Selective brain hypothermia suppresses noxious-evoked movement in canines.

Systemic hypothermia suppresses noxious-evoked movement, but its main site of action is unknown. We examined the effect of hypothermia in the brain on noxious-evoked movement by selectively cooling the brain. Sixteen beagles were randomly divided into two groups and anesthetized with isoflurane/oxygen. After being deeply anesthetized, the dogs' lungs were artificially ventilated, and several major vessels were cannulated for perfusion and monitoring. Cold lactate Ringer's solution was infused into the right vertebral artery to cool the brain while maintaining the trunk temperature relatively warmer. When the brain temperature decreased to 20 degrees C or 25 degrees C, isoflurane administration was discontinued; the trunk temperatures at this stage were approximately 34.7 degrees C and 34.6 degrees C, respectively. After the end-tidal isoflurane concentration reached 0%, the base of the tail was stimulated with an electric current through 2 25-gauge needles. None of the dogs reacted to tail stimulation when the brain temperature was at 20 degrees C, whereas 7 of 8 reacted at 25 degrees C. These results indicate that selective brain hypothermia (20 degrees C) results in suppressing noxious-evoked movement in canines.

Characterization of nociceptin/orphanin FQ-induced pain responses by the novel receptor antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride.

At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC(50) values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.

Central nociceptive role of prostacyclin (IP) receptor induced by peripheral inflammation.

Prostacyclin (PGI2) is well known to play crucial roles in induction of edema and pain behavior in the periphery. In the present study, we investigated the central role of PGI2 in inflammatory pain. Intraplantar injection of carrageenan markedly induced the expression of prostacyclin receptor (IP receptor) mRNA with the maximum at 6 h, coincidently induction of the inducible form of cyclooxygenase (COX-2), although IP receptor mRNA was weakly expressed in the spinal cord of naive mice. Intrathecal administration of the IP agonist cicaprost induced mechanical hyperalgesia 6 h after carrageenan injection. These results suggest that PGI2 is involved in pain transmission at the spinal cord following expression of IP receptor mRNA induced by peripheral inflammation.