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On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Physiological evidence of a postsynaptic inhibition of the tail flick reflex by a cannabinoid receptor agonist 
European journal of pharmacology  2008;602(1):36-40.
Current evidence indicates that cannabinoids are antinociceptive and this effect is in part mediated by spinal mechanisms. Anatomical studies have localized cannabinoid CB1 receptors to pre- and postsynaptic sites within the spinal cord. However, behavioural tests have not clearly indicated the relative importance of each of these sites. In this study, the tail flick test was used as a model of acute pain in the rat to determine the site of action of WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), a synthetic cannabinoid receptor agonist. WIN 55,212-2 (3 mg/kg, i.p.) increased the latency of tail withdrawal from a noxious radiant heat source, indicating it is antinociceptive in this model. Using the same paradigm, WIN 55,212-2 was then tested against the synaptically-induced nociceptive hypersensitivity in response to noxious thermal stimulation of the tail (hot water tail immersion). WIN 55,212-2 blocked this hypersensitivity, confirming a spinal site of action of the cannabinoid receptor agonist. Further, WIN 55,212-2 blocked the nociceptive hypersensitivity induced by intrathecal administration of substance P. As substance P acts on postsynaptic tachykinin NK1 receptors in the dorsal horn of the spinal cord, the data are interpreted to suggest that WIN 55,212-2 expressed its anti-hypersensitivity effects at least partially via a postsynaptic site of action; the data do not rule out a presynaptic site of action. This study suggests that cannabinoids may induce analgesia via a postsynaptic site of action in the spinal cord, as well as the possibility that they may interact with substance P signaling.
PMCID: PMC5130341  PMID: 19027734 CAMSID: cams417
Cannabinoid; WIN 55,212-2; Nociception; Analgesic; Tail flick test; Spinal cord (Rat)
2.  Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat 
European journal of pharmacology  2004;507(1-3):99-105.
Although a wide assortment of agents is currently available for the treatment of depression, this disorder remains poorly managed in a large proportion of patients. Traditional antidepressant treatments target the biogenic amine systems. However, a growing body of evidence is implicating the involvement of neuropeptides in depression, especially the neurokinin substance P. This study evaluated the effects of selective antagonists of the tachykinin NK1, NK2, and NK3 receptors in the forced swim test, a commonly used screen for antidepressants. Rats were given CP-96,345 (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, or SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, antagonists of the NK1, NK2, and NK3 receptors, respectively, at doses of 2.5, 5, and 10 mg/kg, intraperitoneally (i.p.). The time of immobility during the forced swim test was used as an indicator of antidepressant activity of the antagonists. All antagonists decreased immobility times. CP-96,345 and SR 142801 showed dose-related effects; SR 48968 had its maximum effect at 2.5 mg/kg. The magnitude of the effects of the neurokinin receptor antagonists was approximately the same as that of amitriptyline and desipramine, two traditional antidepressants, both given at 10 mg/kg, i.p. This study provides comparative data on the relative effectiveness of NK1, NK2, and NK3 receptor antagonists in this screen for antidepressant drug activity.
PMCID: PMC5127697  PMID: 15659299 CAMSID: cams410
Forced swim test; Depression; Neurokinin receptor antagonist; CP-96,345; SR 48968; SR 142801
3.  Neuropathic pain as a process: reversal of chronification in an animal model 
Journal of Pain Research  2011;4:315-323.
Peripheral neuropathic pain arises from trauma to sensory nerves. Other types of acute neurotrauma such as stroke and spinal cord injury are treated immediately, largely to prevent secondary damage. To pursue the possibility that neuropathic pain may also be amenable to early treatment, a rat model of neuropathic pain was induced using a 2-mm polyethylene cuff implanted around one sciatic nerve. Within 24 hours, hypersensitivity to von Frey hair stimulation appeared, as indicated by decreased paw withdrawal thresholds. When the cuff was removed 24 hours after implantation, readings returned to pre-implantation levels starting as early as day 18. When the cuff was removed after 4 days, there was a period of initial hypersensitivity, and then an increase toward baseline at two time points near the end of the study; therefore, only a partial recovery toward pre-implantation values occurred. Having established that a temporal reversal can occur, the next step examined possible pharmacological reversal. The tachykinin NK1 receptor antagonist, CP-96,345, produced a minor increase in withdrawal thresholds in animals with the cuff left permanently implanted. To determine the effect of early and repeated administration of CP-96,345, it was given daily on days 1–4. The cuff was removed on day 4. Six days later, readings showed reversal of tactile hypersensitivity. We suggest that persistent neuropathic pain occurs from processes that develop over several hours and days, and that some of these processes may be prevented by early medical intervention. Thus, nerve injury in the context of chronic neuropathic pain should be treated in a similar manner to nerve injury resulting from stroke, spinal cord injury, and other types of neurotrauma. We suggest that effective medical intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating pain that may be refractory to later therapies.
