Jian Tian Qiao

Lateral hypothalamus : site involved in pain modulation

The present study is an attempt to examine the neuronal circuitry of a supraspinal site engaged in pain modulation. Five physiological measures were postulated as the criteria for defining a central nervous system site engaged in the circuitry of pain modulation. The lateral hypothalamus met these five measures: (i) 81% of the lateral hypothalamus neurons (247/304) responded to noxious stimuli using a single cell recording procedure; (ii) stimulation of the periaqueductal gray-dorsal raphe area or the habenula modulated 98% and 87% of the lateral hypothalamus noxious-evoked activity; (iii) microiontophoretically applied morphine modulated 77% of the lateral hypothalamus noxious evoked activity; (iv) electrical stimulation of the lateral hypothalamus produced behavioral analgesia proportional to the stimulus intensity as assessed by the tail flick assay; and (v) morphine application into the lateral hypothalamus produced behavioral analgesia in a dose-response manner using the tail flick assay. In conclusion, the lateral hypothalamus can be considered one of the pain modulation sites.

Dorsal raphe stimulation modulates nociceptive responses in thalamic parafascicular neurons via an ascending pathway: further studies on ascending pain modulation pathways

&NA; A study on the nociceptive responses of single cells within the nucleus parafascicularis (PF) thalami of the rat was undertaken to clarify the reported observations of a pain suppression pathway to this nucleus from the dorsal raphe (DR) nucleus. Two types of nociceptive neuron were identified in the PF which were classified as ‘nociceptive‐on’ and ‘nociceptive‐off’ neurons, respectively. DR stimulation exhibits a simple monophasic ‘dose‐dependent’ relationship between the degree of the inhibition elicited and the stimulation intensity used on the ‘nociceptive‐off’ cells. In contrast, biphasic effects following DR stimulation on the ‘nociceptive‐on’ cells was obtained, with low intensities eliciting suppression while high intensities excited the cells. These effects of low intensity DR stimulation upon the responses of the ‘nociceptive‐on’ cells were diminished but not prevented by transection of the well‐known bulbospinal inhibitory fibers descending in the dorsal half of the spinal cord, while the effects of DR stimulation upon the ‘nociceptive‐off’ cells remain unchanged following spinal transection. Thus, our results show that DR stimulation modulates the nociceptive responsiveness of the PF by way of supraspinal pathways in addition to the previously described descending paths.

Modification of nociceptively identified neurons in thalamic parafascicularis by chemical stimulation of dorsal raphe with glutamate, morphine, serotonin and focal dorsal raphe electrical stimulation

The properties of local application of glutamate, morphine and serotonin in the dorsal raphe (DR) area and the effects of DR electrical stimulation on the spontaneous activity and on the nociceptive responses of 135 parafascicularis (PF) neurons were studied. It was observed that local glutamate application within the DR exerts an effect upon the nociceptive-on PF neuronal activity similar to that induced by focal electrical stimulation of the DR in intact animals and in animals after dorsal spinal cord section. In addition, local application of morphine and serotonin in the DR area elicits different effects on the spontaneous activity versus the nociceptive responses of PF neurons. These observations suggest that opioids and serotonin at least in part participate in modulation of pathways from DR to PF. This observation is consistent with the hypothesis that the DR ascending path modulates nociceptive input to the PF (at least in part) via activations of both opioid and serotonergic receptors.

Locus coeruleus modulates thalamic nociceptive responses via adrenoceptors

This study investigated the parafascicular (PF) neuronal nociceptive responses and their modulation following electrical stimulation of the locus coeruleus (LC) and intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration of two alpha-adrenoceptor antagonists, the alpha2-antagonist, yohimbine, and the alpha1-antagonist, prazosin. The main results were as follows: (1) the nociceptive evoked discharges in PF neurons were suppressed by preceding stimulation of LC; (2) the suppressive effect of LC stimulation on PF neurons was replaced by a facilitatory effect following pretreatment of i.t. yohimbine in 14 units tested, while i.t. prazosin failed to alter the LC-induced suppression, even when the prazosin dose was doubled; (3) i.c.v. pretreatment with prazosin strengthened the suppressive effect of LC stimulation on PF neurons; (4) i.c.v. norepinephrine (NE) administration induced, in PF neurons, a biphasic response to noxious stimulation; an early, brief (about 10 min) inhibitory effect followed by a late, long-lasting facilitatory effect; and (5) i.c.v. pretreatment of yohimbine or prazosin prevented the inhibitory or facilitatory responses released by NE, respectively. These results provide evidence that: (1) the LC-descending projections exhibit a suppressive effect on nociceptive transmission at the spinal level through alpha2-receptors; and (2) the LC-ascending projections exhibit dual effects, facilitatory and inhibitory, at the medial thalamus (PF) level through alpha1- and alpha2-receptors, respectively.

