The Role of 5-HT1A Receptors in Research Strategy for Extensive Pain Treatment

Abstract

In the last few years, there has been a great increase in our understanding of pain mechanisms. Given the complexity of the mechanisms involved in pain modulation, it is surprising that the pharmacological control of pain through the application of relatively simple analgesics can be effective. Nevertheless, the application of single analgesics is not always effective in diverse painful conditions such as chronic pain syndromes. In these circumstances, we can take advantage of the complexity of pain regulation and try to identify new targets in these intricate processes. It is becoming clear that the combination of different mechanisms, which improves efficacy with reduced toxicity, is necessary for the reliable pharmacotherapy of pain, and is at the forefront in the search for better analgesics. Serotonin is involved at multiple levels in the regulation of nociception. In particular, the raphe nuclei may play a crucial role in integrating the nociceptive and affective information through descending projections to the spinal cord and ascending projections to the forebrain. In these nuclei, 5-HT1A receptors function as somatodendritic autoreceptors controlling the release of serotonin in terminal areas. Different studies have shown that, by preventing this inhibitory control of serotonin release, it is possible to enhance the analgesic effect of drugs that increase serotonin levels (i.e. antidepressants, opiates, and non-steroidal anti-inflammatory drugs) by facilitating descending, and also ascending, pathways involved in pain modulation. Therefore, 5-HT1A receptors may be used as a new target in the search for new pharmacological approaches in the augmentation of analgesia.

In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat

“…In addition to their potential role in the treatment of depression (Blier and Ward 2003), anxiety disorders (Akimova et al 2009) and schizophrenia ; Newman-Tancredi 2010), 5-HT 1A receptor agonists have been the focus of interest as targets in the treatment of pain and efficacious agonists such as 8-OH-DPAT have shown activity in various models of pain (e.g., Bardin et al 2001; Bardin and Colpaert 2004;Mico et al 2006). However, 8-OH-DPAT, administered acutely, opposed the antinociceptive action of morphine (Millan and Colpaert 1990) demonstrating that an interaction exists between 5-HT 1A receptor activation and μ-opioid activation in the control of nociception.…”

Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice

“…So, the raphe nuclei may represent crossroads in the integration of the pathways of nociception and emotion. In this complex pattern, the role of 5-HT 1A and 5-HT 1B receptors has attracted much attention (Millan 2002;Adell et al 2005;Mico et al 2006). The blockade of the 5-HT 1A autoreceptors, located in the raphe nuclei, and 5-HT 1B receptors, located in 5-HT nerve terminals, has been shown to modulate the antidepressant and the antinociceptive response of 5-HT reuptake inhibitors (Adell et al 2005;Mico et al 2006).…”

“…In this complex pattern, the role of 5-HT 1A and 5-HT 1B receptors has attracted much attention (Millan 2002;Adell et al 2005;Mico et al 2006). The blockade of the 5-HT 1A autoreceptors, located in the raphe nuclei, and 5-HT 1B receptors, located in 5-HT nerve terminals, has been shown to modulate the antidepressant and the antinociceptive response of 5-HT reuptake inhibitors (Adell et al 2005;Mico et al 2006). In addition, the increase in the tonic activation of forebrain 5-HT 1A receptors has been correlated with the antidepressant effect of selective 5-HT reuptake inhibitors (SSRIs) and electroconvulsive shock therapy (Haddjeri et al 1998).…”

Antidepressant Drugs and Pain

“…This analgesic effect is typical of antidepressants that augment the levels of noradrenaline and serotonin. In general, TCAs demonstrated analgesic efficacy in a variety of pain conditions (e.g., back pain, fibromyalgia and migraine) in patients with depression (Barbui et al, 2007;Hansen et al, 2005;McDermott et al, 2006;Mico et al, 2006b). In clinical studies, the SNRI venlafaxine was more efficacious in treating the physical symptoms of depression than SSRIs, suggesting that the emotional and physical symptoms of depression are modulated by distinct mechanisms (Nemeroff CN, 2003;Thase et al, 2001).…”

“…For example, the inhibition of tyrosine hydroxylase (an essential enzyme for noradrenaline synthesis) or tryptophan hydroxylase (an essential enzyme for serotonin synthesis) antagonizes the analgesic effect of antidepressants in a wide range of experimental models (Valverde et al, 1994). Monoamines act on multiple receptor subtypes in the nervous system, some of which mediate the analgesic effect of antidepressants, such as -adrenoceptors (Ghelardini et al, 2000;Yokogawa et al, 2002) and -adrenoceptors (Mico et al, 2006b), 5-HT 1A , 5-HT 2 and 5-HT 3 serotonin receptors (Bonnefont et al, 2005;Yokogawa et al, 2002), and D2 dopamine receptors (Gilbert & Franklin, 2001). …”