Spinal Cord 5-Hydroxytryptamine_1A Receptor Is Involved In Descending Facilitating Nociception

The primary afferent fibres transmitting nociceptive information from periphery to the central nervous system terminate principally in the spinal dorsal horn, where nociception is modulated by descending control systems. Thus, the spinal dorsal horn plays a crucial role in the transmission and modulation of nociceptive information from periphery. 5-hydroxytryptamine (5-HT) containing fibres, which originate majorly from the rostroventromedial medulla (RVM) and terminate within the spinal dorsal horn, are the important components of the descending control systems. 5-HT, released from these fibres, can activate different receptor subtypes to inhibit or facilitate nociception.Till now, 15 kinds of 5-HT receptor subtypes have been cloned. Among them, 5-HT1A receptor subtype has been demonstrated to be the most predominant one in the spinal cord, especially in the spinal dorsal horn. But there is a serious debate about the facilitating, inhibiting or zero effect of spinal cord 5-HT1A receptor in the process of nociception.Subcutaneous injection of bee venom into one hindpaw of rat can elicit acute inflammation together with spontaneous nociceptive responses (spontaneously flinch the injected paw), heat hyperalgesia and mechanical hyperalgesia/allodynia in the injected paw.In the current project, molecular techniques (Semi-quantified reverse transcriptase-polymerase chain reaction, RT-PCR; Western Blot) and Pharmocologic method (Antisense oligodeoxynucleotide, ASO) are combinedwith the bee venom induced inflammatory pain model to elucidate the role of spinal cord 5-HT1A receptor in the inflammatory pain. The results are the followings:(1) By using semi-quantified RT-PCR, we observed marked increases in 5-HT1A receptor mRNA expression in ipsilateral lumbar spinal cord samples taken 1 h or 4 h after subcutaneous bee venom injection into one hindpaw of rat. When compared with control spinal cord samples taken from non-injected animals, ipsilateral expressions of 5-HT1A receptor mRNA 1 h or 4 h after bee venom injection significantly increased by 80.94% or 37.86%, respectively. There were little changes in 5-HT1A receptor mRNA level on the contralateral side at these two time points.(2) Intrathecal injections of 5-HT1A receptor ASO (5 g/5 l, once a day, for 4 days) significantly decreased the bee venom induced spontaneous nociceptive responses as well as reversed the ipsilateral heat hyperalgesia. The number of spontaneously flinching the injected hindpaw per 5 min during the observing time window for normal saline (NS)-, sense oligodeoxynucleotide (SO)- or ASO-pretreated group were 47.87, 46.13 and 34.48, respectively. The percentages of withdrawal latencies of NS-, SO- or ASO-pretreated group after bee venom injection to the baseline are 60.3%, 58.7% and 82.5%, respectively.(3) Intrathecal injection of ASO significantly decreased the 5-HT1A receptor protein whthin the lumbar spinal cord. The relative densities (percentage of protein level from treated group to that from naive group) of 5-HT1A receptor of NS-, SO- and ASO-pretreated group were 92.5%, 89.7% and 29.9%, respectively.To summarize, the results of our present study suggest that 5-HT1A receptor in the spinal cord might take part in the descending facilitation of RVM originated 5-HTergic fibres, thus facilitate bee venom induced spontaneous nociceptive responses and ipsilateral heat hyperalgesia. The physiological significance of such a facilitating role in nociceptive responses may be that the enhancement of nociceptive transmission in inflammatory rats, can encourage endogenous antinociceptive control by continually providing information toincrease the release of 5-HT from terminals originated from RVM and then to improve antinociception by activating other 5-HT receptor subtypes or interacting with other descending control systems.