Spinal muscarinic receptors are activated during low or high frequency TENS-induced antihyperalgesia in rats
Introduction
Transcutaneous electrical nerve stimulation (TENS) is a therapeutic modality, clinically used to relieve acute and chronic pain (Johnson et al., 1992). TENS is easy to use for the patient and is devoid of major side effects. Although the use of TENS is very common, its analgesic mechanism is not fully understood. Two types of TENS are used clinically, low frequency TENS (frequency of stimulation<10 Hz) and high frequency TENS (frequency>50 Hz). Different theories have been proposed for the mechanism of action of TENS, the popular one being the gate control theory proposed by Melzack and Wall (1965). According to gate control theory, the nociceptive information from small diameter afferents is overridden by the stimulation of large diameter fibers and the pain stimulus is prevented from reaching supraspinal centers. However, neuropharmacological studies point towards neurotransmitter-related spinal and supraspinal mechanisms in TENS-induced analgesia. Endogenous opioids released in the central nervous system are implicated in the analgesic mechanism of TENS by various investigators (see Sluka and Walsh, 2003).
The antihyperalgesic effect of TENS predominantly involves central (spinal and supraspinal) mechanisms (Sluka et al., 1999, Kalra et al., 2001) rather than peripheral mechanisms (Janko and Trontelj, 1980). Spinally, opioid and serotonin receptors mediate TENS antihyperalgesia (Sluka et al., 1999, Radhakrishnan et al., 2003). Further, sensitization of dorsal horn neurons induced by carrageenan inflammation is reversed by high and low frequency TENS (Ma and Sluka, 2001). Descending inhibitory systems from the periaqueductal grey (PAG) and rostral ventromedial medulla (RVM) mediate analgesia through opioid, adrenergic and serotonin receptors spinally (Fields and Basbaum, 1999). In the spinal cord, inhibition also involves cholinergic receptors and they are clearly involved in spinal antinociception (Zhuo and Gebhart, 1991, Fang and Proudfit, 1996; reviewed by Eisenach, 1999, Pinardi et al., 2003). Among the spinal receptors, cholinergic receptors are unique in that they mediate antinociception through interactions with most of the inhibitory receptors, i.e. 5-HT, adrenergic or opioid receptors, in the spinal cord (Chiang and Zhuo, 1989, Gordh et al., 1989, Li et al., 1994, Obata et al., 2002, Chen and Pan, 2001, Honda et al., 2002). Both cholinergic nicotinic (Arimatsu et al., 1981, Ninkovic and Hunt, 1983; see review by Coggeshall and Carlton, 1997) and cholinergic muscarinic (Kayaalp and Neff, 1980; see review by Coggeshall and Carlton, 1997, Eisenach, 1999) receptors are localized to the dorsal horn, in laminae I–IV. Although nicotinic receptors are located in the spinal cord, their role in spinal antinociception is controversial. Thus, spinal cholinergic receptors are important in the inhibition of nociception through activation of opioid and 5-HT receptors.
Since there is compelling evidence for spinal and/or supraspinal opioid and 5-HT receptor mediation in TENS analgesia, we investigated the involvement of spinal cholinergic nicotinic and muscarinic receptors in the antihyperalgesic mechanisms of low and high frequency TENS, using selective antagonists. Selectivity and functional differences of the spinal cholinergic receptor subtypes were studied using selective antagonists against the spinal antinociceptive effects of muscarinic agonists.
Section snippets
Animals
Male Sprague-Dawley rats (n=136, Harlan, St. Louis, Missouri, USA), weighing 225–300 g, kept at 12 h dark–light cycle with free access to standard rat chow and water, were used for the experiments. All experiments were approved by University of Iowa Animal Care and Use Committee and were carried out according to the guidelines of the International Association for the Study of Pain and National Institutes of Health.
Behavior testing
Animals were brought to the behavioral testing room the day before to acclimatize
Results
An overall effect for the PWL to heat occurred for treatment (F2,102=95.2, p<0.0001) such that PWLs were significantly higher following treatment with either high (p<0.0001) or low (p<0.0001) frequency TENS, when compared to ‘no TENS’. An interaction occurred between treatment and drug (F10,102=7.8, p<0.0001) for PWLs after treatment with or without TENS. The results below are thus outlined by drug treatments.
Discussion
The data from the present study clearly show that the antihyperalgesia produced by low and high frequency TENS is mediated to a large extent by spinal muscarinic receptors since the non-selective muscarinic antagonist atropine markedly attenuated both low and high frequency TENS-induced antihyperalgesia, when administered intrathecally. Further, pirenzepine and 4-DAMP which are antagonists at M1 and M3 muscarinic receptor subtypes, respectively, also attenuated the effects of both low and high
Acknowledgements
The authors are thankful to Ms. Carol Leigh for secretarial assistance. This work was supported by National Institutes of Health Grant K02 AR02201 (KAS) and the Arthritis Foundation.
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