Neurosteroids in Pain Management: A New Perspective on an Old Player

Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.

GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

Fillingim and Maixner (Fillingim, R.B. and Maixner, W., Pain Forum, 4(4) (1995) 209-221) recently reviewed the body of literature examining possible sex differences in responses to experimentally induced noxious stimulation. Using a 'box score' methodology, they concluded the literature supports sex differences in response to noxious stimuli, with females displaying greater sensitivity. However, Berkley (Berkley, K.J., Pain Forum, 4(4) (1995) 225-227) suggested the failure of a number of studies to reach statistical significance suggests the effect may be small and of little practical significance. This study used meta-analytic methodology to provide quantitative evidence to address the question of the magnitude of these sex differences in response to experimentally induced pain. We found the effect size to range from large to moderate, depending on whether threshold or tolerance were measured and which method of stimulus administration was used. The values for pressure pain and electrical stimulation, for both threshold and tolerance measures, were the largest. For studies employing a threshold measure, the effect for thermal pain was smaller and more variable. The failures to reject the null hypothesis in a number of these studies appear to have been a function of lack of power from an insufficient number of subjects. Given the estimated effect size of 0.55 threshold or 0.57 for tolerance, 41 subjects per group are necessary to provide adequate power (0.70) to test for this difference. Of the 34 studies reviewed by Fillingim and Maixner, only seven were conducted with groups of this magnitude. The results of this study compels to caution authors to obtain adequate sample sizes and hope that this meta-analytic review can aid in the determination of sample size for future studies.