PMCID: PMC3191931  PMID: 22003305
neurotrauma; neuroplasticity; nerve injury; neuropathy; chronic pain; tactile hypersensitivity
4.  Progesterone prevents development of neuropathic pain in a rat model: Timing and duration of treatment are critical 
Journal of Pain Research  2011;4:91-101.
Progesterone is emerging as an important protective agent against various injuries to the nervous system. Neuroprotective and remyelinating effects have been documented for this neurosteroid, which is synthesized by, and acts on, the central and peripheral nervous systems. Neuropathic pain is a severe, persistent condition that is generally resistant to treatment, and poses major personal, social, and economic burdens. The purpose of this study was to determine if single-dose or repeated progesterone administration would alleviate tactile hypersensitivity in a rat model of neuropathic pain, and to determine if early versus late initiation of treatment has an effect on the outcome.
Rats were unilaterally implanted with a polyethylene cuff around the sciatic nerve, and sensitivity to von Frey filament stimulation was measured over approximately 12 weeks.
Rats given progesterone starting one hour after cuff implantation, and daily until day 4, exhibited tactile hypersensitivity similar to that of vehicle-treated rats for the duration of the study. When progesterone was started one hour after cuff implantation and given daily until day 10, rats exhibited no tactile hypersensitivity in the later part of the study, after treatment had stopped. When progesterone treatment was initiated at 20 days, once the model had been fully established, and given daily for 4 or even 11 days, no differences in withdrawal thresholds were observed compared with controls. Progesterone did not have any effect on withdrawal thresholds when given as a single dose, as measured at 30, 60 and 90 minutes after administration.
These results indicate that progesterone, when administered immediately after nerve injury, and for a sufficient period of time, can prevent the development of neuropathic pain, and may offer new strategies for the treatment of this highly debilitating condition.
PMCID: PMC3085268  PMID: 21559355
progesterone; neurosteroid; neuropathic pain; peripheral neuropathy; recovery; neuroprotection
5.  The selective neuronal nitric oxide synthase inhibitor 7-nitroindazole has acute analgesic but not cumulative effects in a rat model of peripheral neuropathy 
Journal of Pain Research  2011;4:85-90.
Chronic neuropathic pain that may arise from various nerve injuries or insults remains notoriously difficult to manage. The neuronal isoform of the enzyme nitric oxide synthase (nNOS) has been shown to be involved in the spinal transmission of nociception in animal models of chronic pain. The aim of this study is to evaluate the effect of single dose and repeated administration of a selective nNOS inhibitor. Rats were unilaterally implanted with a 2-mm polyethylene cuff around the sciatic nerve. Paw withdrawal thresholds were measured using von Frey filament stimulation. Rats were given 10, 20, or 30 mg/kg of 7-nitroindazole (7-NI), or vehicle, on days 2, 5, and 7 after model induction, respectively. Paw withdrawal thresholds were measured before and at 30 and 60 min after injection. 7-NI significantly increased paw withdrawal thresholds at 60 min at the 20 and 30 mg/kg dosages. In the second part of this study, rats were given 20 mg/kg 7-NI daily for five days starting immediately after cuff implantation (days 0 to 4), and the cuff was removed on day 4. Withdrawal thresholds were measured intermittently over a 24-day observation period. No differences in withdrawal thresholds were observed between drug and vehicle-treated rats. Therefore, early and repeated administration of 7-NI did not affect the development or progression of the model. In conclusion, inhibition of nNOS had an analgesic but not a pre-emptive effect in this model of peripheral neuropathic pain.
PMCID: PMC3085267  PMID: 21559354
neuronal nitric oxide synthase; nitric oxide; 7-nitroindazole; neuropathic pain; peripheral nerve injury; nociception

Results 1-5 (5)