Spinal cord antinociception

Sawynok, J., Reid, A. and Isbrucker, R. Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord. Brain Res. 524 187-195,1990. 

Pugh G Jr, Abood ME, Welch SP. (1995). Antisense oligodeoxynucleotides to the kappa-1 receptor block the antinociceptive effects of delta 9-THC in the spinal cord. Brain Res. 689(1) 157-58. 

Neuroanatomically both the locus coeruleus and the raphe nuclei project to the spinal cord where they gate sensory pathways from the skeletomuscular areas. As there is evidence that both noradrenaline and 5-HT are dysfunctional in depression, it is perhaps not surprising to find that the pain threshold is often reduced in patients with depression. Conversely, different types of antidepressants have been shown to have an antinociceptive effect in both rodent models of neuropathic pain, and clinically in fibromyalgia, chronic fatigue syndrome, postherpetic neuralgia and diabetic neuropathy. In general, it would appear that the dual action antidepressants (such as the TCAs and SNRIs) are more effective than the SSRIs. 

Wilcox GL, Carlsson KH, Jochim A, Jurna 1 (1987) Mutual potentiation of antinociceptive effects of morphine and clonidine in rat spinal cord. Brain Res 405 84-93... 

Lopez-Garcia, J. A. and Laird, J. M. Central antinociceptive effects of meloxicam on rat spinal cord in vitro, Neuroreport 1998, 9, 647-651. 

In the spinal cord, a2-agonists act on receptors located on the terminals of primary afferent fibers in the dorsal horn substantia gelatinosa to reduce nociceptive transmission by inhibiting the release of glutamate and substance P (Collin et al., 1994 Hamalainen and Pertovaara, 1995) (see Fig. 2). These receptors appear to be primarily of the a2A subtype which is negatively coupled to adenylate cyclase (Lakhlani et al., 1997 see Millan, 1999 but see Sawamura et al., 2000, and references therein for a discussion of the possible involvement of other a2-receptor subtypes in antinociception). Like activation of p-opioid receptors, the activation of a2-receptors increases the potassium conductance of the cells bearing these receptors, thus reducing cellular excitability. 

Yang, S.-W., Kang, Y.-M., Guo, Y.-Q., Qiao J.-T. ATP-sensitive potassium channels mediate norepinephrine- and morphine-induced antinociception at the spinal cord level, International Journal Neuroscience 1998, 93, 217-223. 

Omote, K., Sonoda, H., Kawamata, M., Iwasaki, H., Namiki, A. Potentiation of antinociceptive effects of morphine by calcium-channel blockers at the level of the spinal cord, Anesthesiology 1993, 79, 746-752. 

Chizh, B. A., Schlutz, H., Scheed, M., Englberger, W. The N-methyl-D-aspartate antagonistic and opioid components of D-methadone antinociception in the rat spinal cord, Neurosci. Lett. 2000, 296, 117-120. 

Naguib, M. and Yaksh, T.L. Characterization of muscarinic receptor subtypes that mediate antinociception in the rat spinal cord, Anesth. Analg. 1997, 85, 847-853. 

Moreover, duration of central NKi receptor blockade is a critical point, as anesthetic-like nerve block caused by non-specific effects on ion channels in peripheral tissues could mask the selective antinociceptive effects of blocking NKi receptors in the spinal cord. The long-acting NKi antagonist L-733,060 maintained blockade of central NKi receptors at a time when peak plasma drug levels had subsided. Therefore, in paw licking experiments, the inhibitory effect of L-733,060 appeared to be due to central NKi receptor blockade (Rupniak et al., 1996). 

Abrahamsson C (2000) Neuropeptide Y1- and Y2-receptor-mediated cardiovascular effects in the anaesthetized guinea pig, rat, and rabbit. J Cardiovasc Pharmacol 36 451-8 Ackley MA, Hurley RW, Virnich DE et al (2001) A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. Pain 91 377-88 Aimone LD, Yaksh TL (1989) Opioid modulation of capsaicin-evoked release of substance P from rat spinal cord in vivo. Peptides 10 1127-31... 

The involvement of NE in pain modulation has been demonstrated in several studies. Thus, electrical stimulation of LC or its spinal cord-projecting efferents induces an antinociceptive effect in rats (West et al., 1993 Yeomans et al., 1992). Paradoxically, lesioning of NE neurons is also increases the pain threshold (Hammond and Proudfit 1980). Other studies demonstrated as well that NE can either enhance or suppress nociception in the spinal cord and brainstem levels. It has, therefore, been suggested that different receptors mediate nociceptive and anti-nociceptive effects of NE. Pain stimulation is probably mediated via the oci-, and pain suppression via a2-adrenoceptors (Wei and Pertovaara 2006). Inflammation and sustained pain induce an increase in a2-and a decrease in oci -mediated NE transmission in the spinal cord. Thus, NE probably increases the sensitivity to acute pain and decreases it to chronic pain. 

The first relevance on pain was activation of PPARa in the spinal cord of rats with peripheral inflammation (Benani et al., 2004). Electrophoretic mobility-shift assay was employed to compare the DNA-binding activity toward a PPRE. The PPARa isoform was observed to be activated in the rat spinal cord after complete Freund s adjuvant injection, which could elicit hyperalgesia. PPARa was provided as a new player in the molecular modeling of pain pathways, although it was discussed that inhibitors of PPARa activation might be relevant antinociceptive drugs. 

Chen, S. R., and Pan, H. L. (2003). Antinociceptive effect of morphine, but not mu opioid receptor number, is attenuated in the spinal cord of diabetic rats. Anesthesiology 99, 1409—1414. 

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