Pain
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Dichotomizing afferents are individual dorsal root ganglion (DRG) neurons that innervate two distinct structures thereby providing a form of afferent convergence that may be involved in pelvic organ cross-sensitization. To determine the distribution of dichotomizing afferents supplying the distal colon and bladder of the Sprague-Dawley rat and the C57Bl/6 mouse, we performed concurrent retrograde labeling of urinary bladder and distal colon afferents using cholera toxin subunit B (CTB) fluorescent conjugates. Animals were perfused 4-5 days after sub-serosal organ injections, and the T10-S2 DRG were removed, sectioned, and analyzed using confocal microscopy. ⋯ In the rat, 17% of the total CTB-positive neurons were retrogradely labeled from both organs with 11% localized in TL, 6% in LS, and 0.8% in thoracic (TH) ganglia. In the mouse, 21% of the total CTB-positive neurons were dually-labeled with 12% localized in LS, 4% in TH, and 4% in TL ganglia. These findings support the existence of dichotomizing pelvic afferents, which provide a pre-existing neuronal substrate for possible immediate and maintained pelvic organ cross-sensitization and ultimately may play a role in the overlap of pelvic pain disorders.
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Neuropathic pain behaviour is not observed in neonatal rats and tactile allodynia does not develop in the spared nerve injury (SNI) model until rats are 4 weeks of age at the time of surgery. Since activated spinal microglia are known to play a key role in neuropathic pain, we have investigated whether the microglial response to nerve injury in young rats differs from that in adults. Here we show that dorsal horn microglial activation, visualised with IBA-1 immunostaining, is significantly less in postnatal day (P) 10 rat pups than in adults, 7 days after SNI. ⋯ In addition, P10 rats developed a small but significant mechanical allodynia in response to intrathecal LPS. Intrathecal injection of cultured ATP-activated microglia, known to cause mechanical allodynia in adult rats, had no behavioural effect at P10 and only began to cause allodynia if injections were performed at P16. The results clearly demonstrate immaturity of the microglial response triggered by nerve injury in the first postnatal weeks which may explain the absence of tactile allodynia following peripheral nerve injury in young rats.
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Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Our group demonstrated that human genetic variants of COMT are predictive for the development of Temporomandibular Joint Disorder (TMJD) and are associated with heightened experimental pain sensitivity [Diatchenko, L, Slade, GD, Nackley, AG, Bhalang, K, Sigurdsson, A, Belfer, I, et al., Genetic basis for individual variations in pain perception and the development of a chronic pain condition, Hum Mol Genet 2005;14:135-43.]. Variants associated with heightened pain sensitivity produce lower COMT activity. ⋯ This phenomenon is completely blocked by the nonselective beta-adrenergic antagonist propranolol or by the combined administration of selective beta(2)- and beta(3)-adrenergic antagonists, while administration of beta(1)-adrenergic, alpha-adrenergic, or dopaminergic receptor antagonists fail to alter COMT-dependent pain sensitivity. These data provide the first direct evidence that low COMT activity leads to increased pain sensitivity via a beta(2/3)-adrenergic mechanism. These findings are of considerable clinical importance, suggesting that pain conditions resulting from low COMT activity and/or elevated catecholamine levels can be treated with pharmacological agents that block both beta(2)- and beta(3)-adrenergic receptors.
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We describe an animal model of nociceptive sensory neuropathy induced by repeat intravenous administration of oxaliplatin in which treated animals partly reproduce the characteristic pain symptoms in oxaliplatin-treated patients. We tested the ability of 1, 2 and 4 mg/kg oxaliplatin doses injected twice-weekly for four-and-a-half consecutive weeks to induce a nociceptive peripheral neuropathy in male Sprague-Dawley rats. ⋯ The 2mg/kg oxaliplatin dose and the tail-immersion test in cold water (10 degrees C) were selected to compare pharmacological sensitivity between single administered drugs as morphine, lidocaine, carbamazepine, gabapentin and repeated administration of drugs as clomipramine, venlafaxine, calcium and magnesium solutions. Magnesium solution (90 mg/kg) and venlafaxine (7.5 mg/kg) administration induced an antinociceptive effect whereas gabapentin (300 mg/kg), clomipramine (2.5 mg/kg) and lidocaine (3 and 6 mg/kg) only induced an antiallodynic effect.
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Intra-articular injection of mono-iodoacetate (MIA) in the rat knee joint induces a histopathology with similarities to osteoarthritis (OA). Typically, a synovitis (days 1-3) is observed followed by thinning of articular cartilage and subsequent lesion of subchondral bone at days 8-14 onwards. Behaviourally, weight-bearing asymmetry is observed, which is sensitive to anti-inflammatory pharmacology at early but not later (days 14+) time points. ⋯ Significant resolution of weight-bearing was observed at high and intermediate doses of amitriptyline and gabapentin at all time points (P<0.05, ANOVA, post-hoc Bonferroni's, vs pre-dose measurements). Transient and weak effects were observed with naproxen (10mg/kg) on days 14 and 28, whereas celecoxib showed no significant effects. Collectively, these data suggest that this putative model of OA is associated with an early phase neuropathy in the L5 innervation territory of the knee.