Does morphine enhance the release of 5-hydroxytryptamine in the rat spinal cord? An in vivo differential pulse voltammetry study

doi:10.1016/0006-8993(87)91077-8

Brain Research

Volume 411, Issue 2, 19 May 1987, Pages 259-266

https://doi.org/10.1016/0006-8993(87)91077-8 Get rights and content

Abstract

Differential pulse voltammetry used in combination with an electrochemically treated carbon fiber electrode allowed the detection of 5-hydroxyindoles (5-HI) in the dorsal horn of the urethane-anesthetized rat. Voltammograms were recorded every 3 min for up to 4 h. One component of the signal, peak 3, corresponding to 5-HI and uric acid was first identified separately in vitro as well as in vivo, and then further examined by means of systemic l- and d-tryptophan administration and by local application of uricase, respectively. It was found that the height of peak 3 was unaffected by systematic morphine. Even following pretreatment with probenecid, the height of peak 3 was increased only 8.6–13.7% over that with saline, by morphine given either intraperitoneally or intracerebrally into the nucleus raphe magnus. However, these increments of peak 3 were not statistically significant. These findings suggest that the serotonin descending system is unlikely to play an important role in morphine analgesia.

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Descending control of pain
2002, Progress in Neurobiology
Citation Excerpt :
As for models of supraspinal SPA, despite initial enthusiasm for a key role of descending serotonergic pathways in the mediation of MIA, it has become apparent that their contribution is at most partial and dependent upon a diversity of parameters, including the precise site and dose of morphine injection and the algesiometric paradigm employed (Besson et al., 1978, 1981; Fields and Basbaum, 1978; Millan, 1982, 1995, 1997; Basbaum and Fields, 1984; Rivot et al., 1984; Le Bars, 1988; Sawynok, 1989; Besson, 1990; Fields et al., 1991; Borszcz et al., 1996a,b; Hamon and Bourgoin, 1999; Yaksh, 1999a). For example, neurotoxin and pharmacological interruption of descending serotonergic transmission variably modifies MIA, and morphine does not consistently activate serotonergic neurones projecting from the NRM to the DH (Chiang and Xiang, 1987; Gao et al., 1998; Le Bars, 1988; Sawynok, 1989; Schaus et al., 1990; Matos et al., 1992; Puig et al., 1993; Borszcz et al., 1996a,b; Peng et al., 1996c; Suh et al., 1996b; Millan, 1997; Hamon and Bourgoin, 1999; Li et al., 2001). Thus, descending serotonergic pathways do not play an indispensable role in the mediation of MIA, whether elicited by systemic or cerebral administration of morphine.
Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at α₂-adrenoceptors (α₂-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
Raphe magnus serotonergic neurons tonically modulate nociceptive transmission
1998, Pain Forum
Serotonin-containing neurons in the medullary raphe magnus (RM) have long been thought to be important mediators of descending nociceptive inhibition. Although pharmacologic and behavioral studies support this idea, recent physiologic evidence demonstrates that RM serotonergic cells do not respond to antinociceptive stimulation in the periaqueductal gray or analgesic doses of morphine with a change in discharge rate. Instead, serotonergic cell discharge is likely to influence the outcome of modulatory circuits by tonically modulating the effects of other synaptic connections in the dorsal horn. Because serotonergic cells discharge in relation to sleep and wake cycles, RM serotonergic cells are hypothesized to subserve the relative decrease in nociceptive responsiveness observed during waking compared to slow-wave sleep.
Effects of electrical stimulation and morphine microinjection into periaqueductral gray on 5-hydroxyindole oxidation current in spinal cord of cats
1996, General Pharmacology
- 1.
  1. The effects of electrical stimulation and microinjection of morphine into the periaqueductal gray (PAG) on the 5-hydroxyindole oxidation current (280–300 mV) in laminae I-VI (800–2500 μm) of the spinal cord were examined using in vivo voltammetry in anesthetized cats.
- 2.
  2. Electrical stimulation of the PAG (PAG-S) both enhanced and attenuated the current. PAG-S increased the signal by 13.3±3.7% (laminae I-II: 800–1200 μm) or 19.0±3.6% (laminae V-VI: 1700–2500 μm) in comparison to control values. Attenuation by PAG-S decreased the signal by 15.3 ± 2.6% (laminae I-II) or 13.3 ± 2.0% (laminae V-VI) of control values. Naloxone antagonized signal enhancement by PAG-S.
- 3.
  3. Morphine (10 μg/μl) microinjected into the PAG significantly increased the height of the signal (laminae I-II: 15.0 ± 3.4%, laminae V-VI; 12.2 ± 1.5%). Enhancement by microinjected morphine was antagonized by naloxone. In contrast, microinjected morphine also significantly decreased the signal by 10.4±2.7% (laminae I-II) and by 10.3 ± 1.3% (laminae V-VI) of control values.
- 4.
  4. Microinjection of morphine and electrical stimulation of the PAG was observed both to enhance and attenuate the oxidation current of 5-hydroxyindole in the superficial and deeper dorsal horn. PAG may function to regulate the RVM-spinal serotonergic pathway, which modulates the transmission of nociceptive messages at the spinal cord.
