115
Pain, 40 (1990) 115-116 Elsevier
PAIN 01524
Serotonin,
serotonin
receptors, serotonin and pain Julio
Department
receptor
subtype agonists
Pascual
of Medicine, Service of Neurology, National Hospital ‘Marqub de Valdecrlla,’ and Department and Pharmacology, Section of Pharmacology, Faculty of Medicine, Santander (Spain)
of Physiology
(Received 16 June 1989, accepted 24 August 1989)
Dear Editor, In a recent paper in Pain [5] Kishore-Kumar et al. examined the possible analgesic effects of receptor agonist, and mbuspirone, a 5-HT,, clorophenylpiperazine (m-CPP), a 5-HT,, receptor agonist, in patients with chronic neuropathic pain. The authors state that, as there is a great deal of data suggesting that serotonin produces the use of selective agonists for analgesia, serotonergic receptor type subclasses may produce analgesic effects. In this paper single high doses of both agents did not relieve neuropathic pain. The authors give some explanations for their negative results. These are as follows: the absence of 5-HT, mediated analgesia, different mechanisms for neuropathic pain, and the failure in the sensitivity of their study methods to detect a modest level of analgesia [5]. I think that there are other explanations which must be taken into account to clarify their results. As these authors point out, the novel anxiolytic agent buspirone is a selective agonist for 5-HT,, receptors. 5-HT,, receptor subtype is now known as a serotonergic presynaptic autoinhibitory receptor. So, stimulation upon these receptors decreases the activity of serotonergic neurons [2]. In fact,
Correspondence to: Dr. Julio Pascual, Service of Neurology, National Hospital ‘ MarquOs de Valdecilla,’ Avda. Valdecilla s/n, 39008 Santander, Spain. 0304-3959/90/$03.50
studies in rats demonstrate that acute buspirone administration results in inhibition of the spontaneous firing of serotonin-containing neurons as well as in a dose-dependent reduction in the levels of serotonin and its principal metabolites [cf., 31. Thus, although indeed buspirone is an agonist of a 5-HT, receptor subtype, finally this compound exerts unequivocal antiserotonergic effects. One must be very cautious not to consider that the agonistic effects upon a receptor always mediate agonistic results upon the level of its specific neurotransmitter. Regarding m-CPP, the 5-HT,, agonist employed in that report, I am greatly surprised that the authors did not consider that, as has been widely demonstrated [4,6], the 5-HT,, subtype is absent in the human brain. So, the proposed serotonergic actions of m-CPP in human brain cannot be explained in terms of agonism upon the 5-HT,, subtype and still need clarifying. Briefly, in the human brain there are 3 known 5-HT, subtypes named 5-HTi,, 5-HT,, and 5-HT,,. This last subtype corresponds to a new 5-HT, subtype, not present in the rat brain, which exhibits a specific pharmacological profile and regional distribution [4,6]. These dramatic species differences are of great importance in the study of new pharmacological compounds emphasizing that caution is needed in the extrapolation of experimental data from rat to man. The specific role of 5-HT, receptor subtypes in pain is open to discussion. It has been suggested
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
116
that spinal 5-HT receptors related to nociceptive control are of the 5-HT, class. Since most serotonin receptors, present in the dorsal horn, are of the 5-HT,, subtype, this might suggest a role of these sites in the regulation of the nociceptive activity [4.6], though the role of the other subtypes. mainly through a raphe-spinal projection interconnected with the endogenous opioid pathways and through the brain-stem serotonergic connections. remains to be assessed [l]. New basic studies in these directions and the development of new 5-HT, compounds for clinical use are needed to clarify the role of the 5-HT, receptor in the analgesia mechanisms.
3
4
5
6
References 1 Berge. O.G., Holle, K. and morphine-induced analgesia
2
Oegren, S.V., Attenuation by chloro-phenylalanine
of and
p-chloroamphetamine: test-dependent effects and evidence for brainstem 5-hydroxytryptamine involvement. Brain Res., 271 (1983) 51-54. Dourish, CT., Hutson, P.H. and Curzon, G., Putatrve anxtolytics 8-OH-DPAT, buspirone and TVX-Q7821 are agonists at 5-HT,, autoreceptors in the raphe nuclei. Trends Pharmacol. Sci., June (1986) 212-214. Eisen, A.S. and Temple, D.L.. Buspirone: review of Its pharmacology and current perspectives on its mechanism of action. Am. J. Med., 80, Suppl. 3B (1986) 1-9. Hoyer, D., Pazos, A., Probst. A. and Palacios, J.M., Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT,, recognition sites. Apparent absence of 5-HT,, recognition sites, Brain Res., 376 (1986) 85-96. Kishore-Kumar, R., Schafer. SC., Lawlor. B.D., Murphy, D.L. and Max. M.B.. Single doses of the serotonin agonists buspirone and m-clorophenylpiperazine do not relieve neuropathic pain, Pain, 37 (1989) 223-227. Pazos, A., Probst. A. and Palacios, J.M.. Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-I receptors, Neuroscience, 21 (1987) 97-122.
