Nada B. Lawand

Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats

The involvement of excitatory amino acid receptors in peripheral nociceptive processing was assessed in two separate experiments. In the first, one knee joint cavity of rats was injected with 0.1 ml of L-glutamate (0.001 mM; 0.1 mM; 1.0 mM), L-aspartate (0.001 mM; 0.1 mM: 1.0 mM), L-arginine (0.1 mM) or different combinations of these amino acids. The animals tested for paw withdrawal latency to radiant heat and withdrawal threshold to von Frey filaments at different time points. Combinations of glutamate/aspartate, aspartate/arginine or glutamate/aspartate/arginine when injected into the joint, in the absence of any other treatment, reduced the paw withdrawal latency and withdrawal threshold immediately after the injection and persisting up to 5 h indicating the development of hyperalgesia and allodynia. Subsequent intra-articular injection of either an NMDA or a non-NMDA glutamate receptor antagonist ((+/-)-2-amino-7-phosphonoheptanoic acid (AP7), 0.2 mM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 0.1 mM) attenuated the thermal hyperalgesia and the mechanical allodynia produced by glutamate/aspartate/arginine. On the other hand, in a second experiment intra-articular injection of AP7, ketamine or CNQX reversed the hyperalgesia and allodynia produced by injection of a mixture of kaolin and carrageenan into the joint. These receptor antagonists, however, did not have an effect on the joint edema. These findings provide evidence for a potential role of peripheral NMDA and non-NMDA receptors in nociceptive transmission.

Is there a pathway in the posterior funiculus that signals visceral pain

&NA; The present report provides evidence that axons in the medial part of the posterior column at T10 convey ascending nociceptive signals from pelvic visceral organs. This evidence was obtained from human surgical case studies and histological verification of the lesion in one of these cases, along with neuroanatomical and neurophysiological findings in animal experiments. A restricted lesion in this area can virtually eliminate pelvic pain due to cancer. The results remain excellent even in cases in which somatic structures of the pelvic body wall are involved. Following this procedure, neurological testing reveals no additional neurological deficit. There is no analgesia to pinprick stimuli applied to the body surface, despite the relief of the visceral pain. Since it is reasonable to attribute the favorable results of limited midline myelotomies to the interruption of axons of visceral nociceptive projection neurons in the posterior column, we have performed experiments in rats to test this hypothesis. The results in rats indicate that the dorsal column does indeed include a nociceptive component that signals pelvic visceral pain. The pathway includes neurons of the postsynaptic dorsal column pathway at the L6‐S1 segmental level, axons of these neurons in the fasciculus gracilis, and neurons of the nucleus gracilis and the ventral posterolateral nucleus of the thalamus.

Amino acid release into the knee joint: key role in nociception and inflammation.

&NA; This study examined the release of several amino acids after induction of knee joint inflammation in rats using kaolin and carrageenan. During the initial 10‐min collection after knee joint injection with the irritants, the concentration of glutamate and the nitric oxide metabolites, arginine and citrulline, doubled. This increase persisted for at least two hours. During the same time period aspartate concentrations remained unchanged. Direct knee joint administration of lidocaine prevented the increases in amino acid concentration measurable by microdialysis probe inserted into the joint. These data suggest the possibility that glutamate may be released by neuronal endings in the joint.

The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin.

&NA; This study was designed to assess the role of calcitonin gene‐related peptide (CGRP) and its receptor in the generation and maintenance of secondary mechanical allodynia and hyperalgesia induced by intradermal injection of capsaicin in rats. Paw withdrawal responses (PWRs) to von Frey hairs with different bending forces applied on the rat paw were tested in this study. CGRP8–37, a specific antagonist of CGRP 1 receptors, was delivered through a microdialysis fiber inserted across the dorsal horn. Post‐ and pretreatment paradigms were followed. When CGRP8–37 was administered 1 h after capsaicin injection, the mechanical allodynia and hyperalgesia were partially reversed in a dose‐dependent manner. On the other hand, when rats were treated with CGRP8–37 prior to capsaicin injection, the PWRs to von Frey applications were significantly reduced as compared to control animals. Collectively, these results suggest that CGRP receptors present in the dorsal horn are involved in the generation and maintenance of nociceptive behaviors associated with cutaneous inflammation.

Mechanical sensation and pain thresholds in patients with chronic arthropathies.