The response of the 5-hydroxyindole oxidation current to noxious stimuli in the spinal cord of anesthetized rats: modification by morphine
1992, Brain Research
The effects of cutaneous noxious heating and of systemic morphine on serotonergic activity in the spinal cord were examined in anesthetized rats. An oxidation current of 5-hydroxyindole signal was seen at 280–200 mV with differential normal pulse voltammetry. Noxious heat stimuli produced a mean signal increase over control values of 15.5±3.4% at 52°C, and 7.2±5.5% at 45°C. These increases lasted for 5–10 min. Non-noxious stimuli (37°C) did not affect the 5-hydroxyindole signal. Morphine (0.5, 2.0 and 5.0 mg/kg, i.p.) in the absence of cutaneous stimulation did not change the signal significantly. Systemic morphine alone did not significantly modify the 5-hydroxytryptamine (5-HT) metabolism, as observed in in vivo voltammetry, in the spinal cord of anesthetized rat. However, a low dose of morphine (0.5 mg/kg, i.p.) attenuated the increase in the signal modified by noxious stimuli, and high doses (2.0 or 5.0 mg/kg, i.p.) enhanced it. Both effects of morphine were antagonized by naloxone (0.5 mg/kg, i.v.). It is likely that morphine with noxious stimuli modify the sensitivity of serotonergic descending inhibitory system. It is concluded that noxious heating of the skin increases the 5-HT metabolism in the spinal cord of anesthetized rats and that systemic administration of morphine modulates this 5-HT metabolism.
Evidence for the involvement of a descending cholinergic pathway in systemic morphine analgesia
1989, Brain Research
The analgesic effect of morphine sulfate (3–5 mg/kg, i.p.) was assessed by both tail-flick and hot-plate tests in unanesthetized restrained rats. Intrathecal administration of atropine sulfate (10 μg) in the lumbar region of the spinal cord powerfully reduced the analgesia induced by systemic administration of morphine. This action did not result from the diffusion of atropine from its administration site to more rostral sites in the central nervous system. In spinal rats, atropine failed to reverse morphine analgesia, thus strongly suggesting that either a cholinergic descending pathway or a spinal local cholinergic circuit activated by an unknown descending pathway may be involved in the systemic morphine analgesia. In addition, the involvement of the α-adrenergic descending pathway in morphine analgesia is confirmed, whereas that of the serotonergic descending pathway is less prominent.
In vivo electrochemical detection of 5-hydroxyindole within the trigeminal nucleus caudalis of freely moving rats: the effect of morphine
1988, Brain Research
The trigeminal nucleus caudalis is considered the equivalent of the orofacial nociceptive system of the dorsal horn of the spinal cord. At the level of this trigeminal area (i.e. medullary dorsal horn) the transmission of noxious inputs is strongly modulated by a descending, serotonergic system mainly originating from the nucleus raphe magnus (NRM). The present study in freely moving animals reports the effect of morphine on the 5-hydroxyindole oxidation current recorded in the medullary dorsal horn. Complementary data from recordings in spinal dorsal horn in acutely anesthetized rats are also presented. A current recorded at 270–290 mV (peak ‘3’), characteristic of 5-hydroxyindoleacetic acid (5-HIAA), was measured with treated multi-fiber carbon electrodes, using differential pulse voltammetry (DPV) or differential normal pulse voltammetry (DNPV). In control rats, the amplitude of the peak remained constant for many hours. Morphine (10 mg/kg i.p.) caused a significant increase which plateaued between 35 and 80 min (mean increase: 127 ± 5 % of control values); recovery was complete by about 3 h. Simultaneous injection of naloxone (1 mg/kg i.p.) totally abolished the effect of morphine. By contrast, morphine was without effect on peak 3 recorded in the spinal dorsal horn of chloral hydrate (450 mg/kg i.p.) anesthetized rats. It is concluded that in non-anesthetized freely moving animals morphine clearly increases the metabolism of serotonin (5-HT) in the medullary dorsal horn. This finding confirms previous neurochemical data showing an increased synthesis or release of 5-HT in the spinal cord after systemic morphine or its microinjection into either the periaqueductal gray matter or the NRM, and underlines the value of in vivo electrochemistry in monitoring changes in 5-HT metabolism directly and continuously during various physiological and pharmacological procedures.

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^*: Present address: Institute of Psychology, Academia Sinica, Xi Yi Bei Guan, Beijing, China.

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Does morphine enhance the release of 5-hydroxytryptamine in the rat spinal cord? An in vivo differential pulse voltammetry study

Abstract

Exp. Neurol.

Neuroscience

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res. Rev.

Neuroscience

Brain Research