Elevation Of Nociceptive Threshold Research Articles

Ethics and Animal Welfare Related to in vivo Pharmacology and Toxicology in Laboratory Animals

Ethics and Animal Welfare Related to <i>in vivo</i> Pharmacology and Toxicology in Laboratory Animals

Spinal cord noradrenergic dynamics in diabetic and hypercortisolaemic states

Disorders of pain sensation including spontaneous pain, allodynia and hyperalgesia are commonly seen in neuropathic diabetic patients. A wealth of evidence indicates that spinal monoamine systems are implicated in pain modulation but whether abnormalities in these systems underlay such disorders is unclear. The present study was therefore initiated to investigate spinal noradrenergic dynamics during diabetes. Spinal release of norepinephrine (NE) represented by 3-methoxy-4-hydroxyphenylglycol (MHPG)/NE ratio was markedly suppressed in 30-day streptozotocin (STZ)-treated diabetic male and female rats. The density of [ 3 H ] p-aminoclonidine binding sites and the level of expression of mRNA encoding for α 2A-adrenoceptor subtype were also reduced as a function of diabetes. In contrast, an increase in the density of [ 3 H ] prazosin binding to spinal synaptosomal membranes was evident in these animals. Clonidine-induced elevation in nociceptive threshold was attenuated in diabetics. Control animals subjected to chronic treatment with a supraphysiological dose of glucocorticoid (GC) exhibited a neurochemical pattern which is similar in many respects to that produced by the diabetic state. Both insulin and the GC receptor blocker, RU 486, restored most of the neurochemical and behavioural abnormalities of diabetes. Overall, the present study supports the concept that a diabetes-related deficit in spinal noradrenergic dynamics may be a reflection of an overactivity of the hypothalamic–pituitary–adrenal axis.

Insulin-Dependent Attenuation in α 2-Adrenoreceptor–Mediated Nociception in Experimental Diabetes

Diabetes mellitus is associated with abnormalities in central noradrenergic dynamics, a system that appears to be involved in the regulation of nociception in both humans and experimental animals. To this end, we investigated the responsiveness of nociceptive threshold to the actions of clonidine (an α 2-adrenoreceptor agonist) and yohimbine (an α 2-adrenoreceptor antagonist) during diabetes. The induction of diabetes was achieved by the administration of streptozotocin (STZ) (55 mg/kg, intravenously). Nociceptive threshold, as indicated by the tail-flick latency of the tail immersion test, was progressively elevated as a function of the duration of diabetes. Systemic administration of clonidine and yohimbine respectively produced dose-dependent analgesic and hyperalgesic effects in control animals. Both of these phenomena were impaired in chronically diabetic animals. In contrast, insulin-treated diabetics displayed supersensitivity to clonidine's antinociceptive effect, especially at low doses. Acute hyperglycemia did not interfere with the α 2-agonist–mediated elevation in nociceptive threshold. Attenuation in clonidine antinociceptive effect was also observed following its intrathecal administration to diabetic animals. Overall, these data suggest that the impaired responsiveness of diabetic rats might be due to a central α 2-adrenoreceptor desensitization and/or biochemical defect in the postreceptor events.

Antinociceptive action of intrathecally administered IGF-I and the expression of its receptor in rat spinal cord

mRNA transcripts for insulin-like growth factor I (IGF-I) and its receptor are expressed in the lumbar region of the spinal cord. Accordingly, we examined the involvement of IGF-I in nociceptive transmission. An intrathecal injection of IGF-I (200–1000 ng) produced a dose-dependent elevation in nociceptive threshold as indicated by tail flick/withdrawal latency. In contrast, comparable doses of insulin had no significant effect. The time-response curve (15–75 min) revealed that the peak for IGF-I's antinociceptive effect is attained at 30 min. Our data provide evidence that the IGF-I system within the spinal cord may serve as a target for novel analgesics.

