Exploration of supraspinal mechanisms in effects of spinal cord stimulation: role of the locus coeruleus.

The neurobiological mechanisms of spinal cord stimulation (SCS) when applied for neuropathic pain are still incompletely known. Previous research indicates that brainstem circuitry is pivotal for the SCS effect. The present study aims at exploring the possible contribution to the SCS effects of the pain controlling system emanating from the locus coeruleus (LC) in the brain stem. Experiments were performed on the rat-spared nerve injury pain model. After evaluation of the attenuation of mechanical hypersensitivity induced by SCS, the effects of SCS on neuronal activity in the LC and on the noradrenaline (NA) content in the dorsal spinal cord were analyzed. SCS produced a significant increase in the discharge rate of LC neurons only in rats behaviorally responding to SCS as compared to non-responding and control animals. The NA content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was analyzed using enzyme-linked immunosorbent assay in responding, non-responding and intact control rats both immediately following SCS and without SCS. No differences were found between these groups. In awake animals, lidocaine silencing of the ipsilateral LC or blocking of spinal noradrenergic system by intrathecal administration of α1,2 adrenoceptor antagonists failed to influence the antihypersensitivity effect of SCS. The present results indicate that the SCS-induced control of hypersensitivity in an experimental animal model of peripheral neuropathic pain may not be explained by the activation of direct spinal projections of noradrenergic LC neurons, while supraspinal projections of LC neurons still may play a role in the SCS effect.

The rostroventromedial medulla is engaged in the effects of spinal cord stimulation in a rodent model of neuropathic pain.

The neurobiological mechanisms underlying the suppression of neuropathic pain by spinal cord stimulation (SCS) are still incompletely known. The present study aims at exploring whether the descending pain control system in the rostroventromedial medulla (RVM) exerts a role in the attenuation of neuropathic pain by SCS. Experiments were performed in the rat spared nerve injury (SNI) pain model. The effects of SCS on neuronal activity of pronociceptive ON-like, antinociceptive OFF-like, and neutral cells, including 5-HT-like cells, in the RVM were analyzed in SCS responding and SCS non-responding SNI animals as well as in naïve controls. Decreased spontaneous activities in OFF-like cells and increased spontaneous activities in ON-like cells were observed in SNI animals, whereas the spontaneous activities of 5-HT-like and neutral cells were unchanged. SCS produced a prominent increase in the discharge of OFF- and 5-HT-like cells in SCS responding, but not in non-responding SNI animals or controls. Discharge rates of ON-like and neutral cell were not affected by SCS. In awake SNI animals, microinjection of a GABAA receptor agonist, muscimol, into the RVM significantly attenuated the antihypersensitivity effect induced by SCS while a non-selective opioid receptor antagonist, naltrexone, was ineffective. It is concluded that SCS may shift the reciprocal inhibitory and facilitatory pain modulation balance controlled by the RVM in favor of inhibition. This increase in the descending antinociceptive effect operates in concert with segmental spinal mechanisms in producing pain relief.

Inhibitors of catechol-O-methyltransferase sensitize mice to pain.

BACKGROUND AND PURPOSE: Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice. EXPERIMENTAL APPROACH: We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone. KEY RESULTS: After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception. CONCLUSIONS AND IMPLICATIONS: Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions.

Some factors influencing the level of clinical sedation induced by medetomidine in rabbits.

Rabbits (n=23) received intravenous bolus medetomidine at 100 mug/kg. Prior to medetomidine administration, heart and respiratory rates were measured, arterial blood was collected and analysed for plasma cortisol, glucose and albumin concentrations. Fifteen minutes after medetomidine administration, heart and respiratory rates were measured again and sedation was scored. The rabbit was afterwards anaesthetized with 20 mg/kg ketamine administered intravenously to enable spinal tap and heart puncture. Cerebrospinal fluid (CSF) was collected (this occurred 20 min post medetomidine administration) and analysed for medetomidine concentration. Blood was collected by heart puncture immediately after the spinal tap and analysed for serum medetomidine concentration. Cerebrospinal fluid medetomidine concentration correlated negatively with sedation. Serum medetomidine correlated positively with CSF medetomidine concentration. Cerebro-spinal fluid medetomidine was 17 +/- 13% of serum medetomidine concentration. Plasma cortisol and glucose concentrations correlated negatively with serum medetomidine. We conclude that after an intravenous bolus administration of a low sedative dose of medetomidine to rabbits; CSF concentration of the drug correlate negatively with sedation and that this may be because of the fact that only the free and unbound medetomidine may be available for detection in the CSF, the concentration of medetomidine detected in the CSF was much lower than that in blood and a positive correlation exists between CSF and serum medetomidine concentrations. Stress may have some effect on the distribution or metabolism of medetomidine in rabbits.

Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effects.

Dexmedetomidine (DEX) may have some therapeutic advantages over the racemate medetomidine (MED). Here we have examined how serum concentrations of DEX correlate with some of its anaesthetic effects. Cats (n = 6) were administered with a continuous stepwise intravenous (i.v.) infusion of DEX or MED on different occasions in a cross-over design. Maintenance infusion rates (mg/kg/min) used were: DEX = 0.25 (MED = 0.50); DEX = 1 (MED = 2) and DEX = 4 (MED = 8) for infusion steps 1, 2 and 3, respectively. Each maintenance infusion lasted at least 50 min and was preceded with a loading dose. There was no significant difference between serum DEX and 0.5 serum MED concentrations at any dose level nor was there a significant difference between serum DEX and the (entire) serum MED concentrations. There was no significant difference between DEX and MED for sedation, analgesia, muscular relaxation and heart and respiratory rates. For both DEX and MED, serum drug concentration and analgesia were dose-dependent and sedation increased until the end of infusion step 2 (dose level 2) and decreased at the end of step 3 (dose level 3). Muscular relaxation was not dose-dependent. We conclude that increasing the blood concentration of DEX or MED beyond a certain level decreases the level of sedation instead of increasing it even though analgesia increases. The rate at which DEX and MED are metabolized in cats may not be the same.

Comparison of three doses of dexmedetomidine with medetomidine in cats following intramuscular administration.

Cats (n = 6) were administered dexmedetomidine (DEX) and medetomidine (MED) at three different dose levels in a randomized, blinded, cross-over study. DEX was administered at 25, 50 and 75 microg/kg (D25, D50 and D75), corresponding to MED 50, 100 and 150 microg/kg (M50, M100 and M150). Sedation, analgesia and muscular relaxation were scored subjectively. Heart and respiratory rates and rectal temperature were measured. Corresponding doses of DEX and MED were compared. Effects were also compared between dose levels for each compound. At dose level 2 (D50-M100), the duration of effective clinical sedation was significantly shorter after DEX (202.5 +/- 16.0 min) than after MED (230.0 +/- 41.2 min). Proceeding from D50-M100 to D75-M150, the duration of effective clinical sedation was increased more after DEX (by 57.5 +/- 38.4 min) than after MED (by 14.2 +/- 41.9 min) Increasing from D50-M100 to D75-M150, heart rate was further decreased after DEX (by 8.1 +/- 13.4%) but not after MED. There was no statistically significant difference between corresponding doses of DEX and MED for any of the other parameters studied. Changes in sedation, analgesia and muscular relaxation were dose-dependent. It was concluded that anaesthetic effects of medetomidine in cats are probably due entirely to its d-isomer and that dexmedetomidine at 25, 50 and 75 microg/kg induces dose-dependent sedation, analgesia and muscular relaxation of clinical significance in cats.