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IB4 (+) neurons contribute to force-induced cancer pain but not cancer proliferation
Ye Y, Viet CT, Dang D, Schmidt BL (2012) IB4 (+) neurons contribute to force-induced cancer pain but not cancer proliferation. Neuroscience 2012 Abstracts 67.10. Society for Neuroscience, New Orleans, LA.
Summary: The primary treatment for cancer pain is μ-opiates; however, often μ-opiates are not effective and they produce multiple debilitating side effects. Recent studies show that μ- and δ-opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which mediate thermal and mechanical pain, respectively. We investigated the contribution of IB4 (+) and IB4 (-) neurons to cancer-induced mechanical and thermal hypersensitivity and investigated the role of these fibers to cancer proliferation. We used two separate mouse cancer pain models: 1) a cancer supernatant injection model, and 2) an orthotopic cancer model. The former model isolated the effect of the cancer secretome while the latter examined the effect of the following constituents within the cancer microenvironment: the cancer, the cancer secretome and the host tissue. Using the cancer supernatant model, along with injection of a selective δ-opioid receptor agonist and a P2X3 antagonist to target IB4 (+) neurons, we showed that IB4 (+) neurons played arole in cancer-supernatant-induced mechanical allodynia, but not thermal hyperalgesia. Selective ablation of IB4 (+) neurons in the spinal cord using IB4-saporin affected cancer-supernatant-induced mechanical but not thermal hypersensitivity. In the orthotopic cancer model, mice with paw cancer exhibited both mechanical and thermal hypersensitivity. Selective ablation of IB4(+) neurons decreased mechanical hypersensitivity; however thermal hypersensitivity was increased. We hypothesized that increased thermal hyperalgesia was associated with a compensatory elevation of TRPV1 expression in the spinal cord. Thermal latency in the mouse cancer paw was increased by intrathecal TRPV1 antagonist and selective removal of TRPV1 terminals by capsaicin in the IB4-saporin treated mice compared to saporin treated mice. Mechanical threshold was not affected by either the TRPV1 antagonist or capsaicin treatment. In the spinal cord, TRPV1 protein levels were increased in cancer mice compared to naïve mice, and TRPV1 was likely to be increased in the IB4-saporin treated cancer mice compared to saporin treated cancer mice. We investigated cancer proliferation by measuring tumor volume. Tumor volume was not affected by selective ablation of IB4 (+) neurons. Our findings suggest that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective δ-opioid receptor agonist or P2X3 antagonist, might be effective for treating cancer pain in patients. Acknowledgements: Supported by NIH/NIDCR R21 DE018561
Related Products: IB4-SAP (Cat. #IT-10)
IB4(+) nociceptors mediate persistent muscle pain induced by GDNF.
Alvarez P, Chen X, Bogen O, Green PG, Levine JD (2012) IB4(+) nociceptors mediate persistent muscle pain induced by GDNF. J Neurophysiol 108(9):2545-2553. doi: 10.1152/jn.00576.2012
Summary: GDNF is found in skeletal muscle and can trigger mechanical hyperalgesia. The authors administered a 3.2-μg intrathecal dose of IB4-SAP (Cat. #IT-10) to rats. Loss of the IB4(+) nociceptors led to decreased hyperalgesic priming as well as a reduction in GDNF-induced hyperalgesia. These data indicate that GDNF plays a role in mediating induction of pain.
Related Products: IB4-SAP (Cat. #IT-10)
Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds.
Man SH, Geranton SM, Hunt SP (2012) Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds. Mol Pain 8(1):35. doi: 10.1186/1744-8069-8-35
Summary: Projections from lamina I neurons regulate mechanical and thermal sensitivity due to injury. Little is known about how these pathways develop immediately after birth. Rats at postnatal day 3 were treated with 2 μl of 5 μM SP-SAP (Cat. #IT-07) injected into the intrathecal space. Blank-SAP (Cat. #IT-21) was used as a control. The data show that neurokinin-1 positive neurons project to the parabrachial nucleus in the hindbrain, and that these neurons and lamina I neurons were responsive to noxious stimulation at postnatal day 3. Treated animals also displayed increased mechanical sensitivity from postnatal day 45 on.
Related Products: SP-SAP (Cat. #IT-07), Blank-SAP (Cat. #IT-21)
Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain.