Pain, 40 (1990) 115-116 Elsevier
PAIN 01524
Serotonin,
serotonin
receptors, serotonin and pain Julio
Department
receptor
subtype agonists
Pascual
of Medicine, Service of Neurology, National Hospital ‘Marqub de Valdecrlla,’ and Department and Pharmacology, Section of Pharmacology, Faculty of Medicine, Santander (Spain)
of Physiology
(Received 16 June 1989, accepted 24 August 1989)
Dear Editor, In a recent paper in Pain [5] Kishore-Kumar et al. examined the possible analgesic effects of receptor agonist, and mbuspirone, a 5-HT,, clorophenylpiperazine (m-CPP), a 5-HT,, receptor agonist, in patients with chronic neuropathic pain. The authors state that, as there is a great deal of data suggesting that serotonin produces the use of selective agonists for analgesia, serotonergic receptor type subclasses may produce analgesic effects. In this paper single high doses of both agents did not relieve neuropathic pain. The authors give some explanations for their negative results. These are as follows: the absence of 5-HT, mediated analgesia, different mechanisms for neuropathic pain, and the failure in the sensitivity of their study methods to detect a modest level of analgesia [5]. I think that there are other explanations which must be taken into account to clarify their results. As these authors point out, the novel anxiolytic agent buspirone is a selective agonist for 5-HT,, receptors. 5-HT,, receptor subtype is now known as a serotonergic presynaptic autoinhibitory receptor. So, stimulation upon these receptors decreases the activity of serotonergic neurons [2]. In fact,
Correspondence to: Dr. Julio Pascual, Service of Neurology, National Hospital ‘ MarquOs de Valdecilla,’ Avda. Valdecilla s/n, 39008 Santander, Spain. 0304-3959/90/$03.50
studies in rats demonstrate that acute buspirone administration results in inhibition of the spontaneous firing of serotonin-containing neurons as well as in a dose-dependent reduction in the levels of serotonin and its principal metabolites [cf., 31. Thus, although indeed buspirone is an agonist of a 5-HT, receptor subtype, finally this compound exerts unequivocal antiserotonergic effects. One must be very cautious not to consider that the agonistic effects upon a receptor always mediate agonistic results upon the level of its specific neurotransmitter. Regarding m-CPP, the 5-HT,, agonist employed in that report, I am greatly surprised that the authors did not consider that, as has been widely demonstrated [4,6], the 5-HT,, subtype is absent in the human brain. So, the proposed serotonergic actions of m-CPP in human brain cannot be explained in terms of agonism upon the 5-HT,, subtype and still need clarifying. Briefly, in the human brain there are 3 known 5-HT, subtypes named 5-HTi,, 5-HT,, and 5-HT,,. This last subtype corresponds to a new 5-HT, subtype, not present in the rat brain, which exhibits a specific pharmacological profile and regional distribution [4,6]. These dramatic species differences are of great importance in the study of new pharmacological compounds emphasizing that caution is needed in the extrapolation of experimental data from rat to man. The specific role of 5-HT, receptor subtypes in pain is open to discussion. It has been suggested
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
116
that spinal 5-HT receptors related to nociceptive control are of the 5-HT, class. Since most serotonin receptors, present in the dorsal horn, are of the 5-HT,, subtype, this might suggest a role of these sites in the regulation of the nociceptive activity [4.6], though the role of the other subtypes. mainly through a raphe-spinal projection interconnected with the endogenous opioid pathways and through the brain-stem serotonergic connections. remains to be assessed [l]. New basic studies in these directions and the development of new 5-HT, compounds for clinical use are needed to clarify the role of the 5-HT, receptor in the analgesia mechanisms.
3
4
5
6
References 1 Berge. O.G., Holle, K. and morphine-induced analgesia
2
Oegren, S.V., Attenuation by chloro-phenylalanine
of and
p-chloroamphetamine: test-dependent effects and evidence for brainstem 5-hydroxytryptamine involvement. Brain Res., 271 (1983) 51-54. Dourish, CT., Hutson, P.H. and Curzon, G., Putatrve anxtolytics 8-OH-DPAT, buspirone and TVX-Q7821 are agonists at 5-HT,, autoreceptors in the raphe nuclei. Trends Pharmacol. Sci., June (1986) 212-214. Eisen, A.S. and Temple, D.L.. Buspirone: review of Its pharmacology and current perspectives on its mechanism of action. Am. J. Med., 80, Suppl. 3B (1986) 1-9. Hoyer, D., Pazos, A., Probst. A. and Palacios, J.M., Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT,, recognition sites. Apparent absence of 5-HT,, recognition sites, Brain Res., 376 (1986) 85-96. Kishore-Kumar, R., Schafer. SC., Lawlor. B.D., Murphy, D.L. and Max. M.B.. Single doses of the serotonin agonists buspirone and m-clorophenylpiperazine do not relieve neuropathic pain, Pain, 37 (1989) 223-227. Pazos, A., Probst. A. and Palacios, J.M.. Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-I receptors, Neuroscience, 21 (1987) 97-122.
