Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A−/−, 5-HT1B−/−, 5-HT2A−/−, 5-HT3A−/− and 5-HTT−/− knock-out male mice

Abstract

Extensive studies in rodents suggest that serotonin (5-HT) modulates nociceptive responses through the stimulation of several receptor types. However, it remains to demonstrate that these receptors participate in the control of nociception under physiological conditions. Pain behaviors of mutants which do not express 5-HT1A, 5-HT1B, 5-HT2A or 5-HT3A receptors, or lacking the 5-HT transporter, compared to paired wild-type mice of the same genetic background, were examined using validated tests based on different sensory modalities. Mechanical (von Frey filaments, tail pressure, tail clip tests), thermal (radiant heat, 46 degrees C water bath, hot-plate test) and formalin-induced nociception were determined in 2- to 3-month-old males. 5-HT1A knock-out mice differed from wild-types by higher thermal sensitivity (hot-plate test only), and 5-HT1B knock-out mice by higher thermal and formalin sensitivity. Both 5-HT2A and 5-HT3A knock-out mice differed from wild-types by a dramatic decrease in the formalin-induced nociceptive responses for phase II (16-45 min after injection/inflammatory phase). In contrast, neither mechanical, thermal nor formalin-induced nociception differed between mutants lacking the 5-HT transporter and paired wild-type mice. Although differences in spontaneous locomotor activity in 5-HT1B-/- (increase) and 5-HT3A-/- (decrease) knock-out mice versus paired wild-types might have confounded differences in nociception, acute 5-HT receptor blockade by selective antagonists was found to replicate in wild-type mice the effects on pain behavior, but not on locomotor activity, of the respective gene knock-out in mutants. These results support the conclusion that the complex control of pain mechanisms by 5-HT, acting at multiple receptors, is physiologically relevant in mice.

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

“…Intrathecal injections were performed under volatile anesthesia (see next paragraph). We injected 20 µl (30,60, 125 ng RS127445) of the antagonist or vehicle directly through the intact skin, between the L5 and L6 vertebrae, with a Hamilton syringe equipped with a 26-gauge needle. We applied 10 µl of solution (125 ng) to the sciatic nerve, as described below.…”

“…Indeed, pain modulation by 5-HT is complex and may involve pro-or antinociceptive effects, depending on the cellular targets and receptor subtypes involved. In the spinal cord, 5-HT acts through bulbospinal descending projections [30,38,54], whereas, in the periphery, it sensitizes nociceptors following both inflammation and nerve injury [53]. By contrast, the role of 5-HT in the immune mechanisms associated with neuropathic pain has never been addressed, despite the abundance of data implicating 5-HT in immune functions [1,9,21,33,44].…”

Serotonin Receptor 5-HT2BMediates Serotonin-Induced Mechanical Hyperalgesia

“…Ionotropic 5-HT 3 is responsible for inflammatory pain (Eschalier et al, 1989;Giordano and Rogers, 1989;Zeitz et al, 2002;Kayser et al, 2007). Lack of the 5-HT 3 gene in mice or blocking by the 5-HT 3 antagonist granisetron elicits normal acute pain responses but reduced responses to persistent pain (Zeitz et al, 2002;Kayser et al, 2007).…”

Acupuncture: Emerging evidence for its use as an analgesic (Review)

“…CCK-8 has been demonstrated to possess notable anti-opioid activity at the spinal level. Thus, inhibition of the spinal cholecystokinin effect may be expected to potentiate opiate analgesia (72). Opioid activity in vivo is able to increase the expression of CCK-8, resulting in negative feedback regulation (73).…”