Identification of discrete sites of action of chronic treatment with desipramine in a model of neuropathic pain.

Tricyclic antidepressants (TCAs) are an important analgesic treatment for neuropathic pain, though the neural substrates mediating these effects are poorly understood. We have used an integrative approach combining behavioural pharmacology with functional magnetic resonance imaging (fMRI) to investigate the effects of chronic treatment with the TCA desipramine, on touch-evoked pain (mechanical allodynia) and brain regional activity in the selective spinal nerve ligation (SNL) model of neuropathic pain. SNL and sham-operated rats received once daily i.p. administration of 10 mg/kg DMI, or saline, for 14 days. Withdrawal responses to the application of a normally non-noxious (10 g) stimulus were recorded in SNL and sham-operated rats over this period. On the final day of the study, SNL and sham-operated rats received a final challenge dose of DMI (10 mg/kg i.p.) during fMRI scanning. Chronic administration of desipramine (DMI) significantly attenuated mechancial allodynia in SNL rats. DMI challenge in chronic DMI-treated neuropathic rats produced significantly greater activation of the deep mesencephalic nucleus, primary somatosensory cortex, insular cortex, medial globus pallidus, inferior colliculus, perirhinal cortex and cerebellum compared to sham-operated rats and saline controls. By contrast, the spatial pattern of brain regional activation by chronic DMI treatment in sham controls encompassed a number of other areas including those associated with learning and memory processes. These novel findings identify key brain regions implicated in the analgesic and mood altering effects associated with chronic treatment with DMI.

The effect of remifentanil on respiratory variability, evaluated with dynamic modeling.

Opioid drugs disrupt signaling in the brain stem respiratory network affecting respiratory rhythm. We evaluated the influence of a steady-state infusion of a model opioid, remifentanil, on respiratory variability during spontaneous respiration in a group of 11 healthy human volunteers. We used dynamic linear and nonlinear models to examine the effects of remifentanil on both directions of the ventilatory loop, i.e., on the influence of natural variations in end-tidal carbon dioxide (Pet(CO(2))) on ventilatory variability, which was assessed by tidal volume (Vt) and breath-to-breath ventilation (i.e., the ratio of tidal volume over total breath time Vt/Ttot), and vice versa. Breath-by-breath recordings of expired CO(2) and respiration were made during a target-controlled infusion of remifentanil for 15 min at estimated effect site (i.e., brain tissue) concentrations of 0, 0.7, 1.1, and 1.5 ng/ml, respectively. Remifentanil caused a profound increase in the duration of expiration. The obtained models revealed a decrease in the strength of the dynamic effect of Pet(CO(2)) variability on Vt (the "controller" part of the ventilatory loop) and a more pronounced increase in the effect of Vt variability on Pet(CO(2)) (the "plant" part of the loop). Nonlinear models explained these dynamic interrelationships better than linear models. Our approach allows detailed investigation of drug effects in the resting state at the systems level using noninvasive and minimally perturbing experimental protocols, which can closely represent real-life clinical situations.

Gabapentin evoked changes in functional activity in nociceptive regions in the brain of the anaesthetized rat: an fMRI study.

BACKGROUND AND PURPOSE: Gabapentin (GBP; 1-(aminomethyl)cyclohexane acetic acid) is used clinically in the treatment of pain. Nevertheless, the sites and mechanisms of action of GBP are poorly defined. Herein, the effects of GBP on brain activation have been studied. EXPERIMENTAL APPROACH: Changes in blood oxygen level dependent (BOLD) haemodynamic signal following intravenous infusion of GBP (equivalent to 30 mg kg(-1) p.o., followed by 100 mg kg(-1) p.o.), compared to saline control, were studied in isofluorane anaesthetized rats (n=8 per group). Effects of GBP on mean arterial blood pressure (MAP) were also recorded. RESULTS: Random effect analysis revealed that the lower dose of GBP produced significant (P<0.001) increases in BOLD signal intensity in several brain regions, including the thalamus and periaqueductal grey (PAG), compared to basal. This dose of GBP also produced significant (P<0.001) decreases in BOLD signal intensity in the amygdala and the entorhinal cortex. Increasing the dose of GBP (100 mg kg(-1)) produced significantly greater changes in BOLD signal intensity in several brain regions including the thalamus and PAG. MAP was not significantly altered by GBP, compared to saline. CONCLUSIONS AND IMPLICATIONS: GBP had marked positive and negative effects on BOLD signal intensity in a number of brain regions in naïve rats. The activation of key areas involved in nociceptive processing indicate a supraspinal site of action of GBP and this may contribute to its well-described analgesic effects in animal models of pain and clinical studies.