Taylor AM, Osikowicz M, Ribeiro-da-Silva A (2012) Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain. Pain 153(6):1311-1319. doi: 10.1016/j.pain.2012.03.023
Summary: The authors used IB4-SAP (Cat. #IT-10; 3.2 μg injected into the mental nerve) to eliminate C-fibers in the lower lip of rats to see if this was enough to induce the sprouting of autonomic fibers. Saporin alone (Cat. #PR-01) was used as a control. Only parasympathetic fibers sprouted in these animals, but after nerve ligation surgery both sympathetic and parasympathetic fibers sprouted.
Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
Analgesia targeting IB4-positive neurons in cancer-induced mechanical hypersensitivity.
Ye Y, Dang D, Viet CT, Dolan JC, Schmidt BL (2012) Analgesia targeting IB4-positive neurons in cancer-induced mechanical hypersensitivity. J Pain 13(6):524-531. doi: 10.1016/j.jpain.2012.01.006
Summary: DOR (δ opioid receptor) agonists produce minimal side effects and do not lead to tolerance, making them potential alternatives to the widely used μ opioid receptor agonists. Utilizing the fact that DOR’s are expressed by IB4-positive neurons, the authors injected the subarachnoid space between the L4 and L5 vertebrae of rats with 2.4 μg of IB4-SAP (Cat. #IT-10). 3 μg of saporin (Cat. #PR-01) was used as a control. The results indicate that pharmacological agents targeting IB4-positive neurons may have use in cancer pain treatment.
Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)
Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn.
Choi JI, Koehrn FJ, Sorkin LS (2012) Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn. Mol Pain 8(1):4. doi: 10.1186/1744-8069-8-4 PMID: 22243518
Summary: In this work the authors administered 100 ng SSP-SAP (Cat. #IT-11) into the intrathecal space of rats (saporin, Cat. #PR-01, was used as a control). Lesioned animals displayed decreased carrageenan-induced mechanical allodynia, and carrageenan-induced phosphorylation of Akt was blocked throughout the spinal cord gray matter. Anti-NK-1 (Cat. #AB-N33AP) was used for immunohistochemistry.
Related Products: SSP-SAP (Cat. #IT-11), Saporin (Cat. #PR-01), NK-1 Receptor Rabbit Polyclonal, affinity-purified (Cat. #AB-N33AP)
IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat.
Alvarez P, Gear RW, Green PG, Levine JD (2012) IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. Exp Neurol 233(2):859-865. doi: 10.1016/j.expneurol.2011.12.019
Summary: In order to clarify the roles of isolectin B4-positive and IB4-negative nociceptors in inflammatory and ergonomic muscle pain, the authors administered 3.2 µg of IB4-SAP (Cat. #IT-10) into the intrathecal space of rats. Although the baseline mechanical nociceptive threshold was not affected in the lesioned animals, mechanical hyperalgesia had a shorter duration. In the ergonomic models peak hyperalgesia was attenuated, and prolongation of PGE2-induced mechanical hyperalgesia was completely prevented.
Related Products: IB4-SAP (Cat. #IT-10)
Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury.
Hayashida K, Peters CM, Gutierrez S, Eisenach JC (2012) Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury. J Pain 13(1):49-57. doi: 10.1016/j.jpain.2011.09.009
Summary: The authors examined what involvement noradrenergic fibers in the spinal cord have in neuronal and glial plasticity associated with neuropathic pain states. Rats received 5 μg intrathecal injections of anti-DBH-SAP (Cat. #IT-03). Lesioned animals did not display altered mechanical withdrawal thresholds, but L5-L6 spinal nerve ligation in these animals caused enhanced mechanical hypersensitivity and analgesia induced by intrathecal clonidine. The data suggest that endogenous noradrenaline may play an inhibitory role on glial activation.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Consequences of the ablation of non-peptidergic nociceptive fibers on neurokinin-1 receptor expression by spinal lamina I neurons
Saeed AW, Ribeiro-Da-Silva A (2011) Consequences of the ablation of non-peptidergic nociceptive fibers on neurokinin-1 receptor expression by spinal lamina I neurons. Neuroscience 2011 Abstracts 804.21. Society for Neuroscience, Washington, DC.
