid Sequence↗

PubMed1997

Opioid-induced release of neurotensin in the periaqueductal gray matter of freely moving rats.

The midbrain periaqueductal gray matter (PAG) is an important region for endogenous pain suppression. Nerve terminals containing opioid peptides and neurotensin (NT), as well as high densities of opioid- and NT-receptors, have been demonstrated in the ventromedial PAG. Local administration of opioids or NT in this region induces antinociception in experimental animals. In the present microdialysis study, the effect of opioids on the release of NT in the ventromedial PAG was investigated. Perfusion of the microdialysis probe with 10 microM morphine induced a significant increase (P < 0.05; n = 5) of the extracellular level of NT-like immunoreactivity (NT-LI), while perfusion with a 10-fold higher concentration of morphine had no significant effect on the NT-LI release in the PAG. Also perfusion of the dialysis probe with the mu-opioid receptor-specific agonist [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephaline (DAGO) (1 or 100 microM) induced a significant (P < 0.05; n = 7-9) increase of the NT-LI level. The increase in NT-LI release in response to 1 microM DAGO was both calcium-dependent and naloxone-reversible. Since opioid agonists generally inhibit neuronal activity, an indirect mechanism, involving inhibition of tonically active inhibitory neurons, e.g. gamma-aminobutyric acid (GABA) neurons, could be of importance for the opioid induced release of NT. However, local administration in the PAG of the GABA(A) antagonist bicuculline (0.1-10 microM) or the GABA(A) agonist muscimol (1-100 microM) had no significant effect on the extracellular NT-LI level in the PAG, suggesting that GABAergic mechanisms are not involved in the opioid-induced release of NT-LI. In conclusion, the present data provide in vivo evidence that mu-opioid receptors mediate stimulation of neurotensin release in the PAG.

Analgesics, Opioid↗

PubMed1997

Temporal changes in spinal cord expression of mRNA for substance P, dynorphin and enkephalin in a model of chronic pain.

We have used a partial sciatic nerve ligation model to examine the time course for changes in the expression of mRNA for three peptides related to pain transmission at spinal sites (dynorphin, enkephalin and substance P), during the development of allodynia. Enhanced expression of mRNA for dynorphin and substance P was observed in the dorsal horn on the same side as the partial nerve ligation. Increased expression of dynorphin mRNA was biphasic. The initial increases in expression of dynorphin mRNA occurred at 3 h, and a secondary peak was observed 1-3 days after surgery. The secondary increases coincided roughly with increased substance P mRNA expression. However, both dynorphin and substance P mRNA returned to control values after 1 week despite continuing allodynia. No significant changes in expression of mRNA for enkephalin were observed. The elevation of substance P mRNA in intrinsic spinal cord neurons may be secondary to changes in immediate early genes c-fos and jun-B, whereas the expression of dynorphin and enkephalin mRNA is differently regulated. The results also suggest that changes in the expression of the three neuropeptides are not critically involved in the development and maintenance of chronic pain or allodynia.

Animals↗

PubMed1997

Spinal expression of mRNA for immediate early genes in a model of chronic pain.

We have used a partial nerve ligation model of chronic pain to investigate if there are changes in the expression of mRNA for several immediate early genes (IEG) that correlate in time with the initial adaptive behavioural changes and with development of allodynia in this model. The animals were inspected for typical changes in posture, and mechanical allodynia was evaluated using von Frey filaments. Expression of three of the immediate early genes examined, c-fos, NGFI-A and jun B, was transiently increased in the ipsilateral dorsal horn of the spinal cord following the partial ligation of the sciatic nerve. The time course and extent of these changes were similar to those reported for acute noxious stimuli. c-jun mRNA expression was significantly enhanced, after a delay of more than 12 h, and then remained elevated over the entire studied period of 4 weeks. These changes occurred only in the ventral horn, particularly in lamina IX. Except for c-jun mRNA, all changes were transient despite behavioural evidence for continuing allodynia. These results from the partial nerve ligation model, when compared with results obtained using other models of acute or chronic nerve injury, suggest that the immediate early genes we have examined are not sufficient to explain the transition to chronic pain states. The results also show that in this model of chronic pain there are prolonged adaptive changes in motor neurons and that these changes are temporally associated with the development of chronic pain and allodynia.