Differential right shifts in the dose-response curve for intrathecal morphine and sufentanil as a function of stimulus intensity

To assess effects of stimulus intensity, dose-response curves in rats for radiant heat-evoked withdrawal of the hind paw was assessed after the intrathecal (i.t.) injection of sufentanil and morphine, mu-opioid agonists differing in intrinsic activity, at Low, Medium, and High stimulus intensities. Baseline latencies observed at the 3 intensities were: low = 14.5 ± 0.3; medium = 8.9 ± 0.2; high = 5.7 ± 0.1 sec. After i.t. administration of sufentanil or morphine, there was a dose-dependent, naloxone-reversible elevation in nociceptive threshold. With increased stimulus intensity, there was a right shift in the dose-response curves with morphine exhibiting a greater magnitude right shift than that of sufentanil. Dose ratios (ED 50 Medium/ED 50 Low and ED 50 High/ED 50 Low) with 95% CI for sufentanil were, respectively, 2.5 (2.2–2.9) and 7.7 (6.7–8.9), and the dose ratio for morphine (ED 50 Medium/ED 50 Low) was 34 (28–41). At the highest intensity, due to a plateau in the morphine dose-response curve, ED 50 and dose ratio calculations could not be performed. The present study supports the pharmacological model of receptor occupany, such that the higher efficacy receptor agonist, sufentanil, demonstrated a lesser magnitude right shift than the lower efficacy agonist, morphine, while at the high stimulus intensity, morphine but not sufentanil, was a partial agonist.

Analgesic synergy and improved motor function produced by combinations of μ-δ- and μ-κ-opioids

This study evaluated the effects of intrathecal administration of a low-analgesic dose of the selective μ-agonist DAMGO co-administered with sequentially increasing doses of either the selective δ-agonist DPDPE or the selective κ-agonist, U50,488H on mechanical nociceptive thresholds in the rat. Potent analgesic synergy was observed with both combinations. Since an elevation in nociceptive threshold can result from motor deficits, as well as true analgesia, we also evaluated the effects of the combination regimens on motor coordination using a rotarod apparatus. The combination regimens produced significantly less motor deficits than those observed when DPDPE and U50,488H were administered as single agents. These findings of enhanced analgesia with decreased motor side-effects associated with administration of fixed μ/δ or μ/κ combinations suggest that co-administration of opiates that act at different receptors may constitute a superior approach to the treatment of pain.

Epidural capsaicin produces prolonged segmental analgesia in the rat

The effect of epidural capsaicin injections on the thermal nociceptive threshold of unrestrained freely moving adult rats was examined. Capsaicin solution (1% 0.05 ml, 0.1 ml) was injected in a single dose or in two consecutive doses through an indwelling lumbar epidural catheter. Effects were compared with 1 ml 1% capsaicin injected intraperitoneally. Twelve rats served as sham-treated and vehicle controls. Nociceptive thermal stimuli were brief pulses of CO 2 laser radiation directed at three body areas, hind limb, forelimb, and pinna. Capsaicin caused prolonged, segmental thermal analgesia. Maximal nociceptive threshold values in the hind limbs, attained within 24 h of epidural injection, were 2.5 ( P ≤ 0.006) and 5.3 ( P ≤ 0.0005) time control values for the 0.05-ml and 0.1-ml doses, respectively. Response thresholds in the forelimbs and pinna were uneffected. Two-stage epidural injection of capsaicin led to a roughly twofold elevation of threshold, as well as prolongation of the analgesia to about 14 days. Intraperitoneal injection of capsaicin resulted in elevation of nociceptive threshold which included all body areas tested. These results indicate that epidural application of capsaicin at the lumbar spinal level produced a profound and long-lasting segmental analgesia.

Evidence for an interrelationship between ventral noradrenergic bundle and CNS endorphins in the control of nociception in the rat

The present paper examines the role of the ventral noradrenergic bundle (VB) in relation to endorphins in the control of nociception in the rat. Selective, bilateral destruction of the VB produced a substantial fall in hypothalamic levels of noradrenaline. On day 4 post-surgery, VB-lesioned rats displayed a pronounced elevation in basal nociceptive threshold. This proved to be reversible by the specific opioid antagonist, naloxone, evidential of its mediation by endorphins. It was, however, unaffected by dexamethasone, a suppressor of corticotrophic secretion of β-endorphin, indicative that this pituitary pool of β-endorphin was not responsible. On day 12, at which time the elevation in nociceptive threshold had disappeared, neither the time course nor the intensity of the antinociception elicited by acute stress or various doses of morphine was attenuated in VB-lesioned as compared to sham rats. These data are evidential that the VB may influence nociceptive thresholds via an interaction with a CNS endorphinergic network. They demonstrate, further, that the VB does not mediate a significant component of the antinociception generated by either morphine or stress.

Protracted analgesia in young and adult rats maternally exposed to methadone.

The analgesic response to the hot-plate test was studied in 21-, 45-, 60-, 120- and 300-day-old rats maternally exposed to methadone (5 mg/kg). An elevation in nociceptive threshold, in the absence of further exposure to methadone, was observed in young and adult rats perinatally subjected to methadone.