This study measured mechanical sensation and pain thresholds in the cutaneous field overlying the knee joints of rheumatoid arthritis (RA; N = 27) and osteoarthritis (OA; N = 28) patients, compared with age- and weight-matched normal control subjects (Norm; N = 27) by using graded von Frey monofilaments. A visual analog scale (VASpain), cutaneous joint temperature and circumference were measured for subjective ongoing pain and inflammation. Compared to Norm, RA and OA groups had (1) significantly higher VASpain scores, joint circumferences and (RA only) surface temperatures, (2) significantly increased average thresholds for innocuous mechanical sensation (0.014 +/- 0.003 vs 0.077 +/- 0.035 and 0.123 +/- 0.043 g, respectively) indicative of hypoesthesia and (3) significantly decreased pain thresholds, indicative of mechanical allodynia (446.683 +/- 0 vs 285.910 +/- 40.012 and 322.681 +/- 34.521 g for Norm vs RA and OA, respectively). Intrapatient joint temperature, circumference, and pain threshold were significantly correlated in RA. The highest scores in average mechanical sensation mapped to the same grid region as the lowest scores in average pain thresholds in RA and OA patients. The simultaneous hypoesthesia and allodynia, with paradoxical decrease in sensation and increased pain thresholds may reflect peripheral and central alterations in neuronal responsiveness to mechanical stimulation and suggests activation of a descending inhibitory system.

Joint inflammation is reduced by dorsal rhizotomy and not by sympathectomy or spinal cord transection.

OBJECTIVES--To investigate the role of primary afferents, sympathetic postganglionic efferents and descending systems on the central control of peripheral inflammation. METHODS--Acute inflammation was induced by intra-articular injection of kaolin and carrageenan into the knee joint cavity of the rat. Before the induction of the arthritis, a unilateral dorsal rhizotomy, a chemical (phentolamine) and/or surgical sympathectomy, or a spinal transection was performed. Joint inflammation (joint circumference and thermographic readings) and behavioural signs were assessed. RESULTS--Only arthritic animals with a dorsal rhizotomy showed a significant reduction of the inflammatory response compared with control arthritic animals. No significant differences in the inflammatory response occurred following sympathectomy or spinal transection. The animals who received sympathectomy showed similar behavioural manifestations to the arthritic animals. CONCLUSIONS--The central terminals of primary afferents are important in the development of acute joint inflammation since dorsal rhizotomy attenuated the inflammatory response in the knee joint. The sympathetic nervous system is not involved in the acute inflammatory phase of this arthritis model. The central processes controlling acute inflammation involve a local spinal circuit since spinal cord transection at T9 has no effect on the inflammation.

Blockade of joint inflammation and secondary hyperalgesia by L-name, a nitric oxide synthase inhibitor

ACUTE arthritis is associated with pain-related behavior, joint swelling and increased joint temperature. Arthritic animals exhibit a significant decrease in paw withdrawal latency 4, 5, 6, 7 and 8 h after induction of inflammation, when compared with baseline values, indicative of secondary hyperalgesia. Intra-articular injection of a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), resulted in a complete reversal of heat hyperalgesia and prevented further increase in joint swelling and temperature, while injection of either isotonic saline or the inactive enantiomer NG-nitro-D-arginine methyl ester (D-NAME) after induction of arthritis had no effect on any of these parameters. Intra-articular injection of 7-nitro-indazole (7-NINA), a selective neuronal NOS inhibitor, reversed the heat hyperalgesia for about 1 h but did not inhibit the increase in joint swelling or temperature. These results suggest an important role for nitric oxide (NO) in mediating peripheral nociceptive transmission and inflammation.

Targeting α-synuclein as a therapeutic strategy for Parkinson's disease.

Introduction: α-Synuclein, a neuronal protein, plays a central role in the pathophysiology of Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder. Cases of PD have increased tremendously over the past decade necessitating the identification of new therapeutic targets to reduce patient morbidity and to improve PD patients’ quality of life. Areas covered: The purpose of this article is to provide an update on the role of α-synuclein in fibrils formation and review its role as an effective immunotherapeutic target for PD. The rapidly expanding evidence for the contribution of α-synuclein to the pathogenesis of PD led to the development of antibodies against the C terminus of α-synuclein and other molecules involved in the inflammatory signaling pathways that were found to contribute significantly to initiation and progression of the disease. Expert opinion: The readers will obtain new insights on the mechanisms by which α-synuclein can trigger the development of PD and other related degenerative disorders along with the potential role of active and passive antibodies targeted against specific form of α-synuclein aggregates to clear neurotoxicity, stop the propagation of the prion-like behavior of these oligomers and reverse neuronal degeneration associated with PD.