Serotonin-1A receptor dependent modulation of pain and reward for improving therapy of chronic pain

Abstract

Chronic pain conditions such as low back pain and osteoarthritis are the most prominent causes of disability worldwide. Morphine and other opioid drugs are the gold standard treatment for severe pain, including surgical pain, but the use of these drugs for chronic pain is limited largely because long term use of these drugs is associated with drug abuse and hyperalgesia which produces a negative impact on the treatment. Non-addictive treatments for chronic pain are, therefore, highly needed. Commonly used opioid drugs activate mu opioid receptors, resulting in an inhibition of tonic activity of nociceptive neurons. The rewarding effects of opioid drugs are also mediated via activation of mu opioid receptors and inhibition of GABA mediated control of the activity of dopamineregic neurons. Enhanced glutamate release and greater activity of NMDA glutamate receptors is linked to the hyperalgesic effects of opioid drugs. Evidence suggests that activation of serotonin (5-hydroxytryptamine; 5-HT)-1 A receptors modulates dopamine neurotransmission to inhibit rewarding effects of drugs of abuse. Activation of these receptors inhibits glutamate release from the sensory neurons to reduce pain transmission. To help develop strategies for improving therapeutics in chronic pain, and draw research interest in the synthesis of non-addictive opioid drugs which do not predispose to hyperalgesia, the present article concerns the potential mechanism involved in 5-HT-1 A receptor mediated inhibition of pain and reward.

Keywords: 5-HT1A receptors; 8-OH-DPAT (8-hydroxy-2-di-n-propylamino tetralin); AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid); Addiction; Buspirone (8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione); Dopamine; Dopamine (3,4-dihydroxyphenyl ethylamine); GABA (Gamma-aminobutyric acid); Hyperalgesia; Kainate ((2S,3S,4S)-3-(carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-c…); Morphine (4R,4aR,7S,7aR,12bS)-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol); NMDA (N-Methyl-D-aspartic acid); Opioid; Pain; Serotonin; Serotonin (5-hydroxytryptamine); Venlafaxine ((R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride).