SAN DIEGO (American Physiological Society) -- Chronic pain affects some 86 million Americans a year, and business and industry loses about $90 billion annually to sick time, reduced productivity, and direct medical and other benefit costs. Many who suffer from chronic pain are told to learn to "live with it." Now new research indicates that relief could be provided in the vitamin counter at the neighborhood grocery story.

B-vitamins, such as thiamin (B1), pyridoxine (B6), and cyanocobalamin (B12), have been proven to be clinically effective in treating various painful conditions such as lumbago, sciatica, trigeminal neuralgia, facial paralysis and optic neuritis as acting as an analgesia (pain reliever). Past research has explored the analgesic and anti-inflammatory effects of vitamin B1, B6 and B12. For example, vitamin B1, B6, and B12 and combinations inhibited chemical- and heat-induced pain evidenced by writhing test, heat coil test, or hot plate test (although some negative results have also been reported).

Nociceptive pain comes from sprains, bone fractures, burns, bumps, bruises, inflammation (from an infection or arthritic disorder), obstructions, and myofascial pain (which may indicate abnormal muscle stresses). The pain originates from the nociceptors, nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. One of the research studies found that noxious heat evoked nociceptive responses of spinal dorsal horn neurons were suppressed by compound of B1, B6 and B12. These studies indicate that the B-vitamins possess the capability to block physical distress in some painful conditions.

Recently, several animal models of painful sequelae in humans after the primary sensory neurons injury have been developed such as the model of chronic compression of dorsal root ganglion (DRG). However, this antinociceptive efficacy of B-vitamins has not been evaluated in animals with neuropathic pain, that is result of an injury or malfunction in the peripheral or central nervous system. The pain is often triggered by an injury, but this injury may or may not involve actual damage to the nervous system. Researchers recently found that intraperitoneal (i.p.)- or intrathecal (i.t.)- injection of B1, B6 and B12 or their combination significantly reduced thermal hyperalgesia in CCD rats. On the other hand, mechanisms underlying the B-vitamins-induced analgesia remain unknown. It has been reported that B complex vitamins can activate potently the soluble guanylyl cyclase (sGC), and cyclase guanosine monophosphate (cGMP) in a wide variety of tissues. cGMP plays an antinociceptive activity in nociceptive processing. Others have suggested that B1 could produce antinociception by the activation of GC mediated by cGMP in p-benzoquinone-induced mouse writhing model.

A New Study

To provide experimental evidence that supports clinical use of the B-vitamins in aiding in the treatment of chronic pain especially neuropathic pain due to primary sensory neuron injury, the present study examined antinociceptive effect of vitamin B1, B6 and B12 using the neuropathic pain model of chronic compression of DRG (CCD, Song et al. J Neurophysiol 1999, 82: 3359-3370), and the possible contributions of cGMP-PKG signaling pathway to B1 induced antinociception. The authors of "Antinociceptive Effects of Thiamin, Pyridoxine and Cyanocobalamin in Rats with Primary Sensory Neuron injury" and "Activation of cGMP-PKG Signaling Pathway Mediates Thiamin Induced-Inhibition of Thermal Hyperalgesia in Rats with Primary Sensory Neuron Injury" are Xue-Jun Song MD, PhD, Associate Professor and Associate Director of Basic Science Research Department of Neurobiology, and Zheng-Bei Wang, MD, both from the Parker Research Institute, Dallas, TX. They are presenting their findings at the American Physiological Society conference, Experimental Biology 2003, being held April 11-15, 2003, at the San Diego Conference Center, San Diego, CA.

Methodology

Experiments were performed on adult, male Sprague-Dawley rats weighing 200-250 g. CCD was produced by surgically implanting stainless steel rods unilaterally into the intervertebral foramen at L4 and L5 as we previously described. In brief, the rats were anesthetized with sodium pentobarbital (40mg/kg, i.p.), the paraspinal muscles were separated from the mammillary and transverse processes and the intervertebral foramina of L4 and L5 exposed. A stainless steel L-shaped rod, 4 mm in length and 0.6 mm in diameter, was implanted into each foramen, one at L4 and the other at L5. Each insertion was guided by the mammillary process and transverse process. As the rod was moved over the ganglion, the ipsilateral hind leg muscles typically exhibited one or two slight twitches. After surgery, the muscle and skin layers were sutured. An oral antibiotic, Augmentin, was administered after surgery in the drinking water for each rat (7.52 g in 500 ml) for seven days.

The presence of thermal hyperalgesia was determined by measuring foot withdrawal latency to heat stimulation of surface of hindpaw. The rats were tested on each of 2 successive days prior to surgery. Postoperative tests were conducted 1, 3, 5, 7, 10, 14 days after surgery and then once weekly for ~10 weeks in some rats for examining the long-term effects of B vitamins. For examining short-term effects, tests were conducted for up to 14 days and additional tests 2, 6, 12, 24 and 36 hours after injection of B vitamins on the third day after surgery.

The rats in different groups each received one of the following treatments via i.p. or i.t. I.p. treatments (0.1 ml/100g): (1) saline (0.9% NaCl); (2) B1 (5, 10 and 33 mg/kg, respectively); (3) B6 (5, 10 and 33 mg/kg, respectively); (4) B12 (0.05, 0.2 and 0.5 mg/kg); (5) complex B vitamins (CBV) (B1+ B6 + B12 at different doses); (6) CBV for 7 consecutive days after surgery. I.t. treatments (20 µl): (1) saline; (2) B1 (33, 66 and 132 µg); (3) PKG inhibitor Rp-8pCPT-cGMPS (0.1 and 1 µM) +B1 (66 µg); (4) guanylyl cyclase inhibitor ODQ (0.02 and 0.2 µM) + B1; (5) cGMP analog 8Br-cGMP (0.1 and 1 µM); (6) PKG activator SP-cGMP (0.1 and 1 µM); (7) Rp-8pCPT-cGMPS + 8Br-cGMP; (8) Rp-8pCPT-cGMPS + SP-cGMP; (9) B1 66 µg for 7 consecutive days after surgery. Additional rats were used as sham or unoperated control.

Results

B1, B6, B12 and their combination, i.p. or i.t., significantly inhibited thermal hyperalgesia (pain) evidenced by reversal of the shortened latency of foot withdrawal to noxious heat stimulation ipsilateral to CCD. This inhibition was in dose-dependent manner. Hyperalgesia was inhibited about 20-100 percent at 2, 6 and 12 hr, and recovered at 24 or 36 hr test dependent on different doses. Repetitive application of CBV for seven days produced long-term inhibitory effects on thermal hyperalgesia. The extreme sensitivity to stimuli disappeared four to five weeks after injury in rats with CBV treatment. In contrast, hyperalgesia lasted for eight to ten weeks in rats with saline or without any treatment. In addition, we found that combination of threshold doses of individual of the vitamins produced a synergetic inhibitory effect on thermal hyperalgesia.

B1, i.t., induced-inhibition of hyperalgesia was reversed by inhibitors of cGMP-PKG signaling pathway ODQ (guanylyl cyclase inhibitor) and Rp-8pCPT-cGMP (PKG inhibitor). cGMP analog 8Br-cGMP and PKG activator SP-cGMP inhibited thermal hyperalgesia, respectively. Such inhibition is similar to that produced by B1. Rp-8pCPT-cGMP again reversed 8Br-cGMP and SP-cGMP induced- inhibition of thermal hyperalgesia. B1 and the activators and inhibitors of cGMP-PKG pathways did not alter the foot withdrawal latency in unoperated control rats.

Summary

The present studies demonstrate that spinal application as well as intraperitoneal injection of vitamin B1, B6, B12 their combination can produce short- and long-term inhibition of hyperalgesia following chronic compression of dorsal root ganglion neurons produced by artificial intervertebral foramen stenosis. Both severity and duration of hyperalgesia are significantly reduced. These results strongly support clinical use of B-vitamins in aiding in treatment of chronic pain and/or other diseases due to similar injuries to the nervous system.

The data also show that vitamin B1 induced-inhibition of hyperalgesia can be reversed by the inhibitors of cGMP-PKG signaling pathway, suggesting that vitamin B1 induced- inhibition of hyperalgesia due to spinal ganglion compression may involve, at least in part, in activation of the cGMP-PKG signaling pathway in the spinal cord.