Gender and the behavioral manifestations of neuropathic pain

doi:10.1016/S0091-3057(00)00461-5

Pharmacology Biochemistry and Behavior

Volume 68, Issue 1, January 2001, Pages 99-104

https://doi.org/10.1016/S0091-3057(00)00461-5 Get rights and content

Abstract

A model of peripheral nerve injury was used to study gender differences in the development and progression of chronic constriction injury (CCI)-induced hyperalgesia and allodynia in male and female Fischer 344 FBNF1 hybrid rats. Rats were randomly assigned to one of the following treatment groups: (1) gonadally intact unligated males (♂); (2) gonadally intact ligated males (♂_CCI); (3) castrated ligated males (♂_CAS/CCI); (4) gonadally intact unligated females (♀); (5) gonadally intact ligated females (♀_CCI); and (6) ovariectomized ligated females (♀_OVX/CCI). A plantar analgesia meter and calibrated von Frey pressure filaments were used as the analgesiometric assays. In the absence of nerve injury, gonadally intact males responded significantly faster than females to a thermal nociceptive stimulus. The onset of the behavioral manifestations of unilateral ligation of the sciatic nerve did not differ as a function of sex or hormonal status (e.g., gonadally intact and gonadectomized male and female rats developed thermal hyperalgesia within 14 days post-CCI). Paw withdrawal latency (PWL) values of gonadally intact males returned to baseline control values after postligation day 14, whereas gonadally intact females, ovariectomized females and castrated males continued to elicit robust thermal hyperalgesic symptoms throughout the 35-day duration of the experiment. Allodynic responses to peripheral nerve injury were less variable across genders. These data suggest that the mechanisms underlying chronic nociceptive processing differ as a function of gender and gonadal hormone status.

Introduction

A thorough understanding of the mechanisms and modulatory factors underlying neuropathic pain associated with peripheral nerve injury is imperative for the development of effective treatment strategies. The effects of gender on nociceptive processing have received increased attention recently, and epidemiologic studies acknowledge that women report more persistent pains Ektor-Andersen et al., 1993, Unruh, 1996 and use analgesic medications more often than men (Eggen, 1993). Females also report lower pain thresholds, higher pain ratings and less tolerance to noxious stimuli than males (Berkley, 1997). Investigations of the effects of gender on nociceptive processing recognize that gender differences exist in the susceptibility of males and females to nociceptive stimuli Bendelow, 1993, McCaffery and Ferrell, 1992; but there is a lack of consensus regarding the precise nature of these differences.

The pathophysiology of peripheral nerve injury-induced neuropathic pain disorders can be investigated using the chronic constriction injury (CCI) model of Bennett and Xie (1988). Unilateral placement of 4-0 chromic gut ligatures around the sciatic nerve evokes behavioral symptoms such as thermally mediated hyperalgesia and tactile-evoked allodynia. Within 2–4 days post-CCI, axonal swelling and large granulomas containing neutrophils, macrophages and multinucleated giant cells surround the chromic gut sutures Clatworthy et al., 1995, Maves et al., 1993. One group of investigators reported that the chromium salts comprising the gut sutures were responsible for producing CCI-induced inflammation, thermal hyperalgesia and guarding behavior in rats (Maves et al., 1993). That CCI-induced inflammatory and immunological responses are crucial for the development of neuropathic pain following the induction of peripheral nerve injury is further substantiated by the finding that these neuropathy-induced behavioral effects are dexamethasone reversible (Clatworthy et al., 1995).

Gonadal steroids can modulate immunological function by establishing crosstalk between the endocrine and immune systems in a sexually dimorphic manner DaSilva et al., 1993, Gaillard and Spinedi, 1998, Spinedi et al., 1994. For instance, female rodents have higher levels of serum immunoglobulin and prolonged antibody responses compared to males DaSilva et al., 1993, Gaillard and Spinedi, 1998 and these inflammatory and immune reactions can be modulated by gonadal hormones (Green et al., 1999). The goal of the present study was to investigate gender-related differences in the behavioral manifestations of chronic neuropathic pain and to determine how gonadal sex hormones affect these differences. The results suggest that chronic nociceptive processing differs as a function of gender and gonadal hormones.

Section snippets

Methods

All experiments were fully approved for the humane use of animals by the Institutional Animal Care and Use Committee at Northeastern Ohio Universities College of Medicine. Age-matched male and female Fischer 344 FBNF1 hybrid rats (Harlan Sprague–Dawley, Indianapolis, IN) were used in all experiments. Rats of both genders were purchased between the ages of 56 and 60 days, and all components of the investigation were conducted while the animals were between the ages of 3 and 6 months. Rats were

Results

Preliminary studies in this laboratory demonstrated a lack of significant effect between PWL and PWT values from the right (control) hind paw of unligated (n=48 rats) vs. sham-ligated (n=51 rats) control animals. Because of the lack of significant difference between these values, CCI sham surgeries were not conducted in control animals in the present study. Gonadectomy sham surgeries were performed in a separate cohort of male and female rats, and it was found that neither the PWL nor PWT

Discussion

We investigated the extent to which neuropathic pain-induced thermal hyperalgesia and tactile-evoked allodynia differ as a function of gender and hormonal status. In the absence of nerve injury, hyperalgesic and allodynic responses were not elicited by gonadally intact male or female rats. However, unligated males responded significantly faster to the thermal stimulus than the unligated females did, implying inherent gender differences in thermal nociceptive processing. These data support

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Gender and the behavioral manifestations of neuropathic pain

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Neurosci Lett

Pain

Brain Res Bull

Neurosci Lett

Neurosci Lett

J Clin Epidemiol

Pharmacol Biochem Behav

Domest Anim Endocrinol

Brain Res

Brain Res

Trends Neurosci

Neurosci Lett

Physiol Behav

Pain