Possible involvement of histamine, dopamine, and noradrenalin in the periaqueductal gray in electroacupuncture pain relief

Abstract

Acupuncture and electroacupuncture are used in pain relief; however, the mechanism underlying the analgesic effect of acupuncture is unclear. Several lines of evidence propose that the periaqueductal gray (PAG), which is one of the regions that contributes to the endogenous pain inhibitory system, is involved in the analgesic effect of acupuncture, and the region receives several neural projections such as histamine and noradrenalin and contains the dopamine cell bodies. The current study examined the effects of electroacupuncture at Zusanli (ST36) and Shangjuxu (ST37) acupoints, which are used for clinical pain control, on the release of neurotransmitters in the PAG in rats. Histamine and dopamine release was increased after pain stimulus, while the changes were completely abolished by electroacupuncture. Pain stimulus had no effect on noradrenalin release, but electroacupuncture increased its release. These findings indicate that acupuncture at Zusanli and Shangjuxu exerts an antinociceptive effect via the activation of neurons in the PAG and that the histaminergic, dopaminergic, and noradrenalinergic systems in the PAG are related to electroacupuncture-induced pain relief.

Introduction

Acupuncture is used all over the world as one of the most important strategies in complementary and alternative medicine, and clinical evidence for its efficacy has accumulated. However, the efficacy and physiological mechanism of acupuncture have not been scientifically clarified.

One of the most well-documented benefits of acupuncture is its analgesic effect. Acupuncture and/or electroacupuncture have been effectively applied to patients suffering from pain due to rheumatoid arthritis, osteoarthritis, and bone metastasis of cancer (Casimiro et al., 2005, Ezzo et al., 2001, Zhang et al., 2007) C:\G. Zusanli (ST36) and Shangjuxu (ST37) are the acupoints used to treat postoperative pain (Chen et al., 1998, Lin et al., 2002), angina chest pain (Richter et al., 1991), gastric pain (Berman et al., 1999), and osteoarthritis- or rheumatoid- related aching of the knee joints and legs (Berman et al., 1999, Jenck et al., 1987, Lee et al., 2008). In animal studies, it was found that electroacupuncture at Zusanli relieves the arthritic pain produced by carrageenan injection (Oh et al., 2006) and the hind limb pain induced by formalin injection in mice (Chang et al., 2004) and rats (Wen et al., 2007). Its analgesic effects were also demonstrated by a tail-flick test in rats (de Medeiros et al., 2003).

The periaqueductal gray (PAG) of the midbrain contains neural fibers that link the cortex, thalamus, hypothalamus, medulla oblongata, and spinal cord (Abols and Basbaum, 1981, Beitz, 1982, Eberhart et al., 1985, Hermann et al., 1997, Mason, 2005, Morrell et al., 1981, Morrell and Pfaff, 1983, Vanegas and Schaible, 2004). Reynolds (1969) showed that electrical stimulation of the PAG can induce analgesia, and the existence of an endogenous descending pain modulatory system was proven in the 1970s and 1980s (Jensen, 1986, Mayer, 1984, Mayer and Liebeskind, 1974). Thus, the PAG is generally regarded as the core of this analgesic system. The PAG receives input from several brain regions (Holstege, 1987, Jenck et al., 1986, Mantyh, 1982, Mason, 2005, Vanegas and Schaible, 2004, Wiberg et al., 1987, Yezierski, 1988) and in turn projects into the rostral ventromedial medulla, which relays midbrain signals from spinal nociceptive inputs; i.e., descending modulation of pain (Mason, 2005). A recent study reported that electroacupuncture at the Zusanli point increased the number of c-Fos positive cells in the ventrolateral PAG (de Medeiros et al., 2003). Morphologically, the PAG receives neural input from histaminergic neurons in the tuberomammillary nucleus (Inagaki et al., 1988, Watanabe et al., 1983) and noradrenergic fibers from the A1 and A2 cell groups in the medial part of the nucleus of the solitary tract and the A6 cell group in the locus coeruleus (Bajic et al., 2000, Herbert and Saper, 1992). In addition, the PAG itself contains the dorsocaudal A10 cell group, which includes dopaminergic cell bodies (Meloni et al., 2006).

Therefore, we hypothesized that electroacupuncture at the Zusanli and Shangjuxu points would have an antinociceptive effect via neuronal changes in the PAG. In the present study, we studied the release of neurotransmitters in the PAG after paraformaldehyde (PFA) induced pain stimuli with/without electroacupuncture using in vivo microdialysis in anesthetized rats.