Locus Coeruleus Stimulation Modulates the Nociceptive Response in Parafascicular Neurons: An Analysis of Descending and Ascending Pathways

The nociceptive responses in parafascicular neurons (PF) were recorded and studied following electrical stimulation of locus coeruleus (LC) combined with intrathecal (IT) or intracerebroventricular (ICV) administration of phentolamine (Ph), an alpha-adrenoceptor antagonist. The results revealed the following. (1) Three different PF neuronal populations were observed according to their response pattern following noxious stimulation: nociceptive-on, nociceptive-off, and nonresponsive units. Only the nociceptive-on units were studied further. (2) The nociceptive discharges in majority of PF neurons (66/87) were inhibited by electrical stimulation of the LC. (3) The inhibitory effect of LC stimulation was prevented and even reversed by pretreatment of IT Ph (40 nmol) in 22 units, or by dorsolateral funiculi transection in 24 units tested. (4) The inhibitory effect of LC stimulation was strengthened by preadministration of ICV Ph (40 nmol) in 17 units tested. (5) ICV administration of norepinephrine (NE 30 nmol) resulted in PF neurons a biphasic response to nociceptive stimulation: an early brief inhibition and a late long-lasting facilitation. (6) Pretreatment of ICV Ph (40 nmol) prior to NE injection prevented the NE-induced biphasic response. The results suggest that stimulation of LC modulates the nociceptive response of PF neurons through both ascending and descending routes. These two diverse routes exert two different effects: a predominantly inhibitory role on the nociceptive transmission at the spinal cord level by descending NE-ergic fibers, and a facilitatory role on the responsiveness of PF to noxious inputs by ascending fibers.

Interrelations of opioids with monoamines in descending inhibition of nociceptive transmission at the spinal level: an immunocytochemical study.

This study was designed to reexamine a previous proposal of whether the opioid-like substances (OLS) being acting mainly as an intrinsic spinal mediator in the descending inhibition of nociception of the bulbospinally projecting NE-ergic, and/or 5-HT-ergic terminals in the dorsal horn by using an immunocytochemical method. The effects of intrathecal (i.t.) phentolamine (Ph), cyproheptadine (Cyp), and naloxone (Nal), administered separately or coadministered by two of them, on the expression of Fos-like-immunoreactive (FLI) neurons were observed on both sides of the lumbar dorsal horn of rats, in which equal volumes of formalin were injected into two hindpaws and the ipsilateral dorsolateral funiculus (DLF) was transected at the thoracic level antecedently. The results showed: (1) when rats were pretreated with i.t. saline, the number of nociceptive FLI neurons was significantly lowered 44% (p<0.01) on the side of the lumbar dorsal horn with intact DLF compared to the opposite side with sectioned DLF; (2) when rats were separately pretreated with i.t. Ph, Cyp and Nal, the reduction of FLI neurons on the DLF-intact side were decreased by 27% (p<0.01), 21% (p<0.01), and 25% (p<0.01), respectively; (3) when rats were pretreated with combined i.t. Ph+Cyp, the reduction on the intact side was eliminated almost completely (4%); (4) when rats were pretreated with combined i.t. Ph+Nal, the reduction on the intact side was 21% (p<0.01); and (5) when rats were pretreated with i.t. Cyp+Nal, the reduction on the intact side was 9.1%. These results suggest that: (1) nearly all the suppressive action exerted by the DLF-descending fibers are produced by the release of either NE or 5-HT as neurotransmitters at the spinal level; (2) most of the opioid-like substances act as an intrinsic spinal mediator mainly for the descending NE-ergic, but in a lesser extent for the 5-HT-ergic terminals in the dorsal horn circuitry; and (3) some OLS-ergic interneurons may only be activated by local nociceptive input.

Dorsal raphe and external electrical stimulation modulate noxious input to single neurons in nucleus parafascicularis thalami

Spontaneous discharges and nociceptive responses of 47 parafascicularis thalami (PF) neurons were recorded extracellularly and comparisons were made between the effects of these discharges following focal dorsal raphe stimulation (DRS) and bilateral pinnal electrical stimulation (PES). Eighty-three percent of PF neurons (N = 39) responded to noxious stimulus, about 69% of the PF responsive cells (N = 27) were excited during noxious stimuli and thus categorized as nociceptive-on cells. The remaining 31% (N = 12) were suppressed by the noxious stimuli, and were categorized as nociceptive-off cells. DRS and PES attenuated the spontaneous activity of the nociceptive-on neurons as well as the noxious input to these cells, while the spontaneous activity of the nociceptive-off cells was suppressed only following DRS and not following PES. Moreover, PES displayed disinhibiting properties, namely, it reduced the suppression effects elicited by noxious input. In conclusion, it was demonstrated that both focal DRS and noninvasive PES were effective in modulating pain input to single neurons in the PF.