Animals↗

PubMed1997

No release of histamine and substance P in capsaicin-induced neurogenic inflammation in intact human skin in vivo: a microdialysis study.

BACKGROUND: Studies in rodents' skin have indicated substance P to be the main inflammatory mediator involved in neurogenic inflammation, acting partly by release of histamine from skin mast cells. The mediators released in neurogenic inflammation in human skin remain to be determined. OBJECTIVES: To determine the effects of intradermally injected and topically applied capsaicin on the release of histamine and substance P and skin responses in intact human skin in vivo. METHODS: Extracellular skin levels of histamine and substance P were measured by microdialysis technique and assayed by enzyme and radio immunoassays. Two kinds of dialysis fibres (210 microm, 2 kDa, and 500 microm, 20 kDa) were inserted intradermally into forearm skin for studies of histamine release to topically administered capsaicin and intradermally injected capsaicin and substance P. RESULTS: Baseline histamine skin levels were 8.0 +/- 0.7 nM. Intradermally injected capsaicin (0.3-30 microM, 7.5-750 pmol) caused significantly and dose-related flare and pain reactions, but no significant histamine release or weals. Intradermally injected substance P (1 and 3 microM, 25 and 75 pmol) released significant amounts of histamine (peak levels being 90 and 475 nM), evoked weal-and-flare reactions, but did not cause pain. Capsaicin 2% ointment, applied on the skin for 2.5 h, increased skin blood flow by 300-400% as measured by laser Doppler flowmetry, elicited a longstanding burning sensation, but did not release histamine. Substance P-like immunoreactivity (SP-LI) was below the 1.8 pM detection limit following insertion of 20 kDa dialysis fibre and after intradermal injection of capsaicin 3 microM. Intradermal injection of injection of 1 microM of substance P increased SP-LI levels to values greater than 4500 pM, confirming the ability of the dialysis fibre to recover this peptide. CONCLUSIONS: Capsaicin-induced neurogenic activation does not involve the release of histamine from mast cells or detectable amounts of substance P release from sensory nerves in normal human skin in vivo.

Administration, Topical↗

PubMed1996

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 gamma-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 microM) 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 microM 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.

Animals↗

PubMed1996

Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats.

OBJECTIVE: The aim of the present study is to monitor the extracellular gamma-aminobutyric acid (GABA) levels in the lumbar dorsal horn of allodynic rats, which respond to spinal cord stimulation (SCS) with a normalization of the tactile withdrawal threshold. In addition, we monitored the GABA levels in nonresponding and sham-stimulated rats. METHODS: Partial constriction injury of the sciatic nerve was performed, and a permanent electrode for SCS was inserted into the spinal canal. The response to SCS was assessed with von Frey hairs in awake animals. Later, microdialysis was performed in the dorsal horn of the spinal cord under halothane anesthesia. The concentration of GABA in the microdialysate was assessed by high-performance liquid chromatography. RESULTS: Extracellular GABA levels in rats with sciatic nerve lesions and allodynia (2.3 +/- 0.5 nmol/L) were significantly lower (P < 0.001) than in control rats with intact sciatic nerves (8.1 +/- 1.0 nmol/L), whereas only slightly decreased GABA levels (5.7 +/- 1.1 nmol/L) were detected in nonallodynic rats with sciatic nerve lesions. In the allodynic rats, which respond to SCS by a normalization of the tactile withdrawal threshold, significantly (P < 0.001) increased GABA levels (6.7 +/- 2.3 nmol/L) were detected after SCS. In contrast, neither the allodynic rats, which did not respond to SCS, nor the sham-stimulated allodynic rats displayed increased GABA levels in response to stimulation. CONCLUSION: Our results indicate that the development of allodynia, a common symptom in neuropathic pain states, may be linked to a decreased spinal release of GABA. We suggest that an SCS-induced release of GABA could be important for the suppression of allodynia observed in rats after SCS. Similar mechanisms could also be involved in the SCS-induced alleviation of pain in patients with peripheral neuropathy.

Animals↗

PubMed1995

Repeated spinal cord stimulation decreases the extracellular level of gamma-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) gamma-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.

Animals↗