Roles of serotonin receptor types 1 and 2 in pain modulation in rat

Abstract

Serotonin (5-HT) is a neurotransmitter that plays a major role in central nociceptive modulation. This transmitter exerts its nociceptive modulation effects via a wide variety of its receptor subtypes. This study was conducted to clarify the roles of 5-HT1A and 5-HT2A receptors in pain modulating mechanism. Adult male Wistar rats were divided into 3 groups (8 rats each), 5-HT1A agonist (receiving 8-hydroxy-2-di-n-propylamino-tetralin: 8-OH-DPAT 3 mg/kg intraperitoneal; i.p), 5-HT2A agonist (receiving 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane: DOI 1 mg/kg i.p.) and control groups. Nociception was quantified by tail flick and formalin tests. The nociceptive behaviors (lifting, licking and scratching) in response to subcutaneous formalin injection were measured within 10 min (phase I) and 10-60 min (phase II) after injection. The spinal cords were then removed for further detection of Fos-immunoreactive neurons by method of immunohistochemistry. Number of dorsal horn neuron with Fos-like immunoreactivity (FLI) was used as an indicator of neuronal activity. The results showed that, pretreatment with 8-OH-DPAT significantly increased tail flick latency (5.91+-0.42 and 12.11+-0.49 seconds, for with and without drug administrations respectively, P<0.001). On the contrary, pretreatment with DOI significantly decreased tail flick latency (7.35+-0.81 and 1.29+-0.13 seconds, for with and without drug administrations respectively, P<0.001). A significant decrease in formalin-induced lifting behavior was observed in 8-OH-DPAT group as compared to the control group (7.10+-1.85, 1.17+-0.30 seconds, in phase I of control and 8-OH-DPAT group, respectively at p<0.05). No significant change in nociceptive behaviors was demonstrated in the DOI group. However, it was observed that DOI produced motor depression in the late phase (30-60 min) of behavioral observation. This motor depression effect may interfere with the quantification of the nociceptive behaviors. Besides effect on nociceptive behavioral modification, administration of 5-HT receptor agonists also modified pattern of noxious stimulation-induced FLI in spinal dorsal horn. A decrease in number of FLI was observed in 8-OH-DPAT group, whereas the reverse was observed in DOI group. The average numbers of FLI in lamina V in control, 8-OH-DPAT and DOI groups were 17.15+-1.65, 12.87+-1.16 and 20.31+-1.12 cells/slide, respectively. Comparison of number of FLI between 8-OH-DPAT and DOI groups revealed statistical significant (P<0.05). However, the 5-HT agonist-induced change in dorsal horn FLI did not reach the statistical significance when compared to the controls. Based on the present behavioral and FLI studies, one may suggest that stimulation of 5-HT1A receptor attenuates both heat and chemical spinal pain processing mechanism while 5-HT2A potentiates.