Sequential mediation of norepinephrine- and dopamine-induced antinociception at the spinal level: Involvement of different local neuroactive substances

The effects of intrathecally (i.t.) administered opioid antagonist naloxone (Nal), adenosine antagonist aminophylline (Aph), and gamma-aminobutyric acid (GABAA)-receptor antagonist picrotoxin (PTX) or Bicuculline (BIC) on the antinociception produced by i.t. norepinephrine (NE), dopamine (DA), morphine (Mor), 5-N-ethylcarboxamidoadenosine (NECA, an adenosine agonist) or muscimol (MUS, a selective GABAA-receptor agonist) were studied and compared using the tail-flick test in rats. The results showed that: (1) both i.t. NE (0.3, 0.5 and 1.0 nmol) and DA (5.5, 8.3 and 16.5 nmol) produced significant and dose-dependent increases in tail-flick latencies (antinociception); (2) both Nal (240 nmol) and Aph (120 nmol) blocked the antinociception produced by NE (1.0 nmol); (3) both Nal (240 nmol) and Aph (120 nmol) blocked the antinociception produced by Mor (0.5 nmol), but only Aph (120 nmol) blocked the antinociception produced by NECA (0.5 nmol), while Nal (240 nmol) did not; (4) neither Nal (240 nmol) nor Aph (120 nmol) altered the antinociception produced by DA (16.5 nmol); (5) both i.t. PTX (1.5 nmol) and BIC (0.5 nmol) completely blocked the antinociception produced by DA (16.5 nmol), but showed no effects on that produced by NE (1.0 nmol); and (6) both PTX and BIC blocked the antinociception produced by MUS (1.0 nmol). These results suggest that: (a) endogenous opiate and adenosine may be involved in the mediation of NE-induced, but not DA-induced, antinociception; (b) NE, opioid and adenosine may act in a sequential order in NE-induced antinociception at the spinal level; (c) endogenous GABA may be involved in the mediation of DA-induced antinociception through the GABAA-receptors, but is not involved in NE-induced antinociception at the spinal level.

Focal Dorsal Raphe Stimulation and Pinnal Electrical Stimulation Modulate Spontaneous and Noxious Evoked Responses in Thalamic Neurons

This study investigated the nocieceptive responses of single neurons within the nucleus parafascicularis (PF) thalami of the rat following two modes of electrical stimulation known to induce analgesia. It was found that both focal electrical dorsal raphe stimulation (DRS) and bilateral pinnal (ear) electrical stimulation (PES) converge on the same PF neurons, affecting both the spontaneous discharges and the noxious evoked responses toward these neurons. The effects of different stimulus current intensity, frequency and pulse duration were also examined. It was found that for both DRS and PES at pulse frequency of 10 Hz and current amplitude of 10 microA are the optimal parameters to modulate both the spontaneous and the noxious evoked responses. These stimuli produced prolonged effects related to the duration of stimulation. The external (PES) low current stimulation which was delivered below the sensory threshold was as effective in modulating noxious responses as the invasive DRS in intact animals and in animals with bilateral dorsolateral-funiculus ablation. It was observed that dorsal lateral funiculus ablation (DLFx) did not modify the DRS and the PES effects. These observations further support the existence of an ascending pain modulation pathway.

ATP-SENSITIVE POTASSIUM CHANNELS AND ENDOGENOUS ADENOSINE ARE INVOLVED IN SPINAL ANTINOCICEPTION PRODUCED BY LOCUS COERULEUS STIMULATION

The effects of locus coeruleus stimulation on nociceptive evoked discharges of thalamic parafascicular (PF) neurons were investigated in lightly urethane-anesthetized rats, aiming to study the mechanisms underlying these effects. Intrathecal (i.t.) administration of aminophylline (an adenosine antagonist), glibenclamide (an ATP-sensitive potassium [K+ATP] channels blocker), nicrorandil (Nico; an agonist of K+ATP channel and a K+ATP channel opener), and 5-N-ethylcarboxamido-adenosine (NECA; an adenosine agonist) were used. The results showed that (1) locus coeruleus stimulation significantly inhibited the nociceptive evoked discharges of parafascicular neurons, (2) locus coeruleus stimulation-produced antinociception in PF neurons was blocked by both i.t. glibenclamide and i.t. aminophylline, (3) nociceptive discharges of PF neurons were also suppressed by both i.t. NECA and i.t. nicorandil, and (4) i.t. glibenclamide showed no effect on the suppression of nociceptive discharges induced by NECA, whereas aminophylline blocked the suppression of nociceptive discharges induced by nicorandil. These results suggest that (a) K+ATP channels and endogenous adenosine may be involved in the mediation of antinociception induced by norepinephrine, which is released in the dorsal horn by descending fibers originating from the locus coeruleus and (b) the opening of K+ATP channels may precede the release of endogenous adenosine in the process of suppressing nociceptive transmission at the spinal level.