Morphine does not affect laser induced warmth and pin prick pain thresholds

The aim of this double–blind, placebo–controlled study was to evaluate the effect of intravenously administered morphine in humans using an argon laser to induce experimental pain. Thirty volunteers were randomised to receive a total of 0.15 mg. kg^-1 morphine intravenously or saline. The argon laser was used to determine the possible change in warmth thresholds and pin prick pain thresholds. Measurements were performed before and at 10, 20, 30 and 40 min after the injection. During the observation period the warmth thresholds increased 20.7% ( P ≤ 0.05) from baseline (0.82 W ± 0.42 W) in the morphine group while an increase of 14.3% ( P ≤ 0.05) was seen in the placebo group (Baseline: 0.91 ±0.37). The pinprick pain thresholds of the morphine group increased 9.4% ( P ≥ 0.05) from baseline (1.39 W ± 0.7 W) while the corresponding thresholds of the placebo group was 4.6% ( P > 0.05) (baseline: 1.73 W±0.44 W). The differences seen between the morphine group and the placebo group were not statistically significant and thus it was demonstrated that morphine had no effect of either the feeling of warmth or the pain elicited by the argon laser. The present study supports other investigations and clinical experience suggesting that intermittent pain is not relieved by morphine unlike continuous pain, which can be relieved by morphine.     

Different mechanisms underlie the analgesic actions of paracetamol and dipyrone in a rat model of inflammatory pain

BACKGROUND AND PURPOSE: The analgesics, paracetamol and dipyrone are weak inhibitors of the cyclooxygenase isoforms 1 or 2 (COX-1, COX-2) but more potent on COX-3. Both are also weak anti-inflammatory agents, relative to their analgesic and antipyretic activities. In a model of inflammatory pain mediated by prostaglandins, both compounds were analgesic. We have analysed this shared effect further in order to elucidate the underlying mechanisms.EXPERIMENTAL APPROACH: Inflammation was induced in one hind paw of rats by intraplantar injection of 250 microg lambda-carrageenan (CG) and the contralateral paw injected with saline. Nociceptive thresholds to mechanical stimulation were measured immediately before and for 6 h after, injection of CG. The analgesics were s.c. or locally (intraplantar) injected either 30 min before or 2 h after CG. In some groups, naltrexone was injected (s.c. or intraplantar), 1 h before CG. KEY RESULTS: Pretreatment with paracetamol or dipyrone (60-360 mg kg(-1)) reversed hyperalgesia induced by CG and increased nociceptive threshold in the inflamed paw above the basal level (hypoalgesia). Paracetamol, but not dipyrone, also raised nociceptive thresholds in the non-inflamed paw. Subcutaneous, but not local, administration of naltrexone, a specific opioid antagonist, reversed the hypoalgesia induced by paracetamol, but similar naltrexone treatment had no effect on dipyrone-induced analgesia.CONCLUSIONS AND IMPLICATIONS: Although both paracetamol and dipyrone are inhibitors of COX isoforms and thus of prostaglandin biosynthesis and were analgesic in our model, their analgesic actions were functionally and mechanistically different. Satisfactory mechanisms of action for these analgesics still remain to be established.     

Novel protein kinase C-beta isoform selective inhibitor JTT-010 ameliorates both hyper- and hypoalgesia in streptozotocin- induced diabetic rats

AIM: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-beta is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-beta isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined. METHODS: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests. RESULTS: JTT-010 inhibited PKC-betaI and -betaII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3-3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher. CONCLUSIONS: These observations suggest that PKC-beta contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-beta inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.     

Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice

Nitrosative stress contributes to nerve conduction slowing, thermal hypoalgesia, and impaired nitrergic innervation in animal models of Type 1 diabetes. The role for reactive nitrogen species in Type 2 diabetes-associated neuropathy remains unexplored. This study evaluated the role for nitrosative stress in functional and structural neuropathic changes in ob/ob mice, a model of Type 2 diabetes with mild hyperglycemia and obesity. Two structurally diverse peroxynitrite decomposition catalysts, Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)-pyridyl porphyrin (FP15) and Fe(III) tetra-mesitylporphyrin octasulfonate (FeTMPS), were administered to control and 8-week-old ob/ob mice for 3 weeks at the doses of 5 mg kg(-1) day(-1) (FP15) and 5 and 10 mg kg(-1) day(-1) (FeTMPS). The 11-week-old ob/ob mice developed motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable ( approximately 78%) loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion neurons. Treatment with two structurally diverse peroxynitrite decomposition catalysts was associated with restoration of normal MNCV and SNCV, and alleviation of thermal hypoalgesia. Tactile response thresholds increased in response to peroxynitrite decomposition catalyst treatment, but still remained approximately 2.7- to 3.2-fold lower compared with non-diabetic controls. Intraepidermal nerve fiber loss was not alleviated by either FP15 or FeTMPS. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglia of peroxynitrite decomposition catalyst-treated ob/ob mice were essentially normal. In conclusion, nitrosative stress plays an important role in functional abnormalities associated with large motor, large sensory, and small sensory fiber neuropathy, but not in small sensory nerve fiber degeneration, in this animal model. Peroxynitrite decomposition catalysts alleviate Type 2 diabetes-associated sensory nerve dysfunction, likely by mechanism(s) not involving arrest of degenerative changes or enhanced regeneration of small sensory nerve fibers.     

Comparison of 2 Lumbar Manual Therapies on Temporal Summation of Pain in Healthy Volunteers

The purpose of this study was to compare the immediate change in temporal summation of heat pain (TSP) between spinal manipulation (SMT) and spinal mobilization (MOB) in healthy volunteers. Ninety-two volunteers (24 male; 23.8 ± 5.3 years) were randomized to receive SMT, MOB, or no treatment (REST) for 1 session. Primary outcomes were changes in TSP, measured at the hand and foot, immediately after the session. A planned subgroup analysis investigated effects across empirically derived TSP clusters. For the primary outcome there were no differences in the immediate change in TSP measured at the foot between SMT and MOB, however, both treatments were superior to the REST condition. In the subgroup analysis the response to a standard TSP protocol was best characterized by 3 clusters: 52% no change (n = 48, 52%); facilitatory response (n = 24, 26%), and inhibitory response (n = 20, 22%). There was a significant Time × Treatment group × Cluster interaction for TSP measured at the foot. The inhibitory cluster showed the greatest attenuation of TSP after SMT and MOB compared with REST. These data suggest lumbar manual therapies of different velocities produce a similar localized attenuation of TSP, compared with no treatment. Attenuation of localized pain facilitatory processes by manual therapies was greatest in pain-free individuals who show an inhibitory TSP response.

Hypoalgesia induced by the local injection of carbachol into the nucleus raphe magnus

The medial region of the caudal medulla which contains the nucleus raphe magnus and magnocellular reticular formation has been demonstrated to modulate pain perception. Recent reports from this laboratory have shown that neurons in this region are under tonic inhibitory control by noradrenergic neurons. The excitability of neurons in the raphe magnus and adjacent reticular formation may also be controlled by cholinergic neurons since there is evidence that cholinergic terminals are located in the medial region of the caudal medulla. The present study was designed to examine this possibility by microinjecting carbachol, a cholinergic agonist, into the region of the nucleus raphe magnus. The results indicate that the injection of carbachol into the caudal brainstem produces dose-dependent hypoalgesia, i.e. decreased pain sensitivity. This hypoalgesia appears to be mediated by cholinergic muscarinic receptors since it was reversed by the muscarinic antagonist atropine. The cholinergic innervation of the raphe magnus does not appear to be important in the maintenance of nociceptive threshold since injection of atropine alone did not alter pain responses.     

Hypoalgesia induced by microinjection of a norepinephrine antagonist in the raphe magnus: reversal by intrathecal administration of a serotonin antagonist

Microinjection of phentolamine in the nucleus raphe magnus produces hypoalgesia as assessed by both the tail flick and hot plate tests. The elevation of tail flick latency appears to results from activation of serotonergic raphe-spinal projections, while the elevation of hot plate latency appears to be mediated by activation of non-serotonergic raphe-spinal neurons and/or by activation of raphe neurons which project to supraspinal nuclei.     

Cold hyposensitivity after topical application of capsaicin in humans

Capsaicin activates the transient receptor potential vanilloid 1 receptor (TRPV1) on small sensory afferents, and capsaicin is commonly used to elucidate mechanisms of neuropathic pain. This study was performed to describe changes in cold and cold pain perception after topically applied capsaicin. Fourteen healthy subjects were included. Cold detection and cold pain thresholds and the response to suprathreshold cold stimuli were evaluated before and after topical application of capsaicin (200 μl, 50 mg/ml in 70% ethanol solution, 10.2 cm²) for 30 min. The skin temperature was kept between 34 and 35°C. At the site of capsaicin application (the primary area), we found profound cold hypoesthesia and hypoalgesia, while outside the application site (the secondary area) there were no difference in the changes in cold detection and cold pain thresholds and cold-induced pain compared to the control arm. These results suggest a peripheral mediated decrease in cold sensation following TPRV1 receptor activation.     

Understanding Facial Expressions of Pain in Patients With Depression

Although depression is associated with more clinical pain complaints, psychophysical data sometimes point to hypoalgesic alterations. Studying the more reflex-like facial expression of pain in patients with depression may offer a new perspective. Facial and psychophysical responses to nonpainful and painful heat stimuli were studied in 23 patients with major depressive disorder (MDD) and 23 matched control participants. As psychophysical data, pain thresholds, tolerance thresholds, and self-report were assessed. Facial responses were videotaped and subjected offline to Facial Action Coding System analysis. One of the key facial responses of pain, which is a known facial signal of negative affect (contraction of the eyebrows), was significantly increased in MDD patients. Moreover, facial expressions and pain ratings were strongly correlated in MDD patients, whereas these 2 response systems were—in line with established findings—only weakly related in healthy participants. Pain psychophysics was unaltered in MDD patients compared with healthy control participants. In conclusion, the facial expression of pain in MDD patients indicates rather hyper- than hypoalgesia, with enhanced affective pain processing. Moreover, the linkage between subjective and facial responses was much stronger in MDD patients, which may be due to a reduced influence of social display rules, which normally complicate this relationship.