A pronociceptive role for the 5-HT2 receptor on spinal nociceptive transmission: an in vivo electrophysiological study in the rat

Abstract

Serotonin (5-HT) plays a major yet complex role in modulating spinal nociceptive transmission as a consequence of the number of 5-HT receptor subtypes. These include the 5-HT2 receptor, which is further sub classified into 5-HT2A, B and C. Studies have described both a pro- and antinociceptive action following 5-HT2A-receptor activation; therefore, to shed light on the directional nature of spinal 5-HT2A receptor activity, we investigated the effects of spinal administration of the 5-HT2A receptor antagonist, ketanserin, on the evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimulation. We also assessed the effects of systemic administration of ritanserin, a 5-HT2A/2C receptor antagonist and spinal application of (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) (3.6 and 17.8μg/50μl), a 5-HT2A/2C agonist, on the same evoked neuronal responses. Ketanserin (1, 10 and 100μg/50μl) produced a dose related inhibition of the evoked responses to noxious mechanical punctate and thermal stimuli only. Ritanserin (2mg/kg) replicated the inhibitory effects seen with ketanserin on the natural evoked neuronal responses and also potently inhibited the C-fibre, post discharge, input and wind-up evoked responses. DOI increased the mechanical and thermal evoked responses, an effect reversed by ketanserin. Thus, our findings show that spinal ketanserin (1-100μg/50μl) and systemic ritanserin (2mg/kg), at these doses, have similar antinociceptive effects, whereas the agonist, DOI, produced excitatory effects, on spinal neuronal activity. Our data, therefore, supports a pronociceptive role for 5-HT2 receptors, most likely through modulation of 5-HT2A receptor activity, on spinal nociceptive transmission under normal conditions.

Fig. 1

Effect of topical spinal administration of ketanserin (1, 10 and 100 μg/50 μl) on the a. electrical b. mechanical punctate and c. thermal evoked responses of wide dynamic range dorsal horn neurones. Ketanserin significantly inhibited the noxious mechanical (26 and 60 g) and heat (45–48 °C) evoked neuronal responses, evoked responses of wide dynamic range dorsal horn neurones. Data expressed as mean ± SEM. Significance at the lower dose of 10 μg/μl is denoted by +, whereas significance at the higher dose of 100 μg/μl is denoted by *p < 0.05.

Fig. 2

Effect of systemic administration of ritanserin (2 mg/kg) on a. electrical b. mechanical punctate and c. thermal evoked responses of wide dynamic range dorsal horn neurones. Ritanserin significantly inhibited the electrically evoked C-fibre, post discharge, input and wind-up neuronal responses. The evoked response to noxious mechanical (60 g) and heat (48 °C) stimuli was also significantly inhibited. Data expressed as mean ± SEM. Significance is denoted by *p < 0.05.

Fig. 3

Effect of topical spinal administration of DOI (3.6 and 17.8 μg/50 μl) on a. electrical b. mechanical punctate and c. thermal evoked responses of wide dynamic range dorsal horn neurones. DOI significantly increased the evoked response to mechanical (26 and 60 g) and heat (48 °C) stimuli. Data expressed as mean ± SEM. Significance is denoted by *p < 0.05.