Summary: Spinal dorsal horn lamina I projection neurons expressing the neurokinin-1 receptor (NK-1r) are important in relaying pain-related information from the periphery to the brain. These lamina I neurons have been classified, based on their morphological and physiological properties, into three types: fusiform, multipolar and pyramidal. Of these cell types, pyramidal neurons seldom express the NK-1r and are non-nociceptive. Previously, our laboratory has demonstrated in a cuff model of chronic constriction injury a de novo expression of NK-1r by pyramidal neurons, starting at the same time as the mechanical allodynia. We have also observed a similar de novo expression of NK-1r by pyramidal neurons in an animal model of arthritis. In the current study, we investigated whether the cytotoxic ablation of the non-peptidergic, isolectin B4 (IB4)-binding subpopulation of nociceptive primary afferents led to changes in NK-1r expression by the different lamina I cell types. We injected IB4 conjugated to saporin (SAP) into the left sciatic nerve of anesthetized male Sprague Dawley rats to specifically lesion IB4-positive non-peptidergic nociceptive C-fibers. Cholera toxin subunit B (CTB) was injected into the parabrachial nucleus to label lamina I projection neurons. Animals were tested for thermal and mechanical sensitivity and sacrificed from 2 weeks to 2 months post-lesion. We cut horizontal sections of spinal segments L4 and L5 and processed the tissue for IB4 binding and NK-1r and CTB immunoreactivities using immunofluorescence. IB4-SAP treated animals showed no behavioral changes compared to sham animals when tested for thermal (Hargreaves test), mechanical allodynia (von Frey test) or mechanical hyperalgesia (pin prick test) at any of the time points studied. Compared to the contralateral side and the sham group, lamina I projection neurons in the IB4-SAP treated group revealed an ipsilateral increase in the expression of NK-1r by the fusiform and multipolar neuronal populations. Nonetheless, there was no significant change in the percentage of pyramidal neurons which expressed NK-1r, which remained very low on the ipsilateral side of the IB4-SAP treated group. From these results, we infer that a loss of non-peptidergic afferents does not induce a phenotypic switch in the pyramidal neurons. However, the increase in NK-1r immunoreactivity in lamina I fusiform and multipolar neurons suggests that these cell populations may be important in maintaining the nociceptive responses in the absence of the IB4-positive non-peptidergic afferents. Finally, we suggest that a chronic pain state may be required for the de novo expression of NK-1r by pyramidal neurons.
Related Products: IB4-SAP (Cat. #IT-10)
Selective activation of dorsal horn inhibitory interneurons produces anti-nociception
Wiley RG, Lappi DA (2011) Selective activation of dorsal horn inhibitory interneurons produces anti-nociception. Neuroscience 2011 Abstracts 804.14. Society for Neuroscience, Washington, DC.
Summary: Intrathecal injections of the excitatory neuropeptide neurotensin are antinociceptive in rats. Lumbar intrathecal injections of the cytotoxic conjugate, neurotensin-saporin (NTS-sap), cause rats to engage in intense scratching, licking and biting of their hindquarters. This observation was interpreted as indicating the rats were experiencing discomfort presumably because NTS-sap selectively destroys nociceptive inhibitory interneurons expressing neurotensin receptors in the superficial dorsal horn of the spinal cord resulting in decreased inhibitory input to nociceptive projection neurons. Based on this finding, we made the excitatory conjugate, neurotensin-cholera toxin A subunit (NTS-CTA) which we hypothesized would tonically activate the same nociceptive inhibitory interneurons and produce anti-nociception/analgesia. Two separate groups of Long Evans hooded female rats were injected, under general anesthesia, with 500 ng of NTS-CTA, produced by Advanced Targeting Systems, San Diego, CA using temporarily positioned subarachnoid catheters which were removed after 15 mins. For the next 72-96 hours, rats showed: 1 – normal spontaneous behavior including grooming, ambulation, defecation and urination; 2 – decreased nocifensive responses on the hotplate at 44C – 47C; 3 – increased hindpaw mechanical withdrawal thresholds; and, 4 – prolonged tail flick response latencies. Systemic naloxone (0.8-2.0 mg/kg, s.c.) did not reverse the anti-nociceptive effect of NT-CTA. Hotplate responses completely returned to baseline within 7 days. These data are interpreted as showing that intrathecal NTS-CTA is reversibly anti-nociceptive by a naloxone-insensitive (non-opioid) mechanism. The likely mechanism of NTS-CTA action is hypothesized to involve tonic activation of NTS receptor-expressing inhibitory interneurons in the superficial dorsal horn of the spinal cord that increases inhibition of nociceptive projection neurons. This strategy may prove useful in treating intractable pain and may be generally useful in the study and manipulation of other populations of inhibitory (or excitatory) interneurons using various neuropeptide-CTA conjugates in such fields as epilepsy, learning and memory, etc. Ongoing work is aimed at identifying the neurons activated by NTS-CTA, testing NTS-CTA in operant pain tests, testing nociceptive effects of other neuropeptide-CTA conjugates and evaluating ways to produce more prolonged activation of the target neurons.
Related Products: Neurotensin-SAP (Cat. #IT-56), Neurotensin-CTA (Cat. #IT-60)